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Zhou, Wang, Ji, and Cottrill. "Coordinated Control Strategy for Multi-Line Bus Bunching in Common Corridors." Sustainability 11, no. 22 (November 6, 2019): 6221. http://dx.doi.org/10.3390/su11226221.
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Improving the sharing rate of public transportation is an important content for the sustainable development of urban transportation. However, bus bunching, a common phenomenon during transit operation, makes negative effects on reliability and service level of the bus system. In most urban centers in China, many bus lines usually serve in a corridor. Different buses may interact with each other in the corridor, which may aggravate the bus bunching. However, previous studies on bus bunching focused on single bus service. In addition, with the popularization of bus data acquisition and the maturity of data processing methods, the accuracy of bus bunching research meets more opportunities. In this paper, we proposed a holding strategy based on two-bus cooperative control. A simulation was carried out after preliminarily processing and analyzing the bus operation data of Foshan, Guangdong City. In the simulation, we compared the performance of three different scenarios, which are before control strategy, under the strategy for a single bus line and under the coordinated strategy for multiple bus lines. We contrastively analyze the results of the two strategies from different aspects. The results show that in aspects, such as holding a frequency, holding time, the total running time and the influence on the other bus line, the cooperative holding strategy manifests better. It illustrates that it is meaningful to do such a research on the effect of corridor service on bus bunching and add this effect into traditional holding strategy to build a multi-bus cooperative control strategy. The results have important theoretical significance for enriching and completing existing theory and methods of transit system and practical value for improving the service level and attractiveness of buses, increasing the share rate of public transportation, and thus, promoting the sustainable development of cities.
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Orihuela, Luis, Pablo Millán, and Álvaro Rodríguez del Nozal. "A Non-Cooperative Game-Theoretic Approach for Distributed Voltage Regulation in DC Grids with a High Penetration of Renewable Energies." Electronics 10, no. 7 (March 24, 2021): 768. http://dx.doi.org/10.3390/electronics10070768.
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This manuscript deals with the situation in which the different agents or buses in a power network have access to local renewable resources and must manage its use in a distributed fashion. The buses distributedly decide the amount of power to be generated using their local renewable power plants, and that to be demanded from the grid. The decisions are made according to the optimization of a cost function that considers both economic and technical factors. The problem is approached resorting to a game-theoretical framework that requires a negotiation process among the neighboring buses. An iterative algorithm is proposed in order to solve this problem, providing existence and convergence conditions under which the buses reach a suitable equilibrium. The algorithm performance is tested in simulations over a modification of the IEEE 14-bus system, in which the lines are modeled as resistances and distributed generation is considered. Simulations on a network of 44 buses are also included to show the scalability of the method.
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ROSENBERG, ARNOLD L., VITTORIO SCARANO, and RAMESH K. SITARAMAN. "THE RECONFIGURABLE RING OF PROCESSORS: EFFICIENT ALGORITHMS VIA HYPERCUBE SIMULATION." Parallel Processing Letters 05, no. 01 (March 1995): 37–48. http://dx.doi.org/10.1142/s0129626495000059.
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We propose a design for, and investigate the computational power of a dynamically reconfigurable parallel computer that we call the Reconfigurable Ring of Processors ([Formula: see text], for short). The [Formula: see text] is a ring of identical processing elements (PEs) that are interconnected via a flexible multi-line reconfigurable bus, each of whose lines has one-packet width and can be configured, independently of the other lines, to establish an arbitrary PE-to-PE connection. A novel aspect of our design is a communication protocol we call COMET — for Cooperative MEssage Transmission — which allows PEs of an [Formula: see text] to exchange one-packet messages with latency that is logarithmic in the number of PEs the message passes over in transit. The main contribution of this paper is an algorithm that allows an N-PE, N-line [Formula: see text] to simulate an N-PE hypercube executing a normal algorithm, with slowdown less than 4 log log N, provided that the local state of a hypercube PE can be encoded and transmitted using a single packet. This simulation provides a rich class of efficient algorithms for the [Formula: see text], including algorithms for matrix multiplication, sorting, and the Fast Fourer Transform (often using fewer than N buslines). The resulting algorithms for the [Formula: see text] are often within a small constant factor of optimal.
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Wei, Junjun, Kejun Long, Jian Gu, Qingling Ju, and Piao Zhu. "Optimizing Bus Line Based on Metro-Bus Integration." Sustainability 12, no. 4 (February 17, 2020): 1493. http://dx.doi.org/10.3390/su12041493.
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Metros are usually built and added on the basis of a completed bus network in Chinese cities. After the metro construction, it is faced with the problem of how to adjust and optimize the original bus lines based on the new metro system. This research mainly proposes a bus line optimization method based on bus and metro integration. In the consideration of the geographical space, the cooperation and competition relationship between bus and metro lines is qualitatively introduced according to the geographical location and service range of metro (800 m radius) and bus (500 m radius) stations. The competition and cooperation indexes are applied to define the co-opetition relationship between bus and metro lines. The bus line optimization model is constructed based on the co-opetition coefficient and Changsha Metro Line Number 2 is chosen as a case study to verify the optimization model. The results show that the positive competition, efficient cooperation, and travel efficiency between metro and bus has been significantly enhanced after optimization. Moreover, this paper provides a reasonable reference for public transport network planning and resource allocation.
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Feng, Shumin, Xianglong Sun, and Dixin Wang. "The analysis and application of competition and cooperation between the bus lines." KSCE Journal of Civil Engineering 20, no. 4 (August 31, 2015): 1540–45. http://dx.doi.org/10.1007/s12205-015-0030-z.
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Haura, E. B., L. Song, F. Lee, and R. Jove. "Effect of dasatinib, a SRC kinase inhibitor, on lung cancer cells with defined epidermal growth factor receptor status." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3019. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3019.
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3019 Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict sensitivity to small molecule inhibitors of EGFR such as gefitinib and erlotinib. Importantly, mutant EGFR selectively activates Akt and STAT pathways that are important in NSCLC cell survival. SRC-family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules such as PI3K/PTEN/Akt and STATs. Despite the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and SRC proteins, and evidence of elevated SRC activity in human lung cancers, the effect of SRC inhibition on cell fate is unknown. Methods: We evaluated the anti-tumor efficacy of a novel orally bioavailable SRC-ABL inhibitor dasatinib (BMS-354825) in non-small cell lung cancer cell lines with defined EGFR status including wildtype EGFR and mutant EGFR sensitive to gefitinib. Western blotting was used to evaluate the effect of dasatinib on downstream signaling pathways and in vitro assays were used to evaluate the effect cell cycle, apoptosis, and cell invasion. Results: Our results show that cell fate (death versus growth arrest) in lung cancer cells exposed to a SRC inhibitor is dependent on EGFR status. Dasatinib reduces mutant EGFR lung cancer cell viability through the induction of apoptosis and G1 cell cycle arrest while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of phosphorylated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, dasatinib induces a G1 cell cycle arrest with associated changes in cyclin D and p27 proteins as well as inhibits activated FAK and prevents tumor cell invasion. Conclusions: Our results demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers through disruption of cell growth, survival and tumor invasion. Our results suggest EGFR status is critical in deciding cell fate in response to SRC inhibition. [Table: see text]
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Balestre, Marcio, Vanderley Borges dos Santos, Antonio Alves Soares, and Moisés Souza Reis. "Stability and adaptability of upland rice genotypes." Crop Breeding and Applied Biotechnology 10, no. 4 (December 2010): 357–63. http://dx.doi.org/10.1590/s1984-70332010000400011.
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The aim of this study was to identify upland rice genotypes with high stability and adaptability by the GGE biplot method based on the predicted genotypic and phenotypic values. Of the 20 genotypes evaluated, 14 were lines developed by the cooperative program for rice improvement of Minas Gerais and six were controls. The GGE biplot analysis showed that cultivar BRS Pepita and MG1097 were closest to the ideal genotype. In the comparison of the fixed with the random models (% G + GE, prediction error sum of squares and correlation), it was observed that the use of phenotypic means in all comparative parameters indicated a lower predictive potential under simulated imbalance than the use of predicted genotypic values. The conclusion was drawn that BRS Pepita and MG1097 are ideal genotypes for southern Minas Gerais and that the predictive power of the phenotypic means underlying the study of stability and adaptability is lower than of genotypic means.
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Palmer, Xavier, Lucas N. Potter, and Saltuk Karahan. "COVID-19 and Biocybersecurity's Increasing Role on Defending Forward." International Journal of Cyber Warfare and Terrorism 11, no. 3 (July 2021): 15–29. http://dx.doi.org/10.4018/ijcwt.2021070102.
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The evolving nature of warfare has been changing with cybersecurity and the use of advanced biotechnology in each aspect of the society is expanding and overlapping with the cyberworld. This intersection, which has been described as “biocybersecurity” (BCS), can become a major front of the 21st-century conflicts. There are three lines of BCS which make it a critical component of overall cybersecurity: (1) cyber operations within the area of BCS have life threatening consequences to a greater extent than other cyber operations, (2) the breach in health-related personal data is a significant tool for fatal attacks, and (3) health-related misinformation campaigns as a component of BCS can cause significant damage compared to other misinformation campaigns. Based on the observation that rather than initiating the necessary cooperation COVID-19 helped exacerbate the existing conflicts, the authors suggest that BCS needs to be considered as an essential component of the cyber doctrine, within the Defending Forward framework. The findings are expected to help future cyber policy developments.
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Yu, Bin, Guan-nan Jin, Mei Ma, Hui-fang Liang, Bi-xiang Zhang, Xiao-ping Chen, and Ze-yang Ding. "Taurocholate Induces Connective Tissue Growth Factor Expression in Hepatocytes Through ERK-YAP Signaling." Cellular Physiology and Biochemistry 50, no. 5 (2018): 1711–25. http://dx.doi.org/10.1159/000494790.
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Background/Aims: Cholestasis is characterized by intrahepatic accumulation of cytotoxic bile acids (BAs), ultimately leading to fibrosis and cirrhosis, but the precise role of BAs in cholestasis-induced liver fibrosis remains largely elusive. In this study, we investigated the role and the potential mechanisms of BAs during cholestasis in vivo and in vitro. Methods: The effect of BAs during cholestasis was studied in bile duct ligation (BDL) rat models in vivo. We performed immunohistochemistry, Western blotting, and quantitative RT-PCR to investigate the expression of connective tissue growth factor (CTGF/CCN2) in rat liver during cholestasis. The hepatic cell lines AML12 and BRL were stimulated with taurocholate (TC) and the level of CTGF/CCN2, and activation of ERK, Akt, p38 MAPK, JNK, YAP, and TGF-β/Smad signaling were examined using Western blotting. Next, to elucidate the mechanism underlying bile acid-induced CTGF/CCN2, we treated the cells with MEK1/2 inhibitor (U0126), YAP function inhibitor (verteporfin), p38 kinase inhibitor (SB203580), Akt inhibitor (MK2206), and small interfering RNA (siRNA) targeting mek1, erk, and yap in cooperation with TC. Besides, we confirmed the activation of these signaling pathways in BDL and sham rat livers by immunohistochemistry, Western blotting, and quantitative RT-PCR. Results: In this study, we confirmed that the expression of CTGF/CCN2 was increased in BDL-induced rodent cholestatic liver fibrosis. In addition, we showed that TC, the main component of BAs, enhanced the synthesis of CTGF/ CCN2 in AML12 and BRL hepatic cell lines. Moreover, we demonstrated that TC activated ERK, Akt, and YAP signaling in hepatocytes, but the precise roles of these signaling cascades in the expression of CTGF/CCN2 were different: TC-induced expression of CTGF/CCN2 was mediated by ERK-YAP signaling, whereas Akt signaling inhibited ERK signaling and YAP and subsequently the expression of CTGF/CCN2 in hepatocytes. Furthermore, YAP functioned as a downstream regulator of ERK signaling in TC-induced CTGF/CCN2 expression in hepatocytes. Conclusion: Our report provides evidence for the role of conjugated BAs in liver fibrosis and suggests that the production of CTGF/CCN2, induced by conjugated BAs via ERK-YAP axis activation, may be a therapeutic target in cholestasis-induced liver fibrosis.
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Thilmany, Jean. "Speaking Different Languages." Mechanical Engineering 123, no. 02 (February 1, 2001): 53–55. http://dx.doi.org/10.1115/1.2001-feb-3.
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This article illustrates the importance of interoperability between computer-aided design (CAD), computer-aided manufacturing (CAM), and computer-aided engineering (CAE) software. Interoperability is an intricate concept, rife with accusation and blame-laying, and dependent on the unseen algorithms and mathematical equations that drive the lines and geometries CAD users see on screen. At the Daratech 2000 summit, a panel of technology users and technology vendors worked together to draft what was called a symposium communique that challenged suppliers to cooperate more with one another to move toward interoperability. The communique calls the interoperability issue one of the most troublesome aspects of CAD, CAM, and CAE usage. PTC in Waltham, MA, has released Associate Topology Bus, a tool that thy company says helps engineers share data between systems by allowing them to exchange geometry as well as what the company calls design-intent, between systems. Autodesk of San Rafael, California, offers interoperable features as what it calls DWG linking between its AutoCAD software and its 3D Studio Viz, a system used by architects. Its Mechanical Desktop software can read printed circuit board data in intermediate data format (IDF) and convert it to AutoCAD objects suitable for further mechanical design and manufacturing applications.
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Latif, Anne-Louise, John J. Cole, Joana Monteiro Campos, William Clark, Lynn McGarry, Claire Brock, Ashley Newcombe, Karen Keeshan, Mhairi Copland, and Peter D. Adams. "Dual Inhibition of MDM2 and BET Cooperate to Eradicate Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 674. http://dx.doi.org/10.1182/blood.v126.23.674.674.
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Abstract Background: There remains a critical requirement for novel therapies for Acute Myeloid Leukemia (AML). Bromodomain and extra-terminal domain (BET) inhibitors are emerging as exciting therapeutic agents for hematopoietic malignancies. Pharmacological inhibition of BET bromodomains targets malignant cells by preventing reading of acetylated lysine residues, thus disrupting chromatin-mediated signal transduction, which reduces transcription at oncogenic loci. Although a heterogeneous disease, most AML retains wild type p53. However, p53 is often rendered functionally deficient by over-expression of MDM2. Potentiating the p53 response though MDM2 antagonism is therefore potentially beneficial to most AML subtypes. We hypothesized that dual inhibition of MDM2 and BET would be synthetic lethal to p53 wild type AML. Methods: For in vitro experiments CPI203 (BET inhibitor, Constellation Pharmaceuticals) and nutlin-3 (MDM2 antagonist, Sigma) were assessed on p53 wild type cell lines (OCI-AML3, MOLM-13 and MV411) and p53 wild type primary murine AML. To assess the combination's dependency on wild type p53; p53 mutated cell lines (KG1a, KASUMI-1 and THP1) were tested. Cell viability was assessed using resazurin (Alamar blue dye) across numerous dose ratios on the OCI-AML3 cell line and analysed using the Envision Fluorescent Reader. Drug combination indices (CI) were evaluated using Calcusyn (version 2.0). Apoptosis was assessed using flow cytometry staining for Annexin V and propidium iodide (PI) on all p53 wild type and mutated cell lines. For in vivo experiments CPI0610 (clinical grade BET inhibitor, Constellation Pharmaceuticals) and RG7112 (MDM2 inhibitor, Roche) were tested as single agents, in combination and with relevant vehicle controls. RNA seq was performed on the GAIIX sequencer and gene ontology analysis was performed using DAVID/INGENUITY pathway analysis (IPA). Results: In the OCI-AML3 cell line, resazurin analysis demonstrated that combining CPI203 with nutlin-3 was potently synergistic in decreasing viable cells for a 1:12.5 (mean CI=0.07) and 1:25 ratio (mean CI=0.299), and synergistic for a 1:50(mean CI=0.44) and 1:100(mean CI= 0.66) ratios. There was no benefit in using the combination treatment on the p53 mutated cell lines. Apoptosis was enhanced at least 1.5 fold (median 1.7, range 1.5-2.65) by the drug combination versus the single agents, in the panel of p53 wild type cell lines tested. Analysis of whole genome RNA seq on OCI-AML3 treated cells, showed that genes up-regulated by the combination of CPI203 and nutlin-3, had a thirty-fold enrichment for p53 signalling (FDR (<0.05). Down-regulated genes were enriched for FOXM1-dependent cell cycle progression genes. To evaluate the combination in vivo, we used a Trib-2 driven primary AML where leukemogenesis is induced through inhibition of C/EBPα. Myeloblasts were transduced with GFP on the same retroviral construct asTrib-2 for disease tracking. Treatment was commenced in all mice (n=40), post confirmation of disease engraftment. Three mice from each treatment group were sacrificed after 48hrs and cells sorted for GFP to perform RNA seq in this in vivo setting. After 21 days of treatment all mice were sacrificed (n=27, one vehicle control succumbed to disease 15 days post engraftment). End of treatment results (primary read out was the GFP% which equates to the blast%) demonstrated superior in vivo efficacy of dual inhibition of MDM2 and BET in comparison with controls in eradicating AML, p<0.0001, (see figure). Importantly, normal haematopoiesis was spared - as evidenced by normal full blood counts and comparable myeloid, B-cell and T-cell populations with our C57bl6 wild type controls. RNA seq of the murine blasts revealed that many more genes significantly (FDR<0.05) changed expression in the combination treated mice than single agent treated mice. The p53 pathway was the most common up-stream regulator of genes changing expression post combination treatment, p<0.0001. The combination affected many more genes in the p53 pathway than RG7112 alone (120 genes versus 20 genes respectively), in line with our in vitro results. Conclusion: This combination of BET and MDM2 inhibition is effective and superior to single agent therapy on all p53 wild type AMLs tested, in vitro and in vivo. In both contexts this is associated with potentiating the p53 response and could be relevant to many patients with p53 wild type AML. Figure 1. Figure 1. Disclosures Latif: Novartis: Honoraria. Copland:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Liu, G., W. Wang, R. Dipaola, M. Carducci, and G. Wilding. "A phase II study of a weekly schedule of BMS-247550 for patients with hormone-refractory prostate cancer: A trial of the Eastern Cooperative Oncology Group (E3803)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 4618. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4618.
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4618 Background: BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistent cancer cell lines. Ixabepilone has been administered using a q3wks schedule with significant neutropenia observed. Here we assess the activity and toxicity of ixabepilone, administered using a weekly schedule, in men with metastatic hormone-refractory prostate cancer. Methods: Patients with metastatic hormone-refractory prostate cancer (chemonaive and prior taxane) were treated with ixabepilone at 20 mg/m2 IV weekly × 3, in 4 wk cycles. This non-comparative study had a planned accrual of 29 chemonaive and 27 prior-taxane treated patients in order to detect a 50% PSA reduction using Consensus Criteria in at least 50% (91% power, α = 0.10) chemonaive and 30% (power 90%, α = 0.10) prior-taxane treated patients. Results: 32 pts with chemonaive and 37 pts with prior-taxane have been enrolled on this study. Median follow-up is 1.8 and 4.1 months respectively. Safety data is reported for the first 56 subjects (24 chemonaive and 32 prior taxane). Hematologic toxicity: Grade 3/4 neutropenia was seen in 10 pts (5 chemonaive, 5 prior-taxane). No significant thrombocytopenia was observed. Grade 3/4 neuropathy was seen in 7 pts (2 chemonaive, 5 prior-taxane). Grade 3 fatigue noted in 8 (3 chemonaive, 5 prior-taxane), grade 3 diarrhea in 5 (4 chemonaive, 1 prior-taxane), and grade 3 nausea in 3 subjects. Lastly, 2 subjects were reported to have developed a grade 3 ileus during therapy. Conclusions: In 56 subjects, BMS-247550 was found to have an acceptable toxicity profile when administered using a weekly schedule. Myelosuppression appeared to be improved, as compared to historical data with the q3wk schedule, using this dose and schedule. PSA/objective responses have been seen but at this time, no conclusion regarding its activity in the first or second-line setting can be made, as the response assessment is ongoing. Complete toxicity and response data will be presented for the entire group. No significant financial relationships to disclose.
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Dilts, D. M., A. B. Sandler, M. Baker, S. Cheng, S. McGuire, G. Menon, A. Wu, K. Karas, D. Sawyer, and R. L. Schilsky. "A timing and process flow analysis of opening clinical trials within an oncology cooperative group setting: The case of the CALGB." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 6015. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.6015.
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6015 Background: Cooperative oncology groups are major sponsors of Phase III clinical trials, yet the number of steps and times required to setup and open such a trial have yet to be studied. This study assesses these items in the Cancer and Leukemia Group B (CALGB) for all Phase III studies opened in a 3 year period. Methods: Step 1: headquarters and statistical center staff were interviewed to discover the detailed steps required for a study to transit from initial concept submission by a potential study chair to final activation of the study. The formal procedures manuals were also reviewed. All study records and draft protocol documents were inspected to verify and identify additional setup steps. Finally, data was collected through direct contact with study chairs and disease committee chairs. Step 2: timing data for each of the major functions or processes were collected. All times are from initial initiation of the function to the final completion of the task. Times represent calendar time. Step 3: creation of stream-lined process flows, currently underway. Members from the CALGB and the Vanderbilt Center for Management Research in Healthcare (cmrhc.org) will spend 2 days creating a process to significantly reduce the time and the number of steps to opening a trial. Results: A total of 13 Phase III studies were activated during the 3 years study period. 372 processes are required to open a Phase III at CALGB, which include 314 work steps, 43 major decision points. Interesting, most of the decision points (63%) are external to CALGB. There are 23 processing loops that require repeating processes. The process map, which lists all processes, is a chart 243.5” × 41 in 8 pt font (or about the length of a 20 passenger bus). Median calendar days to activate a Phase III study at CALGB is 767 days (min = 488, max = 1,441). The three functions requiring the greatest median days are protocol development (477), forms development (434), and regulatory affairs (350). Conclusion: It can require years to open a Phase III study at a major cooperative oncology group. Using process redesign techniques, we expect to be able to significantly streamline the process. Support provided by the NCI. No significant financial relationships to disclose.
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Wang, Shufen, Siqi Lv, Tong Zhao, Meng Jiang, Dehai Liu, Shangtan Fu, Miaomiao Hu, Shuhua Huang, Yu Pei, and Xiaofeng Wang. "Modification of Threonine-825 of SlBRI1 Enlarges Cell Size to Enhance Fruit Yield by Regulating the Cooperation of BR-GA Signaling in Tomato." International Journal of Molecular Sciences 22, no. 14 (July 18, 2021): 7673. http://dx.doi.org/10.3390/ijms22147673.
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Brassinosteroids (BRs) are growth-promoting phytohormones that can efficiently function by exogenous application at micromolar concentrations or by endogenous fine-tuning of BR-related gene expression, thus, precisely controlling BR signal strength is a key factor in exploring the agricultural potential of BRs. BRASSINOSTEROID INSENSITIVE1 (BRI1), a BR receptor, is the rate-limiting enzyme in BR signal transduction, and the phosphorylation of each phosphorylation site of SlBRI1 has a distinct effect on BR signal strength and botanic characteristics. We recently demonstrated that modifying the phosphorylation sites of tomato SlBRI1 could improve the agronomic traits of tomato to different extents; however, the associated agronomic potential of SlBRI1 phosphorylation sites in tomato has not been fully exploited. In this research, the biological functions of the phosphorylation site threonine-825 (Thr-825) of SlBRI1 in tomato were investigated. Phenotypic analysis showed that, compared with a tomato line harboring SlBRI1, transgenic tomato lines expressing SlBRI1 with a nonphosphorylated Thr-825 (T825A) exhibited a larger plant size due to a larger cell size and higher yield, including a greater plant height, thicker stems, longer internodal lengths, greater plant expansion, a heavier fruit weight, and larger fruits. Molecular analyses further indicated that the autophosphorylation level of SlBRI1, BR signaling, and gibberellic acid (GA) signaling were elevated when SlBRI1 was dephosphorylated at Thr-825. Taken together, the results demonstrated that dephosphorylation of Thr-825 can enhance the functions of SlBRI1 in BR signaling, which subsequently activates and cooperates with GA signaling to stimulate cell elongation and then leads to larger plants and higher yields per plant. These results also highlight the agricultural potential of SlBRI1 phosphorylation sites for breeding high-yielding tomato varieties through precise control of BR signaling.
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Mondello, Patrizia, Chiara Tarantelli, Luciano Cascione, Alberto Arribas, Andrea Rinaldi, Anas Younes, and Francesco Bertoni. "Inhibition of PIM Kinases Targets Synthetic Vulnerabilities and Enhances Antigen Presentation in B-Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2858. http://dx.doi.org/10.1182/blood-2019-125123.
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The PIM kinases are highly expressed in activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). Oncogenic cooperation between PIMs and MYC has been demonstrated. Transgenic mice co-expressing Em-PIM and Em-MYC showed accelerated lymphomagenesis. Conversely, knockdown of PIMs dramatically decreased cMYC levels and lowered tumor incidence. Based on these preclinical data, a treatment strategy aiming at disrupting the oncogenic cooperation between PIMs and MYC may improve the outcome of DLBCL. Therefore, we treated a panel of DLBCL cell lines with increasing dose of the clinically relevant pan-PIM inhibitor (PIMi) AZD1208 (from 0.1 to 10μM) for 48 hours (Hrs), which resulted in a dose-dependent growth inhibition with a stronger efficacy in ABC DLBCL cell lines. (Figure 1A)The analysis of a CRISPR loss-of-function screening in three ABC (LY3, TMD8, HBL1) and three GCB (SUDHL-4, Pfeiffer, BJAB) DLBCL cell lines (Reddy et al, 2017) showed that PIM2 silencing led to significantly decreased viability irrespective of cell-of-origin (Figure 1B), suggesting that this oncogene is essential for cell proliferation in DLBCLs. To identify the genes through which PIMs drive the lymphoma phenotype we performed gene expression profiling using 4 ABC DLBCL cell lines (RIVA, TMD8, SUDHL-2, U2932) treated with either DMSO or AZD1208 at 1μM for 4, 8 and 12 Hrs. We observed induction of 3,439 genes whereas 2,473 genes were downregulated. (Figure 1C) Gene pathway analysis showed that AZD1208 led to downregulation of genes regulated by MYC, including its known downstream p53 and NFKB target genes. On the other hand, AZD1208 treatment broadly induced MHC class II and antigen presentation genes as well as PI3K/AKT, cell cycle and glutaminase genes. (Figure 1D) Using a high-throughput screening approach, we found that the inhibitors of cell cycle (such as the BCL2 inhibitor venetoclax/ABT199 and the PLK4 inhibitor CFI-400945) and of glutaminase (CB839) enhanced the antiproliferative effect of AZD1208, whereas combinations with the PI3K/AKT/mTOR inhibitors had negligible synergistic effect. (Figure 1E) In conclusion, our study revealed previously unknown mechanisms of action of PIM inhibitors and provides a framework for future combination strategies. Disclosures Younes: Xynomics: Consultancy; Biopath: Consultancy; Genentech: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; BMS: Research Funding; HCM: Consultancy; Celgene: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Takeda: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Pharmacyclics: Research Funding. Bertoni:Nordic Nanovector ASA: Research Funding; Acerta: Research Funding; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding; NEOMED Therapeutics 1: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants; Jazz Pharmaceuticals: Other: travel grants.
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García-Feijoo, María, Almudena Eizaguirre, and Alvaro Rica-Aspiunza. "Systematic Review of Sustainable-Development-Goal Deployment in Business Schools." Sustainability 12, no. 1 (January 6, 2020): 440. http://dx.doi.org/10.3390/su12010440.
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In 2015, more than 190 countries pledged to meet by 17 sustainable development goals (SDGs) by 2030 that aim to ensure sustainable global social and economic development, and to strengthen universal peace. Public institutions, businesses, organizations and individuals are all called upon to contribute to this challenge. Focusing on business schools (BSs), and the potential impact they have on graduates, we ask what they are doing for the deployment of these objectives. To this end, we conducted a systematic review of the literature related to SDGs and business schools in the WOS, SCOPUS and ERIC databases. A multi-stage exclusion process resulted in 16 documents for review. The findings of this study provide key information on the role that business schools have to play in achieving SDGs and the ways in which they can be incorporated into their activity: from more in-depth actions linked to creating awareness, questioning current paradigms, fostering cooperation and interdisciplinarity with stakeholders, and working on coherence; to more specific interventions such as creating student associations, incorporating new teaching methodologies or increasing students’ participation in extracurricular activities. In addition, this study also allows us to identify gaps in the literature, giving ideas on necessary future lines of research.
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Więckowski, Marek. "Symboliczne łączenie transgranicznych miast nadmorskich. Przykład Świnoujście – Heringsdorf." Studia Polityczne 48, no. 2 (September 25, 2020): 241–59. http://dx.doi.org/10.35757/stp.2020.48.2.09.
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The aim of the article is to show the elements of cooperation that foster the connection of border cities, with particular emphasis on infrastructure, means of transport and tourism, using the example of coastal cities. An example of such a place is the island of Uznam and the coastal cities of Heringsdorf (Germany) and Świnoujście (Poland) separated by the state border. With the opening of the internal borders of the European Union, it became possible to organise the undeveloped spaces between the settlement units in the cross-border areas. This is aimed at both: managing the initial border and the related elements (which can lead to their visual disappearance – destruction, deliberate dismantling and so on – and to maintaining the visibility of these elements) and at symbolically connecting the space by blurring or symbolically highlighting the elements of the border or integration (such as lines, inscriptions, monuments).In the case of Świnoujście and Heringsdorf, the most important elements of the symbolic connection of the neighbouring countries were the creation of border crossings, the launch of ship cruises and bus connections. Moreover, the border has become a symbol of barriers and also of integration, that is, a connecting element. In 2011, the Cross-border Promenade Świnoujście-Heringsdorf was commissioned. It is one of the most interesting architectural projects showing the integration of the states. The promenade itself, as well as special monuments, plaques and border markings have a high symbolic value and therefore function as tourist attractions. At the same time, they contribute to the protection of heritage. The border is an element of modernisation and an impulse for economic growth. Thanks to the European Union’s policy, it is also a specific place for access to financial resources.
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Pylypenko, L., and K. Kalatur. "Breeding and usage of sugar beet cultivars and hybrids resistant to sugar beet nematode Heterodera schachtii." Agricultural Science and Practice 2, no. 1 (April 15, 2015): 12–22. http://dx.doi.org/10.15407/agrisp2.01.012.
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Heterodera schachtii Schmidt, 1871 is one of the most economically important pests of sugar beet (Beta vulgaris L.) worldwide. It is also widespread in most sugar beet growing regions in Ukraine causing serious yield reduction and decreasing sugar content of sugar beet in infested fi elds. An advanced parasitic strategy of H. schachtii is employed to support nematode growth, reproduction and harmfulness. In intensive agriculture systems the nematode control measures heavily rely on nematicides and good agricultural practice (crop rota- tion in the fi rst place). But alternative strategies based on nematode resistant sugar beet cultivars and hybrids are required as none of nematicides approved for the open fi eld application are registered in Ukraine. Here we review the achievements and problems of breeding process for H. schachtii resistance and provide the results of national traditional breeding program. Since the beginning of 1980s fi ve sugar beet cultivars (Verchnyatskyi 103, Yaltuschkivska 30, Bilotcerkivska 45, BTs-40 and Yuvileynyi) and seventeen lines partly resistant or toler- ant to H. schachtii have been obtained throughout targeted crossing and progenies assessment in the infested fi elds. The further directions for better utilization of genetic sources for nematode resistance presented in na- tional gene bank collection are emphasized. There is a need for more accurate identifi cation of resistance genes, broader application of reliable molecular markers (suitable for marker-assisted selection of nematode resistant plants in the breeding process) and methods for genetic transformation of plants. Crop cash value and national production capacity should drive the cooperation in this fi eld. Knowledge as well as germplasm exchange are thereby welcomed that can benefi t breeding progress at national and international level.
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Ravandi, Farhad, Arnaud Pigneux, Daniel J. DeAngelo, Hervé Dombret, Jacques Delaunay, Xavier Thomas, Tapan Kadia, et al. "Preliminary Clinical, Pharmacokinetic (PK) and Pharmacodynamic (PD) Results of the Safety Run-In Part of a Phase II Trial of Orally Available MEK-Inhibitor MSC1936369 in Patients (Pts) with Advanced Hematological Malignancies (HM)." Blood 118, no. 21 (November 18, 2011): 1554. http://dx.doi.org/10.1182/blood.v118.21.1554.1554.
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Abstract Abstract 1554 Background: MSC1936369 is a selective non-competitive inhibitor of MEK1/2 with anti-proliferative activity in leukemia cell lines and in human tumor xenograft models with activation of mitogen-activated protein kinase (MAPK) signaling. We present the preliminary data of the safety run-in part of the phase II trial, in which the primary objective is to determine the maximum tolerated dose (MTD) for different dosing schedules (S). Methods: MSC1936369 was administered orally twice per day (BID), either on days 1–5, 8–12, 15–19 and 22–26 (S1) or on days 1–21 (S2) of a 28-day cycle. Dose escalation within each S followed a modified Fibonacci scheme with 3+3 cohorts. PK samples and peripheral blood leukemia blasts for the measurement of phosphorylated extracellular signal-regulated kinase (pERK) were collected for all pts. Results: 48 pts have been treated, 25 in S1 (8–42 mg BID) and 23 in S2 (8–60 mg BID). Pt characteristics, treatment exposure, and safety signals were similar in both Ss. The median age was 67 years (range 22–80), 66% were male and the Eastern Cooperative Oncology Group Performance Status was 0/1/2 in 25%/58%/17% of pts, respectively. Underlying HMs were: acute myeloid leukemia (AML, n=41), myelodysplastic syndrome (MDS, n=3) and other (n=4). Cytogenetics were known for 42/44 pts with MDS (n=3) and AML (n=39): 3 were favorable, 21 intermediate and 18 unfavorable. RAS mutation was present in 5 pts (not reported in others), of whom 2 also carried a FLT3 mutation. Six additional pts had a FLT3 mutation. The median duration of treatment was 3.7 weeks (range 0.1–77). The MTD has not been reached in either S. One dose-limiting toxicity (DLT) of grade 2 angioedema was seen in S1 at 42 mg BID. The most common non-hematological adverse events (AEs): infections (56%), diarrhea (46%), skin rash (38%), nausea (27%), pyrexia (25%), peripheral edema (21%), dizziness (21%), aspartate aminotransferase increase (21%) and transient visual disorders (with underlying serous retinal detachment in most cases) (21%). Plasma concentrations increased proportionally with dose. Sustained pERK inhibition during the dosing period was observed in blasts and lymphocytes starting at 23 mg BID. Transient clearance or 50% decrease of blasts in bone marrow and peripheral blood have been detected in 6 pts (MDS n=2, AML n=4), 2 RAS mutated. Conclusions: MSC1936369 in intermittent Ss is well tolerated with reversible mild or moderate AEs, PD effect during dosing and signals of activity have been seen. Dose escalation continues in intermittent Ss. Continuous dosing is being introduced. Molecular genotyping is ongoing. Disclosures: Ravandi: EMD Serono Inc: Research Funding. Luepfert:Merck KGaA: Employment. Asatiani:Merck Serono SA: Employment. Donica:Merck Serono SA: Employment. Kantarjian:Novartis, Pfizer, BMS: Consultancy, Research Funding. Smith:infinity, genzyme, synta, celator, BMS, novartis: Research Funding; celgene, BMS, novartis: Membership on an entity's Board of Directors or advisory committees.
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Helmiatin, Helmiatin, and Etty Susanty. "The SWOT Analysis for Chrysanthemum Farmers Business Development Strategies for Fresh Chrysanthemum Farmers." GATR Journal of Business and Economics Review 4, no. 3 (September 30, 2019): 139–48. http://dx.doi.org/10.35609/jber.2019.4.3(3).
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Objective – This paper examines the business strategy at cut flower area. The need for cut flowers, especially chrysanthemums, is very large. The farmers of cut flowers are concentrated in Java, namely Malang, Bandungan, Yogyakarta and Cianjur in West Java. Methodology/Technique – In this study the object is in Bandungan, Semarang area. With large market conditions, it is possible for cut flower farmers to plant various varieties of chrysanthemum that the market likes. In order to fulfil the market prospect that is still wide open, chrysanthemum cut flower farmers must have business strategies that are able to provide guidance on the business being run. Production activities will develop and have an impact on farmers if supported by organizational policies that not only manage internal activities but are also able to face challenges from a dynamic external environment. Findings & Novelty – The SWOT analysis were used at this research. The strategies that should be created are increasing cooperation, maintaining networks, and expanding marketing. The need for cut flowers especially chrysanthemums flowers in Indonesia is very large. This study aims to identify and examine the internal and external factors of the development of chrysanthemum agribusiness in Bandungan Village and to determine the priority of appropriate agribusiness strategies based on the farmer’s needs. This study is descriptive analysis research with a sample of 45 Chrysanthemum farmers. Using SWOT analysis, we found the strength, weakness, opportunity, and threat for the farmers and we could design alternative business strategies. Internal Strategic Factor Analysis Summary (IFAS) is used to identify and evaluate the key internal factors of the company, while External Strategic Factor Analysis (EFAS) is used to organize external strategic factors into generally accepted categories of opportunities and threats. Meanwhile, IE matrix is used to define the business strategy at the company level with greater details. The results suggest that the farmers should strengthen the internal conditions of the farmer groups, improve the production of chrysanthemum flower, and maximize the use of production facilities and equipment, These findings imply that production activities will develop and have a positive impact on farmers if supported by organizational policies that not only manage internal activities but are also able to face challenges of a dynamic external environment. Type of Paper: Empirical. Keywords: Chrysanthemum Flower; Strategic Management; SWOT Analysis. Reference to this paper should be made as follows: Helmiatin; Susanty, E. 2019. The SWOT Analysis for Chrysanthemum Farmers Business Development Strategies for Fresh Chrysanthemum Farmers, J. Bus. Econ. Review 4(3) 139 – 148 https://doi.org/10.35609/jber.2019.4.3(3) JEL Classification: Q20, Q22, Q29.
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Patel, Krish, Neil Bailey, and John M. Pagel. "A Phase 2, Open-Label, Multicenter Study of Tazemetostat in Combination with Rituximab for the Treatment of Relapsed or Refractory Follicular Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 4. http://dx.doi.org/10.1182/blood-2020-136653.
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Background: Patients with follicular lymphoma (FL) who do not achieve a response after 2 or more prior lines of systemic therapy have a poor prognosis when treated with salvage chemotherapy alone or PI3K inhibitors. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that supports germinal center (GC) formation and suspends differentiation during B-cell development by silencing genes that limit proliferation and promote exit from the GC. Throughout the pathogenesis of FL, EZH2 plays a consistent underlying role in maintaining the GC and B-cell proliferation, regardless of the oncogenic drivers. Dysregulation of EZH2 or gain-of-function mutations in EZH2 can lead to accumulation of malignant B cells and may contribute to the development of FL. Tazemetostat, a first-in-class oral EZH2 inhibitor, recently gained approval by the US Food and Drug Administration in patients with relapsed or refractory (R/R) FL after demonstrating single-agent, antitumor activity in patients with mutant (MT) or wild-type (WT) EZH2 R/R FL. Here we examine the efficacy and safety of tazemetostat in combination with rituximab for the treatment of R/R FL. Study Design and Methods: This trial is a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab in patients with R/R FL who have received at least 2 prior lines of systemic therapy, including an anti-CD20-based regimen. Patients eligible for inclusion are aged ≥18 years with grade 1 to 3A FL who have met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria to receive treatment, have an Eastern Cooperative Oncology Group (ECOG) score ≤2, have >5.0 x 109/L circulating malignant cells, and have not received any prior treatment with EZH2 inhibitors. Patients with transformed FL, a history of clinically significant gastrointestinal conditions, or any uncontrolled illness are excluded from this study. EZH2 mutation testing will be performed during patient screening. Patients will receive tazemetostat 800 mg by mouth twice daily beginning on cycle 1 day 1 for continuous 28-day cycles until the end of cycle 24, for a total of 24 months of therapy. Patients will also receive rituximab 375 mg/m2 intravenously (IV) on cycle 1 day 1, then 375 mg/m2 IV or 1400 mg subcutaneously on days 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 4, 5, and 6, for a total of 8 doses of rituximab. The primary endpoint is the objective response rate (ORR; the proportion of patients with complete or partial response) in patients with WT EZH2. Key secondary endpoints include median progression free survival (PFS) in patients with WT EZH2; median PFS in all patients, regardless of mutational status; ORR in patients with MT EZH2; efficacy outcomes in rituximab-refractory patients; and incidence of adverse events. Efficacy and safety analyses will be performed on all patients who receive ≥1 dose of study drug. The evaluation of ORR will be based on Lugano 2014 response criteria and will be presented with corresponding 2-sided Clopper-Pearson 95% confidence intervals. The Kaplan-Meier method will be used to estimate PFS. Survival follow-up will be done following the study treatment period every 6 months for 2 years or until disease progression or death for all patients who complete the 24 months of tazemetostat therapy. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy.
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Atrash, Shebli, Myra Robinson, Manisha Bhutani, Jeffrey A. Zonder, Reed Friend, Barry Paul, Daniel Auclair, et al. "Phase I/II Study of Carfilzomib, Ruxolitinib and Low-Dose Dexamethasone for Carfilzomib-Refractory Multiple Myeloma (CarJak)." Blood 134, Supplement_1 (November 13, 2019): 5570. http://dx.doi.org/10.1182/blood-2019-130290.
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Background: Multiple myeloma (MM) remains an incurable malignancy; the majority of MM patients suffer relapses with progressively shorter disease-free intervals. Carfilzomib (CFZ) is a second-generation proteasome inhibitor (PI) with potent activity against MM. Even after an initial clinical response, virtually all patients will eventually develop resistance to further PI-based therapy. CFZ refractoriness is, partially, due to the development of bone marrow (BM) stromal cell dependent-resistance (Murnane et al ASH, 2015). Janus Associated Kinases-2 (JAK-2) inhibitors demonstrate stroma-induced lethality in preclinical models of MM. The constitutive activation of the JAK/STAT pathway promotes the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, which promote activation and subsequent nuclear translocalization of STATs where they function as transcription factors modulating genes involved in cellular proliferation and inhibition of apoptosis. JAK2 Gene overexpression is showen in around two thirds of MM patients, and approximately one fourth overexpress JAK1. Ruxolitinib (Rux) is a JAK1/2inhibitor with dose-dependent single-agent activity in MM in vitromodels.Rux has previously demonstrated synergistic activity with both bortezomib and lenalidomide (Len) in MM cell lines. In early-phase clinical trials, the addition of Rux to Len in patients with acquired Len resistance resulted in resensitization to Len. The aim of the current Phase I/II study is to evaluate the efficacy of the combination of Rux, CFZ, and low-dose dexamethasone (dex) in CFZ-resistant relapsed and/or refractory MM (RRMM) patients. Study Design and Methods: Study population: 18-75 years with RRMM who have progressed through > 2 lines of therapy including , refractory to CFZ (at doses ≥ 27 mg/m2).Major inclusion criteria:At least one of the following: Serum monoclonal protein ≥0.5 g/dL for IgG, IgA, or IgM, Urinary M-protein of ≥200 mg /24-hours, Involved free light chain (FLC) ≥10 mg/dL, along with an abnormal FLC ratio.Absolute neutrophil count (ANC) ≥ 1000 cells/mm3. Platelet count of ≥75,000 cells/mm3 for BM plasmacytosis of <50%, or ≥50,000 cells/mm3 for BM plasmacytosis of >50%. Within one week of the initiation of treatment.Creatinine clearance ≥30 mL/min.Cardiac ejection fraction ≥ 40%.Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.Major exclusion criteria:Non-secretory MM, amyloidosis, or POEMS syndrome.Statistical design:(1)Phase I: Up to 18 subjects may be required to evaluate 3 dose levels of Rux in combination with CFZ and dex in a standard 3+3 design. (2)Phase II: Progression-free survival at 4 months (PFS4) is the primary endpoint for this study. Based on reported median time on treatment in MM patients receiving 3+ lines of therapy (approximately 2 months, Ref: Kumar et al. IMWG, Leukemia 2017), it is assumed that if MM subjects who are CFZ-refractory were retreated with CFZ plus low-dose dex, unitl progression, they would experience a median PFS of 2 months (corresponding) to a PFS4 rate of 25%. In this patient population, median PFS of 4 months is considered a significant clinical benefit. A Simon's 2-stage design will be used to test the hypothesis that the PFS4 rate ≤25%. Ten subjects will be enrolled in the first stage, and if at least 3 of the 10 subjects are alive and progression free at 4 months, an additional 20 subjects will be enrolled (a total of 30 subjects). If at least 11 of 30 subjects are alive and progression free at 4 months, the null hypothesis will be rejected (based on binomial probabilities). Assuming a one-sided α= 0.10 significance level, this sample size will provide at least 90% power to reject the null hypothesis, assuming the true PFS4 rate is 50%Study endpoints: - Primary endpoints: For Phase I, dose limiting toxicities during Cycle 1 of Rux treatment administration. For Phase II, PFS4 determined for each subject as a binary variable per IMWG 2016 criteria. - Secondary endpoints: PFS, time to progression, overall response rate, clinical benefit rate, disease control, duration of response, overall survival, and safety. -Exploratory endpoints: Correlation of toxicities and disease response with serial serum cytokine profile, peripheral blood mononuclear cells (PBMC) JAK and proteasome inhibition. Disclosures Atrash: Nektar: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Bhutani:Sanofi Genzyme: Consultancy; Amgen: Speakers Bureau. Zonder:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees. Friend:Takeda Oncology: Speakers Bureau; Amgen: Speakers Bureau. Paul:Bristol-Myers Squibb Company: Other: Former employee with retirement plan including pension, stock, stock options. Symanowski:Carsgen Therapeutics: Consultancy; Eli Lilly: Consultancy; Immatics: Consultancy; Boston Biomedical: Consultancy. Voorhees:Adaptive Biotechnologies: Honoraria; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Research Funding; Novartis: Consultancy; Oncopeptides: Consultancy; Takeda: Honoraria, Research Funding; TeneBio: Honoraria, Research Funding. Usmani:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; SkylineDx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding.
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Colin, Elia, Genevieve Courtois, Lydie Da Costa, Carine Lefevre, Michael Dussiot, Julie Galimand, Joël Veiga, et al. "Whole Exome Sequencing of a Patient with Atypical Congenital Pure Red Cell Aplasia Has Enabled the Identification of a Novel Key Actor of Erythropoiesis That May be Involved in CDAI Physiopathology." Blood 136, Supplement 1 (November 5, 2020): 3–4. http://dx.doi.org/10.1182/blood-2020-136078.
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Background: The development of next generation sequencing techniques has brought important insights into the molecular mechanisms of erythropoiesis and how these processes can be perturbed in human diseases. This strategy may be valuable in some hereditary erythroid disorders where a subset of patients does not carry any mutations in the supposed causal gene and for which transgenic mouse models do not recapitulate the phenotype, suggesting that additional genetic events may be involved in pathogenesis. Here, we report the case of an adult patient presenting with atypical pure red cell aplasia associated with facial dysmorphy and chronic leg ulcers. Whole exome sequencing revealed a heterozygous missense mutation (R725W) in the CDAN1 gene, which has been previously reported in congenital dyserythropoietic anemia type I (CDAI). However, this mutation was also detected in her healthy brother, suggesting that this event alone was not sufficient to explain her phenotype. According to this hypothesis, we found an additional germline heterozygous nonsense mutation (Q732X) in the MMS22L gene, which was not shared by her unaffected relatives. MMS22L is a protein involved in homologous recombination-dependent repair of stalled or collapsed replication forks. Additionally, MMS22L is able to bind newly synthesized soluble histones H3 and H4 and exhibits a histone chaperone activity. MMS22L loading onto ssDNA during homologous recombination is promoted by the histone chaperone ASF1. Interestingly, CDAN1 acts as a negative regulator of ASF1 by mediating its sequestration in the cytoplasm, which results in the blocking of histone delivery. Aims: As MMS22L has never been reported in erythropoiesis before, we aimed to investigate the role of MMS22L in human erythropoiesis. Based on the data summarized above, the purpose of this study was also to determine the effect of combined inactivation of MMS22L and CDAN1 on in vivo erythropoiesis, while exploring the functional cooperation between both proteins. Results: To decipher the role of MMS22L in human erythropoiesis, we assessed the consequences of complete MMS22L inactivation in human cord blood CD34+ progenitors as well as in CD36+ immature erythroblasts using shRNA lentiviruses. This resulted in a severe decrease of cell proliferation and differentiation due to G1 cell cycle arrest, with a slight increase of apoptosis. Interestingly, this phenotype was not observed when MMS22L was inactivated in the granulo-monocytic lineage, in which differentiation was maintained, suggesting that erythroid cells, that are highly proliferative, are more sensitive to MMS22L inactivation. To better understand the effect of combined CDAN1 and MMS22L haploinsufficiency observed in the proband, we used zebrafish as an in vivo model. Mms22l and cdan1 expression were simultaneously or separately downregulated by about 50% using antisens morpholino oligomers. 48 hours later, zebrafish embryos were stained with o-dianisidine to detect hemoglobin-containing cells. We found that combined knock-down of mms22l and cdan1 resulted in severe anemia, while knock-down of mms22l or cdan1 alone did not lead to any erythroid disorder. This experiment provides a proof-of-concept, indicating that the phenotype of the proband is indeed caused by the combination of both MMS22L and CDAN1 mutations. Finally, in order to decipher the cooperation between MMS22L and CDAN1 we used the human erythroid UT-7 cell line. We found that CDAN1 inactivation resulted in a severe decrease in MMS22L expression within the nucleus, suggesting that CDAN1 may regulate MMS22L expression or localization. We therefore wanted to confirm these results by assessing MMS22L expression in B-EBV cell lines established from two CDAI patients with CDAN1 compound heterozygous mutations. We found a great decrease in MMS22L expression within the nucleus of the CDAI patients' cells when compared to three control B-EBV cell lines. Based on these results, we suggest that impairment of MMS22L trafficking to the nucleus could be involved in CDA1 physiopathology. Conclusion: Through comprehensive genetic analysis of a single case with atypical congenital anemia, we demonstrated for the first time that MMS22L, a cell cycle regulator, is essential for the process of erythropoiesis. The crosstalk between MMS22L and CDAN1 is currently under investigation and could bring important new insights into the physiopathology of CDAI. Disclosures Hermine: Novartis: Research Funding; Alexion: Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Roche: Consultancy.
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Xiao Zhu, Yuan, Laura Bruins, Chang-Xin Shi, Jessica Schmidt, Chris Sereduk, Mia Champion, Esteban Braggio, Holly Yin, and A. Keith Stewart. "A Synthetic Lethality Druggable Genome RNAi Screen Identifies Genes Mediating Sensitivity To Lenalidomide In Multiple Myeloma Including RSK2." Blood 122, no. 21 (November 15, 2013): 3084. http://dx.doi.org/10.1182/blood.v122.21.3084.3084.
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Abstract Immunomodulatory drugs (IMiDs) are widely used in the treatment of patients with Multiple Myeloma (MM) however, only 30% of relapsed MM patients respond to single agent therapy and most patients eventually develop drug resistance. The molecular target of IMiDs in MM is cereblon but other parallel pathways or downstream events which enhance or preclude drug responsiveness are unknown. We therefore conducted a genome scale small interfering RNA (siRNA) lethality study in MM in the presence of increasing concentrations of lenalidomide. Primary screening was performed in a single-siRNA-per-well format with the human druggable genome siRNA set V4 comprising four siRNAs targeting each of 6,992 genes (total 27968 siRNAs). Lenalidomide was added 24 hours post transfection and cell viability was measured by ATP-dependent luminescence at 144 hours after transfection. Primary screen data was rigorously evaluated for multiple quality control metrics and found to exceed all expected performance parameters with >98% global transfection efficiency, <0.25 CV values, and minimal plate-to-plate and set-to-set variations observed. Hit selection was performed by analysis of IC50 value shift in the presence of each testing siRNA compared with three different control siRNA oligos. 160 candidate genes that enhance lenalidomide sensitivity upon silencing (sensitizers) were selected and re-screened with four siRNA oligos targeting each gene. 50 genes were identified as reproducible lenalidomide sensitizers including three Peroxisome (PEX) family proteins (PEX1, PEX10 and PEX7) and seven RAB family proteins (RAB17, RAB1A, RAB26, RAB30, RAB36, RAB4A and RAB8A). Four kinase genes were also identified in sensitizer hits and two of these, I-Kappa-B Kinase-Alpha (IKK1 or CHUK) and ribosomal protein S6 kinase (RPS6KA3 or RSK2), encode proteins that associate with significance together with a phosphorylation dependent transcription factor (CREB1) in Toll signaling pathways (p-value 0.0068). RSK2 is a serine/threonine-protein kinase that acts downstream of oncogenic FGFR3 mediated signaling and is phosphorylated by ERK (MAPK1/ERK2 and MAPK3/ERK1 signaling) during hematopoietic transformation. Phosphorylated RSK2 was previously reported to be frequently expressed in myeloma cell lines and primary myeloma cells. Using lentiviral shRNA expression, we demonstrated that knockdown of RSK2 in three genetically variable MM cell lines induced cyctocytoxiticy and consistently sensitized to lenalidomide. Two selective small molecular inhibitors of RSK2 (SL 0101-1 and BI-D1870) were then demonstrated to synergize with lenalidomide to induce myeloma cell cytotoxicixity. To further understand the mechanism underlying sensitization, immunoblotting analysis was performed to look at downstream changes after either RSK2 knockdown or RSK2 inhibition by BI-D1870. We found that both RSK2 knockdown and BI-D1870 treatment, mimicking lenalidomide treatment or cereblon inhibition, induced downregulation of both IRF4 and MYC in MM cells. The combination of lenalidomide and BI-D1870 not only produced a substantial synergistic effect inducing MM cytotoxicity, but also demonstrated a significant enhancement of downregulation of IRF4 and MYC. Forced overexpression of RSK2 attenuated the synergistic effects of lenalidomide and BI-D1870. In summary, our high throughput screen identified multiple gene targets that associate with increasing sensitivity to IMiDs in MM cells, of which, RSK2 was further validated by both shRNA silencing and specific inhibitors as an effective target to cooperate with IMiDs to induce myeloma cytotoxicity. Clinical studies of RSK2 inhibition in concert with IMiD (cereblon inhibitor) therapy would be appropriate. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millennium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria.
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Herrera, Alex F., Carmelo Carlo-Stella, Graham P. Collins, Kami J. Maddocks, Nancy L. Bartlett, Kerry J. Savage, Paolo F. Caimi, et al. "Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 21–23. http://dx.doi.org/10.1182/blood-2020-137451.
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Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.
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Siegel, David S., Gary J. Schiller, Kevin W. Song, Richy Agajanian, Keith Stockerl-Goldstein, Hakan Kaya, Michael Sebag, et al. "Pomalidomide + Low-Dose Dexamethasone Following Second-Line Lenalidomide-Based Therapy in Relapsed or Refractory Multiple Myeloma: A Phase 2 Study Investigating Efficacy and Safety." Blood 128, no. 22 (December 2, 2016): 4497. http://dx.doi.org/10.1182/blood.v128.22.4497.4497.
Full textAbstract:
Abstract Background: Pomalidomide (POM) in combination with low-dose dexamethasone (LoDEX) is approved for the treatment (Tx) of patients (pts) with multiple myeloma (MM) who have had ≥ 2 prior lines of therapy, including lenalidomide (LEN) and a proteasome inhibitor. Although LEN and POM are both IMiD® immunomodulatory agents, preclinical studies have shown that LEN is not cross-resistant with POM (Ocio et al, Leukemia, 2015) and that LEN-resistant myeloma cells remain sensitive to POM (Lopez-Girona et al, Leukemia, 2012). Furthermore, sub-analyses of the MM-002 and MM-003 trials demonstrated that POM + LoDEX had comparable efficacy in pts refractory to their last prior Tx with LEN as in the overall pt population (San Miguel et al, Lancet Oncol, 2013; Richardson et al, Blood, 2014). Here, we present an updated analysis of MM-014, a single-arm, phase 2 trial of POM + LoDEX in pts with MM relapsed or refractory to LEN-based second-line therapy. Methods: Pts were ≥ 18 years old with a documented diagnosis of MM, measurable disease, 2 prior lines of Tx, and progressive disease after ≥ 2 cycles of second-line Tx with a LEN-based therapy. The Tx regimen was POM 4 mg/day on days 1-21 and LoDEX 40 mg/day (20 mg/day for pts > 75 years old) on days 1, 8, 15, and 22 of a 28-day cycle; thromboprophylaxis was mandatory. Responses were assessed using modified International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]). Secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Secondary primary malignancies (SPMs) were monitored and recorded as serious AEs regardless of relationship to Tx. Exploratory endpoints included measures to identify potential molecular, immune, and cellular biomarkers for POM + LoDEX response, resistance, or mechanism of action. Results: Of 51 enrolled pts (N = 85 planned), 16 (31.4%) remain on Tx, and 35 (68.6%) discontinued from Tx (n = 20 due to PD, n = 7 due to withdrawal by pt, and n = 2 each due to adverse event [AE], death, lack of efficacy, and other reasons). The median age was 68.0 years, and most pts (92.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1; 34 pts (66.7%) were refractory to their last Tx with LEN, and 37 (72.5%), 2 (3.9%), and 1 (2.0%) pts had prior Tx with bortezomib, carfilzomib, or ixazomib, respectively. A total of 33 pts (64.7%) had prior stem cell transplant. The median duration of the most recent prior LEN-containing Tx was 24.6 months, and the median study follow-up time was 11.4 months. The ORR was 31.4%, including 3.9% (n = 2) with complete response, 5.9% (n = 3) with very good PR, and 21.6% (n = 11) with PR. The clinical benefit rate (≥ minimal response) was 41.2%. Of the 16 pts who achieved ≥ PR, 12 (75.0%) have an ongoing response; median TTR in these pts was 1.9 months. The median DOR based on Kaplan-Meier estimates was not reached. The 1-year PFS, OS, and TTP rates were 60.2%, 87.4%, and 64.6%, respectively. Common (≥ 5%) grade 3/4 AEs included anemia (23.5%), neutropenia (13.7%), thrombocytopenia (9.8%), fatigue (7.8%), and infections (19.6%; including pneumonia [7.8%]). AEs of special interest (any grade) included pulmonary embolism (3.9%), deep vein thrombosis (2.0%), and peripheral sensory neuropathy (3.9%); no SPMs were observed. The immune subset analysis showed a significantly elevated proportion of CD3+/CD8+ T cells after Tx (cycle 3, 5, day 1) compared with baseline (37.6% vs 30.5% of total lymphocytes; P < .01). A similar trend toward elevated proportions of CD3+ T cells (73.7% vs 66.6%) was observed; however, the difference was not significant. There was no significant change in CD3+/CD4+ T cells (35.9% vs 35.5%). Conclusions: This updated analysis of the MM-014 trial demonstrates the safety and efficacy of POM + LoDEX in pts who were relapsed or refractory to their last prior Tx with LEN. Results suggest that POM + LoDEX can be used immediately following LEN-based therapy to treat pts with relapsed/refractory MM. The study has been amended to include a cohort of pts treated with POM + LoDEX + daratumumab. Investigations of additional biomarkers, high-risk genetic aberrations, clonal evolution, and minimal residual disease in MM-014 are currently underway. Disclosures Siegel: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Merck: Honoraria. Schiller:Incyte Corporation: Research Funding. Song:Otsuka: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaya:Celgene, Amgen, Takeda: Honoraria. Sebag:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reu:Celgene, Novartis and Takeda: Research Funding; Signal Genetics, Inc.: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Chung:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Qian:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria.
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Raab, Marc S., Enrique M. Ocio, Sheeba K. Thomas, Andreas Günther, Daniel Lebovic, Shaji K. Kumar, Andrzej J. Jakubowiak, et al. "Phase 1 Study Of The Novel Pan-Pim Kinase Inhibitor LGH447 In Patients With Relapsed/ Refractory Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 3186. http://dx.doi.org/10.1182/blood.v122.21.3186.3186.
Full textAbstract:
Abstract Background LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. Furthermore, LGH447 was well tolerated and demonstrated significant inhibition of tumor growth in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary antimyeloma activity, and pharmacokinetic (PK) profiles of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Following determination of the MTD for LGH447, additional patients will be enrolled in an expansion cohort to further characterize the safety and tolerability profile of LGH447. Results At the data cutoff, 19 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 4), 250 mg (n = 4), with enrollment ongoing in dose escalation. Median age was 66 years (range, 41-75 years). Most patients (94.7%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Most patients (73.7%) had received ≥ 2 prior regimens (median 4; range, 1-11), 89.5% had received prior bortezomib, and 84.2% had received prior lenalidomide and/or thalidomide (68.4% and 47.4%, respectively). Ten patients are ongoing at doses between 150-250 mg, with a median duration of exposure of 6 weeks (range, 1-26.6 weeks), and 9 patients discontinued (disease progression [n = 6], AEs [n = 2], withdrawal of consent [n = 1]). There was 1 DLT consisting of grade 3 thrombocytopenia at the 200 mg dose level and no reported suspected unexpected serious AEs. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (31.6%), anemia (21.1%), and neutropenia (15.8%). No deaths have occurred on study. LGH447 displayed time-dependent PK with a 3- to 6-fold accumulation from day 1 to steady state (day 14). After a single oral dose, area under the curve and maximum concentration increased somewhat more than in proportion to the dose from 70 to 250 mg. Evidence of single-agent activity, as determined by investigators using IMWG criteria, has been seen in multiple patients, with best response to date being a very good partial response (VGPR). Conclusion In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of single-agent efficacy in multiple patients, validating Pim kinase inhibition as a promising therapeutic rationale and supporting its further clinical development in patients with MM and other hematologic malignancies. Dose escalation is ongoing and updated results will be presented. Disclosures: Ocio: BMS: Consultancy; Arry-520: Consultancy; Pharmamar: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding. Günther:Novartis: Consultancy, Research Funding. Lebovic:Celgene: Speakers Bureau; Allos/Spectrum: Speakers Bureau; Genentech: Speakers Bureau; Onyx: Speakers Bureau. Kumar:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Jakubowiak:Onyx: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. Song:Novartis: Employment. Xiang:Novartis: Employment. Hynds:Novartis: Employment. Vanasse:Novartis: Employment. Goh:Jannsen: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.
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Morelli, Eugenio, Mariateresa Fulciniti, Mehmet K. Samur, Caroline Ribeiro, Leon Wert-Lamas, Annamaria Gulla, Anil Aktas-Samur, et al. "RNA Regulator of Lipogenesis (RROL) Is a Novel Lncrna Mediating Protein-Protein Interaction at Gene Regulatory Loci Driving Lipogenic Programs in Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-142514.
Full textAbstract:
Long noncoding RNA (lncRNAs) are key epigenetic factors that drive the origin and progression of human cancers via mechanisms that are largely unknown. We have previuosly reported the clinical significance of a lncRNA signature in multiple myeloma (MM) as independent risk predictor for clinical outcome; and recently identified a lncRNA RROL (RNA Regulator of Lipogenesis) with impact on MM cell proliferation. Here we describe a unique regulatory function for RROL in the control of gene networks involved in the de novo lipogenesis (DNL) pathway, ultimately impacting MM cell growth and survival. Based on growth and survival impact of RROL depletion, we performed integrated transcriptomic analysis of RNA-seq data after RROL depletion in MM cell lines and CD138+ patient MM cells, and identified a set of significantly modulated metabolic genes including the acetyl Co-A Carboxylase 1 (ACC1) gene, encoding a rate-limiting enzyme of the DNL pathway. This metabolic pathway converts nutrients into fatty acids serving for energy storage or biosynthesis of membranes and signaling molecules. Consistent with the transcriptional control of ACC1, we have observed that RROL inhibition in cell lines and primary MM cells significantly decreased the incorporation of C14-radiolabeled glucose into de novo synthesized lipids. Importantly, supplementation with exogenous palmitate, the main downstream product of DNL pathway, rescued the growth inhibitory effect of RROL depletion on MM cells, further confirming the importance of the DNL pathway in the oncogenic activity of RROL in MM. To understand the molecular mechanism through which RROL regulates ACC1 expression and its metabolic axis, we evaluated the RROL interactome in MM cells. RNA-Protein Pull Down (RPPD) and in vivo RNA yeast three-hybrid (Y3H) assays led to the identification of MYC as relevant direct partner of RROL. These results were further validated by qRT-PCR analysis of MYC-bound RNA obtained through RNA immunoprecipitation (RIP) assay. Using experimental model of conditional MYC KD (P493-6), we found that RROL exerts regulatory activity on ACC1 only in the presence of MYC. Mapping of MYC genomic occupancy by ChIP-seq and gene expression after MYC KD in MM cells revealed that ACC1 is a direct transcriptional target of MYC in cells expressing RROL. These data indicate that RROLand MYC cooperate in the transcriptional control of ACC1. Moreover, we found that RROL itself is transcriptionally regulated by MYC, suggesting the existence of a feed-forward regulatory loop in which MYC enhances the expression of RROL that, in turn, drives MYC transcriptional activity to ACC1. We hypothesized that RROL may shape the protein interacting network of MYC to confer specificity for ACC1 promoter. To this end, we performed mass spectrometry analysis of MYC interactome in three MM cell lines in the presence or in the absence of RROL and identified the transcriptional modulator WDR82 as RROL-dependent MYC partner. Interestingly, WDR82 directly interacts with RROL as assessed in the RPPD and RNA Y3H assays, and transcriptionally regulates ACC1 in RROL-dependent manner. These data indicate that RROL catalyzes the interaction of MYC with the transcriptional modulator WDR82 to form a transcriptional ternary complex regulating ACC1 expression. To therapeutically antagonize the RROL lipogenic signaling we have pre-clinically tested small molecule inhibitors of ACC1 (ACC1i). We have observed significant anti-MM activity of ACC1i in vitro in a large panel of MM cell lines and primary MM cells from patients; and in vivo in mouse models of human MM including the localized subcutaneous model and the disseminated model that establish a more aggressive systemic disease. Importantly, we have now developed clinically applicable ASOs and small molecule-like compounds to directly target RROL in MM cells. These studies are ongoing and will be presented. In conclusion, we here report a unique regulatory function of a novel lncRNA supporting MM cell growth via its control of the lipogenic metabolic axis. The availability of oral inhibitors of ACC1 as well as the ongoing development of RROL inhibitors may allow clinical application of this unique targeted therapy in MM. Disclosures Fulciniti: NIH: Research Funding. Chauhan:Oncopeptide AB: Consultancy; consultant to Stemline Therapeutics, Inc., and Equity owner in C4 Therapeutics.: Consultancy, Other: Equity owner in C4 Therapeutics.. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.. Munshi:Takeda: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; Legend: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; C4: Current equity holder in private company; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy.
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Pilke, Riina, and Marikki Stocchetti. "Inequality and poverty: The ill-fitting pieces in the EU’s development partnerships." Regions and Cohesion 6, no. 1 (March 1, 2016): 1–22. http://dx.doi.org/10.3167/reco.2016.060101.
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[Full article is in English]English: This article reviews the main policy guidelines set by the European Union (EU) for eradicating poverty and inequality in the context of its development cooperation partnerships. Drawing on the structure of the EU’s treaty, the EU’s offi cial development policies since 2005, and the related European Commission documents over the past five years, it examines the conceptions of poverty and inequality and how the EU translates them into operational diff erentiation. The scope of the diff erentiated cooperation encompasses diff erent types of developing countries, including a variety of both low-income countries (LICs) and middleincome countries (MICs). The article argues that diff erentiation poses a challenge to the EU’s internal development policy coherence. While the EU has adopted a multifaceted understanding of poverty, its conception of inequality is very narrow. In addition, the authors contend that the EU lacks clear criteria for diff erentiation in diverse country contexts in both regards.Spanish: El propósito de este trabajo es revisar los principales lineamientos de política pública establecidos por la Unión Europea (UE) para la erradicación de la pobreza y la desigualdad en el contexto de sus asociaciones de cooperación al desarrollo. Con base en la estructura de los tratados de la UE, las políticas oficiales de desarrollo de la UE desde 2005, y los documentos relacionados de la Comisión Europea en los últimos cinco años, este artículo examina las concepciones de pobreza y desigualdad así como la traducción sistemática que hace la UE de dichos conceptos en una diferenciación funcional en sus asociaciones de cooperación al 22 Regions & Cohesion • Spring 2016 desarrollo. El alcance de la cooperación diferenciada abarca diferentes tipos de países en desarrollo, incluyendo una variedad de países con bajos y medios ingresos (LIC y MIC por sus siglas en inglés). El artículo sostiene que la diferenciación plantea un desafío a la coherencia de la política pública de desarrollo al interior de la UE. Mientras que la UE ha adoptado una comprensión multifacética de la pobreza, su concepción de la desigualdad es muy estrecha. Además, las autoras argumentan que la UE carece de criterios claros para una diferenciación que tome en cuenta las dimensiones tanto de pobreza como de desigualdad en diversos contextos de países.French: L’objectif de ce texte consiste à passer en revue les principales lignes de politique publique de l’Union Européenne (UE) en matière de lutte contre la pauvreté et des inégalités dans le cadre de son partenariat de coopération pour le développement. A partir d’une révision des traités de l’UE, des politiques officielles de développement depuis 2005 et de documents de la Commission Européenne datant des cinq dernières années, l’article évoque les conceptions de la pauvreté et des inégalités et comment l’UE les traduit par une différenciacion opérative en matière de coopération pour le développement. La portée de la coopération differenciée inclut différents types de pays en développement, y compris divers pays à revenus bas et intermédiaires. Cet article défend l’idée que la différentiation présente un défi pour la cohérence de la politique de développement au sein de l’UE. Alors que celle-ci a adopté un point de vue multifacétique de la pauvreté, sa conception des inégalités est extrêmement limitée. Ainsi, les auteures affirment que l’UE manque de critères clairs pour établir une différenciation qui prenne en compte à la fois les dimensions de la pauvreté et les inégalités dans les différents contextes nationaux.
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Rifkin, Robert M., Kevin Boyd, Sebastian Grosicki, Kihyun Kim, Francesco Di Raimondo, Meletios A. Dimopoulos, Katja Weisel, et al. "DREAMM-7: A Phase III Study of the Efficacy and Safety of Belantamab Mafodotin (Belamaf) with Bortezomib, and Dexamethasone (B-Vd) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)." Blood 136, Supplement 1 (November 5, 2020): 53–54. http://dx.doi.org/10.1182/blood-2020-139181.
Full textAbstract:
Introduction: Belantamab mafodotin (belamaf; GSK2857916) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate. In the pivotal Phase II DREAMM-2 study, single-agent belamaf demonstrated deep and durable responses and a manageable safety profile in patients refractory and/or intolerant to ≥3 lines of therapy, including an anti-CD38 monoclonal antibody such as daratumumab (Lonial et al. Lancet Oncol 2020). Responses were sustained at 13 months of follow-up with belamaf (2.5 mg/kg intravenously [IV] every 3 weeks [Q3W]); overall response rate (ORR) was 32% and median duration of response (DoR) was 11.0 months (Lonial et al. ASCO 2020 Poster 436). Triple combination regimens, such as daratumumab plus bortezomib and dexamethasone (D-Vd), are considered a standard of care for patients with RRMM and have demonstrated superior antimyeloma activity to monotherapy and dual combination regimens, such as bortezomib and dexamethasone. Preclinical data suggest synergistic antimyeloma activity of belamaf and bortezomib (a proteasome inhibitor), and initial results from the ongoing Phase I/II DREAMM-6 study of B-Vd indicate an acceptable safety profile for the combination (Nooka et al. ASCO 2020 Oral 8502). The DREAMM-7 study (NCT04246047) will evaluate the efficacy and safety of B-Vd compared with D-Vd in patients with RRMM. Methods: DREAMM-7 is an ongoing, randomized, open-label, global, multicenter, Phase III, two-arm study in patients with measurable RRMM who had received ≥1 prior therapy with documented disease progression during or after their most recent therapy. Patients aged ≥18 years with Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ system function, and who provide informed consent will be eligible. Patients intolerant/refractory to daratumumab or bortezomib, or with prior exposure to anti-BCMA therapy, will be excluded. Patients will be stratified by the Revised International Staging System, prior exposure to bortezomib, and number of prior lines of therapy. Approximately 478 patients will be randomized (1:1) to Arm A (B-Vd) or Arm B (D-Vd). In Arm A, patients will receive belamaf 2.5 mg/kg (IV) Q3W on Day 1 of each cycle; bortezomib 1.3 mg/m2 (subcutaneously) on Days 1, 4, 8, and 11 of Cycles 1-8 (21-day cycles); and dexamethasone 20 mg (IV or orally) on the day of, and the day after, bortezomib treatment. In Arm B, patients will receive daratumumab 16 mg/kg (IV) in 21-day cycles: Cycles 1-3 Q1W, Cycles 4-8 Q3W, and from Cycle 9 onwards Q4W; dexamethasone and bortezomib schedules will be the same as in Arm A. Treatment will continue in both arms until disease progression, death, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is progression-free survival (PFS; time from randomization to the earliest date of documented disease progression or death [any cause]). The key secondary endpoint is minimal residual disease negativity rate, as assessed by next-generation sequencing. Additional secondary endpoints include complete response rate, ORR, DoR, PFS2 (PFS after initiation of new anticancer therapy), overall survival, and endpoints related to pharmacokinetics, antidrug antibodies, safety, and health-related quality of life. As of August 2020, the study is enrolling. Funding: GSK (Study 207503); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Rifkin: McKesson: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Stock ownership; Takeda, Amgen, Celgene, BMS, Mylan, Coherus BioSciences, Fresenius: Consultancy; AbbVie: Other: Investigator in AbbVie sponsored clinical trials; Takeda, Amgen, BMS (Celgene): Membership on an entity's Board of Directors or advisory committees. Boyd:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Di Raimondo:Amgen: Consultancy, Honoraria; GILEAD, Incyte: Research Funding; Amgen, Takeda, Novartis: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Arnulf:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Hajek:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Davis:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Riccio:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Kim:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Wilkes:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rutledge:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Talekar:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Mateos:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Muchtar, Eli, Moshe Gatt, Ory Rouvio, Chezi Ganzel, Evgeni Chubar, Celia Suriu, Tamar Tadmor, et al. "Efficacy and Safety of Salvage Therapy Using Carfilzomib for Relapsed or Refractory Multiple Myeloma Patients: A Multicentre Retrospective Observational Study." Blood 126, no. 23 (December 3, 2015): 5371. http://dx.doi.org/10.1182/blood.v126.23.5371.5371.
Full textAbstract:
Abstract Introduction: Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. Methods: All consecutive patients with RR-MM who received carfilzomib-containing salvage therapy outside of a clinical trial between March 2013 and April 2015 were included in this study. For the response and survival analyses, patients were included only if they received at least one full cycle of carfilzomib and response evaluation was available. Carfilzomib was used either as a single agent or in combinations with other drugs, according to the treating physician's choice. Per manufacturer's recommendations, carfilzomib was given by intravenous infusion over 10-30 minutes on days 1, 2,8,9,15,16 of 28-days cycle. The recommended dose of carfilzomib was 20 mg/m2 on days 1 and 2 in cycle 1, which was increased on subsequent administrations to 27 mg/m2 (the 20/27 mg/m2 schedule), provided that the previous dose was well tolerated. Doses, however, were modified according to the treating physician's discretion. Results: One-hundred and thirty-five patients were included. The median age at carfilzomib initiation was 67.9 years (range, 41-88). Male and female patients were equally balanced. Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 was evident in 14.8% of patients. All patients were previously exposed to bortezomib and 93% to lenalidomide as well. The median time from last treatment to carfilzomib was 5.5 months (range, 0.3-43). Patients had received a median of 3 lines of therapy prior to carfilzomib (range, 1-7). The median number of administrated cycles of carfilzomib was 4 (range, 0.3-22). The majority of patients (79.3%) received carfilzomib according to the 20/27 mg/m2 dose schedule. The remaining patients received carfilzomib either at a dose that did not exceed 20 mg/m2 (11.8%) or at maximal dose higher than 27 mg/m2 (8.9%, mostly as a 20/27/56 mg/m2 dose schedule). Carfilzomib was administrated as a single agent in 5.1% of patients or combined with a second agent in 43% of them. Additionally, 46.7% of patients received carfilzomib as part of a three-drug combination and 5.2% of patients as part of four-drug combination or more. In comparison to patients who received two-drug combination (or carfilzomib alone), patients who received three-drug (or more) combination were younger, with less prior treatment lines and higher baseline haemoglobin, albumin and eGFR (Table I). There was also pre-selection by lower frequency of ImIds resistance in the three-drug combination sub-group, but bortezomib resistance was similar between sub-groups. One hundred and twenty three patients (91.1% of patients) were evaluable for response and survival analysis. The overall response rate was 48.8%, with one patient (0.8%) achieving complete response (CR), 30 patients (24.4%) attaining very good partial response (VGPR) and 29 patients (23.6%) with partial response (PR). Additionally, 15 patients (12.2%) achieved minimal response (MR), reaching a clinical benefit response (CBR) rate of 61%. A multivariate analysis revealed three parameters negatively impact the likelihood of achieving response: bortezomib resistance (odds ratio 0.33, 95% CI 0.12-0.94, p=0.03); lenalidomide resistance (odds ratio 0.31, 95% CI 0.11-0.91, p=0.03), and albumin <3.5 g/dL (odds ratio 0.32, 95% CI 0.14-0.71 p=0.005). The median duration of response was 8.3 months, significantly higher in patients receiving three-drug combination and in patients presenting without extramedullary disease. The median progression free survival (PFS) and overall survival for the entire cohort were 4.9 months (95% CI 3.9-6.9) and 19.3 months (95% CI 9.4-not yet reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. Conclusion: In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields an effective results with a manageable toxicity. Drug resistance is an important factor in determining response quality to carfilzomib. Disclosures Raanani: Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding.
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Kumar, Shaji K., Magdalini Migkou, Manisha Bhutani, Andrew Spencer, Sikander Ailawadhi, Anna Kalff, Farzana Walcott, et al. "Phase 1, First-in-Human Study of MEDI2228, a BCMA-Targeted ADC in Patients with Relapsed/Refractory Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-136375.
Full textAbstract:
Background: B-cell maturation antigen (BCMA) is widely expressed on normal plasma cells and malignant plasma cells in multiple myeloma (MM). MEDI2228 is an antibody-drug conjugate (ADC) that targets the extracellular domain of human BCMA with preferential binding to membrane-bound versus circulating soluble BCMA. The ADC is comprised of a fully human antibody to BCMA, site- specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker. After cell surface binding to BCMA, MEDI2228 is internalized and cleaved in the lysosomal compartment, releasing the active PBD, which cross-links DNA and leads to apoptotic cell death. We report the results from a phase 1, first-in-human, open-label, dose-escalation and expansion trial (NCT03489525) that evaluated the safety, pharmacokinetics (PK), and clinical activity of MEDI2228 in patients (pts) with relapsed/refractory MM (R/R MM). Methods: Eligible pts were ≥18 years old with confirmed R/R MM as defined by International Myeloma Working Group consensus criteria, had measurable disease, and had an Eastern Cooperative Oncology Group performance status ≤1. Pts had to have progressed after treatment with three classes of standard-of-care anti-myeloma drugs, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). Dose escalation was based on an accelerated titration design, with an mTPI-2 algorithm. During dose escalation, MEDI2228 was administered in sequentially ascending dose levels (0.0125, 0.025, 0.05, 0.1, and 0.2 mg/kg) intravenously every 3 weeks (Q3W). Due to dose-limiting toxicities (DLTs), the dose was de-escalated from 0.2 mg/kg to an intermediate dose level of 0.14 mg/kg. The primary endpoint was safety and tolerability. Secondary endpoints included assessment of preliminary efficacy, PK, and immunogenicity. Results: As of May 15, 2020, 82 pts received MEDI2228 during dose escalation and expansion. All pts had received prior therapy with an IMiD, PI, and mAb: lenalidomide, 76 (94%); pomalidomide, 68 (84%); bortezomib, 77 (95%); carfilzomib, 64 (79%); and daratumumab, 71 (87%). Pts received between 2-11 lines of prior regimens. At 0.2 mg/kg, 2 pts experienced DLTs (grade 3/4 thrombocytopenia) without bleeding; no DLTs were reported for other dose levels. The maximum tolerated dose was 0.14 mg/kg Q3W. Treatment-related adverse events (TEAEs) occurring in ≥20% of pts in the 0.14 mg/kg cohort were photophobia (53.7%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (19.5%), and pleural effusion (19.5%). No reports of keratopathy or visual acuity loss were observed in the 0.14 mg/kg cohort. The TEAE profiles at lower-dose levels were similar but with lower incidences compared with the 0.14 mg/kg level. Efficacy was demonstrated at all dose levels (dose, objective response rate [ORR], [n]): 0.0125 mg/kg, 33.3% [1/3]; 0.025 mg/kg, 16.7% [1/6]; 0.05 mg/kg, 33.3% [3/9]; 0.10 mg/kg, 27.8% [5/18]; 0.14 mg/kg, 61.0% [25/41]; 0.2 mg/kg, 40.0%, [2/5]. In the 0.14 mg/kg cohort, ORR was 61.0% (95% confidence interval [CI]: 44.5%, 75.8%); there were 10 (24.4%) very good partial responses (VGPRs), 15 (36.6%) partial responses, and 3 (7.3%) minimal responses. Four of the VGPR pts were immunofixation negative. Most (90.2%) pts in the 0.14 mg/kg cohort had received prior daratumumab. Median duration of response (DOR) in the 0.14 mg/kg cohort was not reached. MEDI2228 exhibited linear PK at doses of ≥0.05 mg/kg Q3W that was minimally impacted by circulating levels of soluble BCMA at baseline. There was no difference in BCMA expression by IHC in the bone marrow of responders compared with nonresponders. Thirty-six pts in the 0.14 mg/kg cohort discontinued treatment due to adverse events (n=24), progressive disease (n=8), patient decision (n=2), investigator decision (n=1), or death (n=1). Conclusion: MEDI2228 is a BCMA-targeted ADC that demonstrated clinical efficacy at all dose levels explored. MEDI2228 0.14 mg/kg Q3W had a manageable safety profile and an ORR of 61% in a heavily pretreated population with myeloma that is R/R post PI, IMiD, and mAb therapies. Disclosures Kumar: Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy. Bhutani:Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute. Spencer:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; Servier: Consultancy, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Other, Speakers Bureau; Secura Bio: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Antegene: Consultancy, Honoraria; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Pharmamar: Other. Ailawadhi:Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding. Kalff:Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; CSL: Honoraria. Pore:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Gibson:AstraZeneca: Current Employment, Other: Paid as a clinical scientist contractor. Wang:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Williams:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Kinneer:AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Other: Personal fees; BCMA Monoclonal Antibody-Drug Conjugate: Patents & Royalties: Pending. Zonder:Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Caelum: Consultancy; Celgene: Research Funding. Larsen:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Oncopeptide: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau.
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Ludwig, Heinz, Evangelos Terpos, María-Victoria Mateos, Mario Boccadoro, Bhuvan Kishore, Karthik Ramasamy, Sylvie Fernandez, et al. "Effectiveness and Safety of Ixazomib-Based Therapy in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated Outside the Clinical Trial Setting Via an Early Access Program (EAP) in Europe: Second Interim Analysis of the 'Use Via Early Access to Ixazomib' (UVEA-IXA) Study." Blood 136, Supplement 1 (November 5, 2020): 42–44. http://dx.doi.org/10.1182/blood-2020-136519.
Full textAbstract:
Background It is becoming increasingly important in the treatment of MM to improve our understanding of routine clinical practice and of the effectiveness of new agents and regimens outside the clinical trial setting. UVEA-IXA is a European, multicenter, observational, longitudinal cohort study of RRMM pts who received therapy with ixazomib, the first oral proteasome inhibitor (PI), at MM specialist centers via an Early Access Program (EAP) in 8 European countries (Czech Republic, Greece, Hungary, Italy, Slovakia, Slovenia, Spain, UK). Ixazomib was available in Europe via the EAP from Nov 2015, when it was initially approved in the US in combination with lenalidomide and dexamethasone for the treatment of MM pts who have received ≥1 prior therapy, until European approval in Nov 2016. Approvals were based on the results of the phase 3 TOURMALINE-MM1 study (Moreau NEJM 2016). We report data from the second interim analysis of pts enrolled in the UVEA-IXA study. Methods The UVEA-IXA observation period comprises two parts: a retrospective chart review, starting from ixazomib therapy initiation in the EAP, followed by a 1-yr prospective follow-up period from the date of chart abstraction, with data captured quarterly per local regulations. Pts eligible for the UVEA-IXA study were adult MM pts in biochemical and/or symptomatic relapse after 1-3 prior lines of therapy, who had not received any anti-MM therapy for >3 cycles (except steroids) at the time of ixazomib therapy initiation, and who had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Lenalidomide- or PI-refractory (disease progression on treatment or within 60 d after last dose) pts were excluded from UVEA-IXA. The primary endpoints of UVEA-IXA were response (per International Myeloma Working Group criteria) and progression-free survival (PFS; from ixazomib therapy initiation in the EAP to first documented disease progression/death during the observation period). Results A total of 359 pts were enrolled into UVEA-IXA. At data cutoff (May 22, 2020), 302 pts were evaluable for analysis; 55% were male; median age at enrollment was 68 yrs (range 36-92), with 39% aged ≥70 yrs. At the time of initiating ixazomib therapy, 36/117 (31%) pts had International Staging System (ISS) stage III disease, and 61/301 (20%) had an ECOG PS of 2; 60% of all evaluable pts had ≥1 comorbidity, including hypertension (26%), renal disease (23%), and diabetes (10%). Median time from MM diagnosis was 37.0 mos (range 4.9-231.7), and 39%, 43%, and 18% of pts had received 1, 2, and 3 prior lines of therapy. These included (in any line) bortezomib (89%), thalidomide (52%), transplant (47%), melphalan (22%), lenalidomide (17%), carfilzomib (5%), and pomalidomide (2%). The median follow-up period among 295 pts with available data was 24.9 mos (range 0.2-49.3); of all evaluable pts, 160 (53%) discontinued the study (of these, 88% discontinued due to death). Pts received ixazomib for a median of 10.8 mos (range 0.2-49.3), and most pts also received lenalidomide (97%) and dexamethasone (96%). Among 275 pts with data on best response, the overall response rate (ORR) was 60% (Table 1). Median PFS was 15.6 mos (95% CI 11.8-20.0; Figure). Ixazomib and lenalidomide dose reductions and discontinuations are summarized in Table 2. In 187 pts who received ≥4 cycles of ixazomib, rates of any-grade, grade ≥3, and serious adverse events (AEs) were 60%, 33%, and 23%; the most common AEs of any grade were diarrhea and thrombocytopenia (14% each), rash (7%), peripheral neuropathy (6%), and nausea/vomiting (5%); the most common grade ≥3 AE was thrombocytopenia (6%). Conclusions Data from the second interim analysis of UVEA-IXA demonstrate that ixazomib-based therapy is effective outside the clinical trial setting, with an ORR of 60% and a median PFS of 15.6 mos. Compared with TOURMALINE-MM1 pts (ixazomib arm; ORR 78%, median PFS 20.6 mos), UVEA-IXA pts have higher rates of ECOG PS 2 (20% vs 5%) and ISS stage III MM (31% vs 12%), and had received more prior therapies (61% vs 38% had ≥2 prior therapies). The most common AEs were gastrointestinal and hematologic AEs, in line with the well-characterized and manageable safety profile of ixazomib, although data are not directly comparable with clinical trial safety data due to the retrospective/infrequent prospective collection schedule. Ixazomib-based therapy is an effective and tolerable treatment option outside the clinical trial setting. Disclosures Ludwig: Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau. Terpos:Genesis: Research Funding; Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Janssen: Research Funding; Takeda: Research Funding; BMS: Honoraria; Amgen: Research Funding; Celgene: Honoraria. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kishore:Celgene: Other. Ramasamy:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Fernandez:MediNeos Observational Research: Current Employment. Ferri:MediNeos Observational Research: Current Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Current Employment. Zomas:Takeda Pharmaceuticals International AG: Current Employment. Gavini:Takeda Pharmaceuticals International AG: Current Employment. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
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Kastritis, Eftathios, Evangelos Terpos, Argiris Symeonidis, Sosana Delimpasi, Michele Cavo, Elena Zamagni, Eirini Katodritou, et al. "Efficacy of Daratumumab with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma and Severe Renal Impairment: An Interim Analysis of a Phase 2 Study (the DARE Study)." Blood 134, Supplement_1 (November 13, 2019): 1881. http://dx.doi.org/10.1182/blood-2019-124630.
Full textAbstract:
Introduction: About 20-40% of patients (pts) with multiple myeloma (MM) present with moderate or severe renal impairment (RI) and about 25% of pts will also experience RI later during the disease course (Dimopoulos MA, et al; Leukemia 2008; 22:1485-1493). Moderate or severe RI is associated with poorer overall survival (OS) and higher risk of early death but also with challenges in the management and administration of the appropriate treatment. Daratumumab, an IgG1κ human monoclonal antibody that targets CD38, has shown efficacy and a favorable safety profile in pts with relapsed or refractory MM (RRMM) both as a monotherapy (Lonial S, et al; Lancet 2016; 387(10027):1551-1560) and in combination with other anti-myeloma agents (Dimopoulos MA, et al; N Engl J Med 2016; 375:1319-1331, and Palumbo A, et al; N Engl J Med 2016; 375:754-766). In population pharmacokinetic analyses, no clinically important differences in exposure to daratumumab were observed between pts with renal impairment and those with normal renal function. However, there are no prospective data on the safety and efficacy of daratumumab in pts with RRMM and severe renal dysfunction or those requiring dialysis. Methods: DARE is an ongoing multicenter, single arm, open-label, phase 2 study, aiming to enroll ~38 adult pts with documented RRMM and severe renal impairment (estimated glomerular filtration rate [eGFR]< 30 ml/min/1.73m2) or in need for hemodialysis. Pts must previously have had ≥ 2 lines of therapy with both bortezomib- and lenalidomide-based regimens and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤ 2. Exclusion criteria include previous treatment with daratumumab or other anti-CD38 therapy. All pts receive 28-day cycles of treatment with daratumumab given intravenously at 16 mg/kg weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, followed by every 4 weeks thereafter, with dexamethasone 40 mg given weekly for each 4-week cycle. The primary endpoint of the study is the evaluation of progression-free survival (PFS). Key secondary endpoints include overall response rate (ORR; defined as the proportion of pts with partial response or better), renal response rate (RRR; defined as the proportion of pts with best response of renal partial response or better), and the assessment of daratumumab safety and tolerability. All responses were based on investigators' assessment per International Myeloma Working Group criteria. This interim analysis presents study results for pts who received the first dose of study treatment at least 3 months prior to the cut-off date (06/05/2019). Results: Eighteen pts, enrolled in 4 centers, were included in this prespecified analysis. The pts' median age was 74.0 years, and most were males (77.8%). The median time from MM diagnosis to first dose of daratumumab was 3.6 years. The number of pts with baseline ECOG PS 0, 1, and 2 were 4 (22.2%), 13 (72.2%), and 1 (5.6%), respectively. At the start of the study, 22.2% and 77.8% of patients had ISS Stage II and III disease, respectively. Moreover, 44.4%, and 55.6% of pts had a revised ISS stage II and III, respectively. Median number of prior lines of therapy was 3.5, and two (11.1%) pts had previous autologous stem cell transplantation; Median eGFR at baseline was 12 mL/min/1.73m2. The median number of therapy cycles received per patient was 4.5. The median time from first daratumumab dose to first partial response or better was 0.9 months. The median follow-up is 4.4 months and the Kaplan-Meier estimate of the 6-month PFS rate is 51.9% (Figure), ORR was 44.4% (8/18 pts) (including VGPR in 4, and PR in 4 pts), and RRR was 27.8% (5/18 pts). By the cut-off date, 10 (55.6%) pts were still on daratumumab; 7 (38.9%) pts discontinued treatment due to progressive disease and 1 (5.6%) due to a fatal serious adverse event (SAE). Overall, ten (55.6%) pts had ≥ 1 AE of grade 3 or 4. Of all grade 3 or 4 AEs, the most frequent were anemia (4, 25%), hyperglycemia (3, 18.8%), and hypocalcemia (2, 12.5%). Three (16.7%) pts suffered a single SAE each: lung infection, sepsis (fatal), and stroke. Conclusions: The combination of daratumumab with dexamethasone is efficacious and with a favorable safety profile and no new safety signals, in pts with RRMM with severe renal impairment. Importantly, hematologic responses are high in these heavily pretreated patients while about 28% achieved also a renal response. The study is ongoing and updated results will be presented at the meeting. Figure Disclosures Kastritis: Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Symeonidis:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi:Genesis: Honoraria, Other: Travel grant; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Cavo:Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene: Speakers Bureau; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria. Zamagni:Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau. Katodritou:Takeda: Honoraria; Janssen: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Gamberi:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Hatjiharissi:Janssen: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.
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Maddocks, Kami J., Johannes Duell, Eva González-Barca, Wojciech Jurczak, Anna Marina Liberati, Sven de Vos, Zsolt Nagy, et al. "Long-Term Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 19–21. http://dx.doi.org/10.1182/blood-2020-140314.
Full textAbstract:
Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) have a poor prognosis. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, which is broadly expressed across B-cell malignancies, including DLBCL. The immunomodulatory drug lenalidomide (LEN) has antiproliferative and antiangiogenic effects. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + LEN in patients with R/R DLBCL who are ineligible for ASCT. L-MIND results from prespecified patient subgroup analyses were presented previously (primary analysis: data cut-off Nov 30, 2018). Here, we report long-term clinical efficacy from the L-MIND study after a median follow-up of 31.8 months for overall survival (OS) (data cut-off: Nov 30, 2019). Methods Patients enrolled were aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen), ASCT-ineligible and with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint is objective response rate (ORR; partial response [PR] + complete response [CR]), assessed centrally by an independent review committee. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), OS and safety analyses. Results Of 81 patients enrolled, 80 patients received tafasitamab + LEN and were included in the full analysis set (FAS) for efficacy. Median follow-up was 22.7 months. In the FAS, ORR was 57.5% (95% confidence interval [CI]: 45.9-68.5) (Figure 1A). The CR rate was 40.0% (n=32/80), of which 90.6% (n=29/32) were PET-confirmed. Median time to response (PR or CR) was 2.0 months and median time to CR was 6.1 months. Median DOR was 34.6 months (95% CI: 26.1-34.6); median PFS was 12.1 months (95% CI: 6.3-not reached [NR]); and median OS was 31.6 months (95% CI: 18.3-NR). The 24-month DOR and OS rates were 71.3% (95% CI: 52.8-83.7) (Figure 1B) and 57.2% (95% CI: 45.1-67.5) (Figure 1C), respectively. In the subgroup analysis, patients with CR as best objective response had better outcomes than those with PR: median DOR, NR (95% CI: 26.1-NR) vs 5.6 months (95% CI: 2.2-34.6); 24-month DOR rate, 86.4% (95% CI: 61.3-95.7) vs 38.5% (95% CI: 14.1-62.8); and 24-month OS rate, 90.6% vs 42.7%. Patients with 1 prior line of therapy had a trend for better outcomes than those with ≥2 prior lines: ORR, 67.5% vs 47.5%; 24-month OS rate, 67.9% vs 46.3%. The 24-month DOR rate was similar by the number of prior lines (1 prior line: 67.9% [95% CI: 42.5-84.0] vs ≥2 prior lines: 77.8% [95% CI: 51.1-91.0]). ORR was similar by primary refractory vs non-primary refractory status (53.3% vs 58.5%); however, primary refractory status impacted 24-month DOR (50.0% vs 74.8%, respectively). Patients refractory to their last line of therapy achieved similar ORRs to those who were not (60.0% vs 55.6%). The 24-month DOR was similar regardless of refractory status to last therapy (Figure 1B), and 24-month OS rates were higher in non-refractory patients (Figure 1C). As expected, patients with a low/low-intermediate International Prognostic Index score had better outcomes than those with an intermediate-high/high score: ORR, 67.5% vs 47.5%; 24-month DOR rate, 92.1% vs 44.3%; and 24-month OS rate, 76.5% vs 36.5%. Based on the Hans algorithm, outcomes were encouraging independent of germinal center B-cell (GCB) DLBCL (n=38) or non-GCB DLBCL (n=22) disease: ORR, 47.4% vs 68.2%; median DOR, 34.6 vs 26.1 months; 24-month DOR rate, 66.7% vs 62.9%; and 24-month OS rate, 51.3% vs 65.0%. Conclusions Long-term L-MIND subgroup data show that encouraging activity observed at primary analysis remains durable after ≥2 years of follow-up; patients with CR continue to experience long DOR and high OS. Although the influence of poor prognosis risk factors is still evident, the clinical activity of tafasitamab in combination with LEN followed by tafasitamab monotherapy continues to show promise in difficult-to-treat ASCT-ineligible patients with R/R DLBCL. Disclosures Maddocks: Pharmacyclics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Duell:Morphosys: Research Funding. González-Barca:Sandoz: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Roche: Honoraria; MorphoSys: Other; Celtrion: Consultancy; Kiowa: Consultancy; Celgene: Consultancy. Jurczak:Janssen, MeiPharma, Merck, Pharmacyclics, Roche, Tekeda, TG Therapeutics: Research Funding; Jagiellonian University: Ended employment in the past 24 months, Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology: Consultancy, Current Employment. Liberati:Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Janssen: Honoraria, Research Funding; Oncopeptides: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Verastem: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Nagy:MorphoSys AG: Patents & Royalties. Obr:Roche: Honoraria. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. André:Celgene: Other, Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Takeda: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment. Dreyling:Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Dirnberger-Hertweck:MorphoSys AG: Current Employment. Weirather:MorphoSys AG: Current Employment. Ambarkhane:MorphoSys AG: Current Employment. Salles:Takeda: Honoraria; BMS/Celgene: Honoraria, Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; Epizyme: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria.
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Deng, Changchun, Mark Lipstein, Luigi Scotto, Yun Hao, Nicholas P. Tatonetti, Michael Mangone, Shirong Li, et al. "Disruption of the mTOR-eIF4F Axis By Selectively Targeting PI3Kdelta and Proteasome Potently Inhibits Cap Dependent Translation of c-Myc in Aggressive Lymphomas." Blood 126, no. 23 (December 3, 2015): 593. http://dx.doi.org/10.1182/blood.v126.23.593.593.
Full textAbstract:
Abstract Background: c-Myc is one of the most frequently altered genes across a vast array of human cancers. Overexpression of c-Myc is observed in up to 30% of cases of diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive lymphoma. Although DLBCL can be cured in 60-70% patients, a substantial minority of patients with DLBCL still die from their lymphoma. There is emerging evidence that c-Myc expression is an adverse risk factor independent of the cell-of-origin classification. To date no drugs that directly target c-Myc have been approved for the treatment of any cancer. In fact, since c-Myc is involved in many normal cellular functions, direct c-Myc inhibitors may be associated with significant toxicity. The goal of our study is to develop novel strategies targeting c-Myc that will have an improved therapeutic index. The c-Myc protein has a very short half-life of less than 30 minutes, and its translation is highly dependent on the eukaryotic initiation factor 4F (eIF4F). eIF4F is activated by the mammalian target of rapamycin (mTOR), which is regulated not only by the PI3K-AKT pathway but also the proteasome pathway. These observations led us to hypothesize that if the proteasome and PI3K pathways cooperate in the activation of mTOR and its downstream target eIF4F, then combinations of proteasome and PI3K inhibitors should potently suppress eIF4F dependent translation of c-Myc and the growth of c-Myc dependent lymphoma. Methods: Cytotoxicity was studied in lymphoma cell lines and primary lymphoma cells using Cell TiterGlo. The Bliss additivism model was used to determine the expected inhibition of cell growth. The difference of the expected and observed levels of inhibition was used to calculate the excess over Bliss (EOB) values. EOB values above 0 indicate synergy, with higher values indicating higher levels of synergy. Mechanisms of synergy were determined through interrogation of PI3K/AKT/mTOR pathway and its downstream targets. Expression of c-Myc was investigated at the translation and transcription levels, using a combination of Western blot, qPCR, and a bi-cistronic luciferase reporter we developed to study cap dependent translation. Gene expression profiling (GEP) studies were conducted using RNAseq, and analyzed by the Fisher t-test and running enrichment score (RES) between different treatment groups. Results: We used a high-throughput platform to screen the cytotoxicity of two PI3Kdelta inhibitors (TGR-1202 & idelalisib/Cal-101), two proteasome inhibitors (bortezomib & carfilzomib), and four combination pairs using these drugs. We found that TGR-1202 and Cal-101 caused only minimal to mild inhibition of lymphoma cells, while bortezomib and carfilzomib caused potent inhibition as single agents. The combination of TGR-1202 and carfilzomib was consistently the most synergistic doublet, while the combination of Cal-101 and bortezomib the least synergistic in numerous lymphoma cell lines studied to date (Figure 1). TGR-1202 and carfilzomib were also highly synergistic in primary lymphoma cells, while Cal-101 and bortezomib were not. Importantly, normal lymphocytes were resistant to the combination of TGR-1202 and carfilzomib. At the molecular level, only the combination of TGR-1202 and carfilzomib potently inhibited mTORC1 dependent phosphorylation of 4E-BP1, leading to marked reduction of c-Myc protein (Figures 2 & 3). In contrast, the combination of TGR-1202 and carfilzomib produced no reduction of the mRNA level of c-Myc (Figures 3). A luciferase reporter demonstrated that the synergistic combination TGR-1202 and carfilzomib specifically inhibited the translation downstream of the 5'UTR of c-Myc (Figure 3). GEP studies confirmed that the canonical c-Myc target genes were potently downregulated at the level of transcription by the combination of TGR-1202 and carfilzomib (Figure 3). These results demonstrate that TGR-1202 and carfilzomib in combination potently inhibited the translation of c-Myc and the c-Myc transcriptional program, which appears to be primarily through disruption of the PI3Kdelta and proteasome pathways that converge on mTOR. Ongoing experiments are focused on confirmation of these observations in vivo. Further, a phase I/II clinical trial evaluating this combination regimen in aggressive c-Myc driven lymphomas is being planned. Disclosures Deng: TG Therapeutics: Research Funding; Gilead: Research Funding; Amgen/Onyx: Research Funding. Lentzsch:Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. O'Connor:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Research Funding; Acetylon: Consultancy, Other: Consultancy fee; Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Other: Consultancy fee; Takeda Millenium: Consultancy, Honoraria, Other: Consultancy fee, Research Funding; Novartis: Consultancy, Honoraria, Other: Consultancy fee; Seattle Genetics: Research Funding; Bayer: Consultancy, Honoraria.
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Madduri, Deepu, Jesus G. Berdeja, Saad Z. Usmani, Andrzej Jakubowiak, Mounzer Agha, Adam D. Cohen, A. Keith Stewart, et al. "CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 22–25. http://dx.doi.org/10.1182/blood-2020-136307.
Full textAbstract:
Background: Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells) is a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity. In the phase 1 LEGEND-2 study in China, LCAR-B38M yielded deep, durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (R/R MM). The phase 1b/2 CARTITUDE-1 study (NCT03548207) is further evaluating cilta-cel in this pt population in the US. We present updated data from the phase 1b portion along with initial phase 2 data. Methods: Eligible pts (aged ≥18 y) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria and had measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 d were used for lymphodepletion. A single infusion of cilta-cel at a target dose of 0.75×106 (range 0.5-1.0×106) CAR+ viable T cells/kg was administered 5-7 d after start of lymphodepletion. The primary objective of the phase 1b portion was to characterize cilta-cel safety and establish the recommended phase 2 dose; the primary objective of the phase 2 portion was to evaluate cilta-cel efficacy. Response was assessed per IMWG criteria and minimal residual disease (MRD) by next-generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0. In the phase 1b portion, cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE v5.0; in the phase 2 portion, CRS and neurotoxicity were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. In this combined analysis, Lee et al and CTCAE v5.0 were mapped to ASTCT criteria for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Results: As of the May 20, 2020 clinical cutoff, 97 pts (58.8% male; median age 61.0 y [range 43-78]) with R/R MM received cilta-cel (29 in phase 1b; 68 in phase 2). Median follow-up duration was 8.8 mo (range 1.5-20.4). Pts had received a median of 6 prior lines of therapy (range 3-18); 83.5% were penta-exposed, 87.6% were triple-refractory, 41.2% were penta-refractory, and 97.9% were refractory to last line of therapy. Overall response rate per independent review committee (primary endpoint) was 94.8% (95% CI 88.4-98.3), with a stringent complete response rate of 55.7% (95% CI 45.2-65.8), very good partial response rate of 32.0% (95% CI 22.9-42.2), and partial response rate of 7.2% (95% CI 3.0-14.3). All pts achieved a reduction in M-protein. Median time to first response was 1.0 mo (range 0.9-5.8; 80.4% ≤1.0 mo), and median time to complete response or better was 1.8 mo (range 0.9-12.5; 74.1% ≤3.0 mo); responses deepened over time (Figure). Median duration of response was not reached (NR). Of 52 MRD-evaluable pts, 94.2% were MRD-negative at 10-5. The 6-mo progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 87.4% (78.9-92.7) and 93.8% (86.7-97.2), respectively; median PFS and OS were NR. Ten deaths occurred during the study; 8 were due to AEs (both related and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myelogenous leukemia [n=1 each]), and 2 due to progressive disease. AEs reported in >70% of pts were CRS (94.8%; grade [gr] 3/4 4.1%), neutropenia (90.7%; gr 3/4 90.7%), anemia (81.4%; gr 3/4 68.0%), and thrombocytopenia (79.4%; gr 3/4 59.8%). Median time to CRS onset was 7.0 d (range 1-12) and median duration 4.0 d (range 1-27, excluding n=1 with 97 d). CAR-T cell-related neurotoxicity was reported in 20.6% of pts (gr 3/4 10.3%). Cilta-cel CAR+ T cells showed maximum peripheral expansion at 14 d (range 9-43). Among pts with 6 mo' individual follow-up, 67% had cilta-cel CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood. Conclusions: Preliminary phase 1b/2 data from CARTITUDE-1 indicate a single low-dose infusion of cilta-cel leads to early, deep, and durable responses in heavily pretreated pts with MM with a safety profile consistent with LEGEND-2. Further investigation of cilta-cel in other MM populations is underway. Disclosures Madduri: Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Berdeja:Teva: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; Celgene: Consultancy, Research Funding; EMD Sorono: Research Funding; Kite Pharma: Consultancy; Prothena: Consultancy; Cellularity: Research Funding; Karyopharm: Consultancy; Servier: Consultancy; Legend: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Kesios: Research Funding; Novartis: Research Funding. Usmani:Celgene: Other; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Patents/Intellectual property licensed, Research Funding. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Htut:City of Hope Medical Center: Current Employment. Munshi:OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; C4: Current equity holder in private company. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; GenMab: Consultancy, Honoraria. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Zhuang:Janssen: Current Employment. Infante:Janssen: Current Employment. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Rizvi:Legend Biotech USA Inc.: Current Employment. Fan:Legend Biotech USA Inc.: Current Employment. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; GSK: Consultancy; Sanofi: Research Funding.
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Perl, Alexander E., Naval G. Daver, Keith W. Pratz, Joseph Maly, Wan-Jen Hong, Erkut Bahceci, Bo Tong, Tian Tian, and Kimberley Dilley. "Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Phase 1b Study." Blood 134, Supplement_1 (November 13, 2019): 3910. http://dx.doi.org/10.1182/blood-2019-127416.
Full textAbstract:
BACKGROUND: The FLT3 tyrosine kinase inhibitor (TKI) gilteritinib improves the survival of patients with relapsed/refractory (R/R) FLT3 mutated (FLT3mut+) acute myeloid leukemia (AML) compared to standard salvage chemotherapy; however, single agent TKI therapy is not curative and long-term survival remains low. Combination therapy with agents that induce apoptosis may enhance cytotoxicity against FLT3mut+ and WT clones and potentially delay or prevent drug resistance. Preclinical data demonstrate that the combination of venetoclax with a FLT3 tyrosine kinase inhibitor is highly synergistic, and BCL-2 inhibition by venetoclax directly triggers apoptosis, which may help overcome resistance to FLT3-targeted therapy. Therefore, we sought to define the safety and activity of venetoclax plus gilteritinib in R/R AML. METHODS: This is a multicenter, open-label, phase 1b clinical trial (NCT03625505) evaluating the safety and efficacy of venetoclax in combination with gilteritinib for patients with relapsed or refractory (R/R) AML. Patients had to have R/R AML and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Here, we present data in patients that had either wild type (WT) or mutated FLT3, and were treated with 400 mg venetoclax in combination with 80 mg or 120 mg gilteritinib daily, from the dose escalation portion of the study. For study purposes, gilteritinib was administered alone for one day. On day two venetoclax was initiated in a three-day ramp-up from 100 to 200 to 400 mg; thereafter, target doses of each were administered, daily, in 28-day cycles unless venetoclax was shortened for cytopenia recovery. Interruptions of venetoclax or both drugs simultaneously were permitted for adverse events (AEs). RESULTS: Data cutoff was July 10, 2019. Of 15 patients enrolled and treated, 5 had WT FLT3 and 10 had mutant FLT3 (8 ITD, 1 TKD, and one with both included with the ITD group). The median age for all patients was 58 (range: 23-81). Both patients with WT or mutant FLT3 had a median of 2.0 prior lines of therapy, with ranges of 2-4 and 1-4 prior lines, respectively. Six (60%) of the FLT3 mutant patients had previously received a FLT3 blocking TKI (2 of those receiving both midostaurin and sorafenib), and 5 (50%) had prior stem cell transplant (SCT). None of the patients with WT FLT3 were FLT3 inhibitor-experienced, and one patient had prior stem cell transplant. Key treatment emergent grade ≥3 AEs across all patients were: febrile neutropenia (47%), anemia (27%), thrombocytopenia (7%) and neutropenia (7%). One patient receiving 80 mg of gilteritinib had a protocol-defined dose limiting toxicity of prolonged neutropenia, and one receiving 120 mg of gilteritinib was still within the protocol-defined count recovery period at analysis. Seven (47%) patients had venetoclax interrupted, the majority due to neutropenia; 3 (20%) patients had gilteritinib interrupted. No cases of tumor lysis syndrome were observed. Pharmacokinetic studies showed comparable drug levels to those observed with single agent use of each drug. Key efficacy results are shown in the Table. Fifty percent of patients with mutant FLT3 achieved CRc, and another 40% of patients achieved morphologic leukemia free state, for an ORR of 90% (9/10). The ORR in patients with WT FLT3 was 20% (1/5). 0-32); this patient had WT FLT3. Among the 5 patients who achieved CRc, 2 had relapse after documented CRi (at 2.6 months and 1.6 months). Patient monitoring is ongoing, and enrollment in an expansion cohort has also commenced (FLT3 mutant patients treated with 400 mg venetoclax plus 120 mg of gilteritinib); results will be updated for the presentation. CONCLUSIONS: Venetoclax in combination with gilteritinib was well tolerated and demonstrated blast clearance in 90% of patients with FLT3 mutated AML. The high overall rate of response in patients with FLT3 mutated AML, particularly in patients with previous FLT3 TKI exposure, suggests venetoclax in combination with gilteritinib may be a highly effective treatment option for AML patients with FLT3mut+, even in patients with relapsed/refractory AML. Disclosures Perl: Bayer: Research Funding; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; BioMed Valley Discoveries: Research Funding; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.. Daver:Otsuka: Consultancy; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Genentech: Consultancy, Research Funding; Agios: Consultancy; Agios: Consultancy; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Astellas: Consultancy; Jazz: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Servier: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; NOHLA: Research Funding; Astellas: Consultancy. Pratz:Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Boston Biomedical: Consultancy; Millenium/Takeda: Research Funding. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Bahceci:Astellas: Employment, Patents & Royalties. Tong:AbbVie: Employment, Other: stock or options. Tian:AbbVie, Inc.: Employment, Other: stock or options. Dilley:AbbVie, Inc.: Employment, Other: stock or options.
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Richardson, Paul G., Craig Hofmeister, Noopur S. Raje, David Siegel, Sagar Lonial, Jacob P. Laubach, Yvonne A. Efebera, et al. "A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)." Blood 126, no. 23 (December 3, 2015): 3036. http://dx.doi.org/10.1182/blood.v126.23.3036.3036.
Full textAbstract:
Abstract Background: The combination of an immunomodulatory drug with the proteasome inhibitor (PI), bortezomib (BORT), and low-dose dexamethasone (LoDEX) has demonstrated preclinical synergy and considerable clinical activity in relapsed and refractory multiple myeloma (RRMM; Mitsiades et al Blood, 2002; Richardson et al Blood, 2014). Treatment (Tx) with the immunomodulatory drug pomalidomide (POM) + LoDEX has been shown to delay disease progression and extend survival in patients (pts) with myeloma previously treated with lenalidomide (LEN) and BORT (Richardson et al Blood, 2014; San Miguel et al Lancet Oncol, 2013). This approach was tested using POM + BORT + LoDEX (PVd) in MM-005; preliminary results showed that PVd was effective and well tolerated in LEN-refractory and BORT-exposed pts. Subcutaneous (SC) BORT was shown to be non-inferior to intravenous (IV) BORT and had an improved safety profile in RRMM (Moreau et al Lancet Oncol, 2011). In addition to a cohort of PVd with IV BORT, MM-005 included a cohort of PVd with SC BORT. Methods: In this phase 1 dose-escalation trial, pts must have received 1-4 lines of prior Tx, with ≥ 2 consecutive cycles of LEN plus a PI. Pts had to be PI exposed and refractory to LEN but not to BORT. A 3 + 3 design with 21-day cycles was used to determine the maximum tolerated dose (MTD). Cycles 1-8 of dose-escalation cohorts received POM (1-4 mg/day on days 1-14), IV or SC BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11), and LoDEX (20 mg/day, or 10 mg/day for pts aged > 75 years, on days 1, 2, 4, 5, 8, 9, 11, and 12) until progressive disease (PD) or unacceptable adverse event (AE). After cycle 8, BORT was administered on days 1 and 8, and LoDEX was administered on days 1, 2, 8, and 9. The primary endpoint was MTD, and secondary endpoints included safety, overall response rate (ORR; ≥ partial response [PR]), duration of response (DOR), and time to response. Results: Of the 34 pts enrolled from March 2012 to August 2014, the median age was 58.5 years (range, 36-76 years) and 59% were male. The median number of prior antimyeloma Tx lines (PAMTL) was 2 (range, 1-4), the proportion of pts with ≥ 2 PAMTL was 56%, and the Eastern Cooperative Oncology Group performance status was ≤ 1 for all pts. All pts were refractory to LEN, and all were exposed to prior PI (33 pts [97%] received prior BORT and 2 pts [6%] received prior ixazomib). All pts discontinued Tx, most commonly due to PD (n = 23), but none due to Tx-related AEs. No dose-limiting toxicities were reported in the dose-escalation cohorts or at the maximum planned dose (MPD) of POM 4 mg, BORT 1.3 mg/m2, and LoDEX 20 mg (10 mg for pts aged > 75 years). The median number of Tx cycles received was 9 (range, 2-36) for all pts and was 11 (range, 2-19) vs 8 (range, 3-15) in the MPD with IV BORT (n = 10) vs SC BORT (n = 12) cohorts. The ORR for all pts was 65% (n = 22), with 2 complete responses (CRs), 1 stringent CR, 10 very good PRs (VGPRs), and 9 PRs; all pts achieved at least stable disease. The median DOR for the 22 responders was 7.4 months. Commonly reported grade 3/4 AEs were more frequent at the MPD level with IV BORT vs SC BORT (90% vs 75%), including neutropenia (60% vs 17%), thrombocytopenia (40% vs 8%), and pneumonia (30% vs 8%). There were no reports of grade 3/4 peripheral neuropathy (PN) or deep vein thrombosis (DVT) in any of the cohorts. Conclusions: PVd was effective, with an ORR of 65% in pts with LEN-refractory and PI-exposed myeloma. PVd was well tolerated, with no grade 3/4 PN or DVT and no Tx discontinuation due to Tx-related AE; toxicities were well managed. Moreover, AEs were generally less frequent with SC vs IV BORT. Thus, the favorable tolerability and efficacy of PVd, which could be a highly attractive therapeutic option in pts with RRMM, is under further evaluation in the large ongoing phase 3 trial MM-007. Disclosures Richardson: Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide in combination with bortezomib. Raje:BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Onyx: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Acetylon: Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; Celgene Corporation: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Nooka:Spectrum Pharmaceuticals: Consultancy; Onyx: Consultancy. Zaki:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Anderson:Oncocorp: Equity Ownership; Celgene Corporation: Consultancy; acetylon pharmaceuticals: Equity Ownership; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy.
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Borthakur, Gautam M., William B. Donnellan, Scott R. Solomon, Camille Abboud, Aziz Nazha, Milena Mazan, Michal Mikula, et al. "SEL120 - a First-in-Class CDK8/19 Inhibitor As a Novel Option for the Treatment of Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome - Data from Preclinical Studies and Introduction to a Phase Ib Clinical Trial." Blood 134, Supplement_1 (November 13, 2019): 2651. http://dx.doi.org/10.1182/blood-2019-127835.
Full textAbstract:
Deregulated transcription, one of the key features of acute myelogenous leukemia (AML), remains largely unactionable by recently approved therapies. Preclinical studies indicate that targeting Cyclin Dependent Kinase 8 (CDK8) may be a novel therapeutic strategy for AML. CDK8 and its paralog CDK19, restrain activation of super-enhancer-associated tumor suppressors and lineage commitment genes in AML cells. SEL120 is a first-in-class, specific and selective inhibitor of CDK8/CDK19 and has shown activity in preclinical AML models. Preclinical characterization of SEL120 demonstrated a unique mechanism of action, related to known functions of CDK8 in the regulation of transcription. Cells sensitive to SEL120 show enrichment for leukemia stem cells (LSCs) signatures and higher signal transducer and activator of transcription 5 (STAT5) levels. Treatment with SEL120 reduced STAT5 phosphorylation in sensitive cell lines both in vitro and in vivo. Transcriptomic analysis of AML cells revealed that SEL120 regulated genes involved in lineage controlling functions. Specifically, trimethylation of lysine 27 on histone H3 (H3K27me3) by the polycomb repressive complex 2 (PRC2), was proposed to maintain the stemness of LSCs by preventing differentiation. Derepression of lineage commitment genes marked with H3K27me3, was one of the earliest transcriptional events in sensitive cells treated with SEL120. Consistent with its transcriptional effects, SEL120 induced differentiation of AML cells. Additionally SEL120 significantly repressed the MYC Proto-Oncogene-dependent transcriptomic signatures. Efficacy of SEL120 in AML was confirmed in models with high translational potential, including patient-derived AML cells (PDC) in vitro and in vivo. PDCs treated with SEL120 showed reduced viability, induction of apoptotic cell death and differentiation commitment. Administration of SEL120 in orthotopic AML patient-derived xenograft models reduced tumor burden to the level undetectable by flow cytometry, decreased splenomegaly and resulted in partial bone marrow recovery. CLI120-001 is a first-in-human, open-label, multi-center, modified 3+3 dose escalation phase Ib study of SEL120 with a dose-escalation cohort (DC) followed by an enrichment cohort (EC) in adult patients with AML or high-risk myelodysplastic syndrome who have relapsed or refractory disease and have received no more than 3 prior lines of therapy. Other key inclusion criteria are Eastern Cooperative Oncology Group performance status of 0-2, white blood cell (WBC) count <10000/µL (prior hydroxyurea is permitted to reduce WBC), platelet count >10000/µL, adequate organ function defined as: aspartate aminotransferase and alanine aminotransferase ≤3x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine clearance ≥60 ml/min, left ventricular ejection fraction ≥40%. Major exclusion criteria include Q to T wave interval corrected for heart rate (QTc) ≥450 ms, taking concomitant medications that are known to be strong inhibitors or inducers of cytochrome P450 1A2 or that can prolong QTc and/or cause torsade de pointes. The primary objective of the study is to assess safety and tolerability of SEL120 and to establish the recommended dose (RD) for further clinical development. Secondary objectives include evaluation of preliminary anti-leukemic activity and characterization of the pharmacokinetic profile of SEL120. The exploratory objective is to assess pharmacodynamics of SEL120 by using relevant biomarkers, including STAT5 pS726, transcriptional profiling by RNAseq and immunophenotypic changes related to stemness and differentiation of AML cells. SEL120 is administered as a single oral dose every other day for a total of 7 doses i.e. on days 1, 3, 5, 7, 9, 11 and 13, in a 21-day treatment cycle. Patients receive SEL120 until disease progression, unacceptable toxicity, or withdrawal of consent. The DC is now enrolling patients who are treated at dose levels defined by a modified Fibonacci sequence, and will end with selection of the RD based on all available study data. In the EC, additional patients will be treated at the RD to further support the evaluation of the RD of SEL120 monotherapy. The study is currently running in the United States and is planned to be completed in 2020. The ClinicalTrials.gov Identifier: NCT04021368. Disclosures Borthakur: Eli Lilly and Co.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Strategia Therapeutics: Research Funding; BMS: Research Funding; PTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; AbbVie: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Mazan:Selvita S.A.: Employment. Majewska:Selvita S.A.: Employment. Wiklik:Selvita S.A.: Employment. Golas:Selvita S.A.: Employment. Bialas:Selvita S.A.: Employment. Windak:Selvita S.A.: Employment. Juszczynski:Selvita S.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chrom:Selvita S.A.: Employment. Rzymski:Selvita S.A.: Employment, Equity Ownership. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Jaeger, Ulrich, Nina Worel, Joseph P. McGuirk, Peter A. Riedell, Isabelle Fleury, Peter Borchmann, Jufen Chu, et al. "Portia: A Phase 1b Study Evaluating Safety and Efficacy of Tisagenlecleucel and Pembrolizumab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5325. http://dx.doi.org/10.1182/blood-2019-129120.
Full textAbstract:
Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after ≥ 2 prior lines of therapy. T-cell exhaustion due to an immunosuppressive environment has been a hypothesized mechanism for CAR-T cell therapy failure. Subgroup analyses of the JULIET trial suggested an association between programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) interaction in baseline biopsies and lack of response (Agoulnik et al. EHA. 2018). Moreover, the anti-PD-1 monoclonal antibody pembrolizumab has shown clinical activity in r/r DLBCL after failing tisagenlecleucel therapy (Chong et al. Blood. 2017). PORTIA is a phase 1b, multicenter, open-label trial investigating the safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL. We report data from a completed cohort of the ongoing study. Methods: Eligible patients must be ≥ 18 years old with a confirmed diagnosis of DLBCL that has relapsed after or is refractory to ≥ 2 prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients treated with prior allogeneic stem cell transplantation, anti-CD19 therapies, or checkpoint inhibitors are excluded. Lymphodepleting chemotherapy consists of fludarabine-cyclophosphamide. Patients receive a single tisagenlecleucel intravenous infusion (target dose: 0.6-6.0x108 cells) on Day 1. Pembrolizumab is given at 200 mg every 21 days, for up to 6 doses. Pembrolizumab was started on Day 15 post-tisagenlecleucel in Cohort 1, with the option of moving to Day 8 or 22 in subsequent cohorts, based on observed data and guided by a Bayesian Logistic Regression Model with Escalation with Overdose Control principle, evaluating the distribution of dose-limiting toxicities (DLTs) occurring in the 21 days following the first pembrolizumab dose. As per study protocol, a total of 20 patients will be treated at the optimal dose timing. Primary endpoints are the proportion of patients receiving pembrolizumab per protocol schedule, the incidence of DLTs in the dose-timing selection phase, and the overall response rate in the dose-expansion phase. Secondary outcomes include duration of response, progression-free survival, overall survival, safety, cellular kinetics, and immunogenicity. Results: As of 5 March 2019, 5 patients were screened for Cohort 1. Four patients were enrolled and received tisagenlecleucel and pembrolizumab. Median age was 54 (range, 35-79). Median follow-up from time from tisagenlecleucel infusion to data cut-off was 46 days (range, 36-85). Patients received 1.7-3.0x108 CAR-positive T cells, and 1, 2, 2 and 4 pembrolizumab doses, respectively, with no delays. All 4 patients experienced at least 1 adverse event (AE), with no exacerbation or recurrence of tisagenlecleucel-related AEs following pembrolizumab infusion. No pembrolizumab-related AEs were observed. No DLTs or grade 3-4 treatment-related adverse events (TRAEs) were observed. TRAEs and AEs are summarized in Table 1. Two patients discontinued pembrolizumab treatment (after 1 and 2 doses, respectively) due to disease progression. All 4 patients experienced initial expansion between Days 6 and 15 post-tisagenlecleucel infusion, with peak transgene levels ranging from 1,980 to 77,200 copies/µg DNA (Figure 1). No secondary expansion was observed after pembrolizumab administration. The overall exposure is consistent with the observed exposure in r/r DLBCL patients in the JULIET trial. With very limited follow-up, 1 partial response has been observed. Cohort 2 (pembrolizumab starting Day 8) was ongoing at the time of submission. Conclusions: Overall, PD-1 blockade with pembrolizumab on Day 15 after tisagenlecleucel infusion was feasible and showed a manageable safety profile in the first 4 patients. No DLTs and no clinically significant exacerbation of AEs were observed, supporting the initiation of Cohort 2. Efficacy and safety data with an updated cutoff for Cohort 1 and new data from Cohort 2 will be presented at the congress. Clinical trial information: NCT03630159. Disclosures Jaeger: Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau. Fleury:AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chu:Novartis: Employment. Abdelhady:Novartis: Employment. Forcina:Novartis: Employment. Bubuteishvili Pacaud:Novartis: Employment. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy.
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Raab, Marc S., Enrique M. Ocio, Sheeba K. Thomas, Andreas Günther, Yeow-Tee Goh, Daniel Lebovic, Andrzej Jakubowiak, et al. "Phase 1 Study Update of the Novel Pan-Pim Kinase Inhibitor LGH447 in Patients with Relapsed/ Refractory Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 301. http://dx.doi.org/10.1182/blood.v124.21.301.301.
Full textAbstract:
Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.
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Hájek, Roman, Jarkovsky Jiri, Bouwmeester Walter, Treur Maarten, DeCosta Lucy, Campioni Marco, Brozova Lucie, and Gonzalez-McQuire Sebastian. "Predictors of Overall Survival (OS) in Patients with Multiple Myeloma (MM) Initiating First- and Second-Line Treatment in the Czech Republic." Blood 128, no. 22 (December 2, 2016): 3607. http://dx.doi.org/10.1182/blood.v128.22.3607.3607.
Full textAbstract:
Abstract MM is a heterogeneous disease. The International Staging System (ISS) and the revised-ISS (R-ISS) can be used to stratify patients in terms of risk of mortality in newly-diagnosed MM (NDMM) however; there is less understanding of the predictors of OS in the relapsed setting. This retrospective analysis of the Registry of Monoclonal Gammopathies database, which covers ~80% of all Czech patients with MM, was designed to explore how predictors of OS differ between initiation of first- and second-line treatments, in order to further understand patient heterogeneity as the disease progresses. Eligible patients initiated first-line treatment for symptomatic MM between May 2007 and April 2016. Factors considered prognostic of OS in both NDMM and relapsed/refractory MM were identified from targeted literature searches. Predictors of OS in second-line treatment included historical parameters that reflect outcomes to previous therapy. OS data was then fitted with multiple Cox-regression models. Backward selection was performed using Akaike's Information Criterion (AIC) as selection criterion. Patient characteristics at both first- (N=3027) and second-line (N=1418) treatment initiation are presented in Table 1. Comparison of these characteristics shows that as patients progress, on average their profile becomes less severe (e.g. ISS stage III 28% vs 20% in first- and second-lines, respectively), mainly explained by the dropout rate between first- and second-line treatment (Raab et al 2016) as patients either died or did not continue therapy due to adverse prognosis. Median OS (95% CI) from initiation of first- and second-line treatment was 49.9 (46-54) and 27.6 (25-30) months. Results of OS predictive variables are shown in Table 2. Predictors of OS differ between initiation of first-line versus second-line therapy, both in terms of type of predictor as well as strength. At initiation of first-line, calcium level, bone lesions and bone marrow aspiration cytology were not significant predictors of OS, however they became significant at initiation of second-line or were selected by backward selection procedure. At initiation of second-line, historical parameters defining outcomes of prior treatments remained strong predictors, however only refractory status to prior bortezomib [HR=1.626 (1.267-2.087 p=0.0001)] and time to next treatment (TTnT) [HR=1.280 (1.051-1.559, p=0.014)] were significant predictors of OS. The significance of prediction of age and Eastern Cooperative Oncology Group (ECOG) performance status remained in both settings, with a lower impact of age in second-line treatment. Data for cytogenetics was not collected for initiation of second-line, however it is included in the R-ISS component. Although only measured at diagnosis, it remained a significant predictor in both settings (N.B. this variable had 82% missing values). Restaging of ISS at initiation of second-line was predictive, especially for those ISS III vs ISS I, HR=1.56 (1.23-1.97 p=0.0002). Additionally, lactate dehydrogenase (LDH), which is also a component of R-ISS was significant in both settings with as stronger effect in second-line. Elements normally considered predictive of OS at initiation of second-line did not appear in the final model: prior stem-cell transplant status or time-to-progression of previous therapy, perhaps explained by age and TTnT, respectively. Creatinine level was not significant at initiation of second-line, perhaps as patients with renal impairment during first-line treatment may not receive second-line treatment. This real-world analysis of data from Czech patients revealed that predictors of OS differ between initiation of first- and second-line treatments. Prediction of OS in the relapsed setting should consider patient-related factors (age, ECOG), factors reflecting the disease activity and severity (LDH, bone lesion, calcium level) as well as historical elements, including those that were dependent on patient experience in the first treatment line (treatment response and duration of response). Additionally, there seems to be value in reclassification of patients in terms of severity at the relapse setting in order to improve prognosis and treatment selection in the relapsed setting. Disclosures Hájek: Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; BMS: Honoraria; Janssen: Honoraria. Jiri:Amgen: Consultancy. Walter:Amgen: Consultancy. Maarten:Amgen: Consultancy. Lucy:Amgen: Employment, Other: Amgen Stock. Marco:Amgen: Employment, Other: Holds Amgen Stock. Lucie:Amgen: Consultancy. Sebastian:Amgen: Employment, Other: Holds Amgen Stock.
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Gasparetto, Cristina, Brea Lipe, Sascha A. Tuchman, Natalie S. Callander, Suzanne Lentzsch, Muhamed Baljevic, Adriana C. Rossi, et al. "Selinexor in Combination with Carfilzomib and Dexamethasone, All Once Weekly (SKd), for Patients with Relapsed/Refractory Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 14–15. http://dx.doi.org/10.1182/blood-2020-137183.
Full textAbstract:
Background : Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins that cause cell cycle arrest and apoptosis in cancer cells. The combination of SEL with dexamethasone (dex), each administered twice weekly (BIW), received accelerated approval from the FDA in relapsed refractory multiple myeloma (RRMM). Subsequent evaluations of combination regimens have utilized once weekly (QW) SEL. The addition of oral SEL 100 mg QW to bortezomib also QW with dex (SVd) showed superior PFS and ORR with reduced peripheral neuropathy compared with standard BIW bortezomib plus dex (Dimopoulos et al. JCO 2020). SEL sensitized the activity of carfilzomib (CAR) in PI-resistant MM cell lines in vitro and ex vivo in PI-refractory MM cells derived from bone marrow aspirates of patients (pts) with RRMM. SEL and CAR also showed synergistic anti-tumor activity in a NOD-SCID mice xenograft model in vivo. Furthermore, a phase I trial in RRMM pts demonstrated that the combination of SEL and CAR both administered BIW with DEX showed high overall response rates (ORR) in pts with MM refractory to CAR. Carfilzomib QW was recently approved and we hypothesized that the addition of SEL QW to CAR QW plus dex (SKd) would be synergistic and convenient with an acceptable adverse event (AE) profile. Methods: STOMP is a phase 1b/2 multicenter, open-label, clinical trial with the goals of determining the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the ORR according to the International Myeloma Working Group (IMWG) criteria. The starting SEL dose was 100 mg QW with 20/56 mg/m2 QW CAR (20 mg/m2 only on C1D1 and 56 mg/m2 thereafter, dosed Day 1, 8, and 15, 28 days cycle) with 40 mg QW DEX (Table 1). Eligible pts had MM progressing on study entry that was not refractory to CAR, were ≥ 18 years old, with Eastern Cooperative Oncology Group (ECOG) score of 0-2, WBC ≥ 1,500/mm3,Hb ≥ 8.0 g/dL, and platelet count ≥ 75,000/mm3. Results: The MTD was 20/56 mg/m2 CAR + 80 mg SEL + 40 mg DEX, all given QW. As of May 1, 2020, a total of 24 pts enrolled, of which 17 received the MTD. Median age was 70.5 (range, 50-76) years, 62.5% male, median number of prior therapies 3 (range, 1-8). Median years from initial diagnosis 5.0 (range, 2.7-11.3) years. Prior therapies in the 24 pts included bortezomib 24 pts (100%), lenalidomide 23 pts (95.8%), pomalidomide 15 pts (62.5%), daratumumab 14 pts (58.3%) and 19 (79.2%) stem cell transplantation. Common hematopoietic treatment-related AEs (TRAEs) were thrombocytopenia (70.8% all grades, 54.2% grades 3/4) and anemia (54.2%, 20.8%). Common non-hematological TRAEs were nausea (66.7%, 0%), fatigue (54.2%, 8.3%), anorexia (45.8%, 4.2%), weight loss (37.5%, 0%), and dysgeusia (37.5%, 0%). All TRAEs were expected and manageable with appropriate supportive care (eg, TPO receptor agonists for thrombocytopenia) and/or dose modifications; long term cumulative toxicities have not been observed. ORR was 75.0% including 4 CR (16.7%), 7 VGPR (29.2%) and 7 PR (29.2%). There was 1 MR yielding a clinical benefit rate of 79.2%. Amongst the 14 pts previously treated with daratumumab, 8 pts (57.1%) achieved ≥PR, 9 pts (64.3%) achieved ≥MR. Median time to the first response (≥PR) was 28 days (range, 27-98 days). Median progression free survival has not been reached with a median follow-up of 4.4 months. Conclusions: Weekly SKd (20/56 mg/m2 CAR + 80 mg SEL QW + 40 mg DEX QW) is active with an ORR of 75.0% and deep responses (CR 16.7%, VGPR 29.2%) in pts who had a median of 3 prior lines of therapy including bortezomib and lenalidomide. The ORR of 57.1% in patients previously treated with daratumumab warrants further investigation of this once weekly regimen in 1st or 2nd relapse including among patients with prior daratumumab. Disclosures Lipe: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Tuchman:Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding; Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Lentzsch:Sanofi: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Celularity: Consultancy; Sorrento: Consultancy; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Karyopharm: Research Funding. Baljevic:NCCN Hematologic Malignancies Congress: Honoraria; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Exelixis: Research Funding; MediCom Myeloma CME: Honoraria. Rossi:BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. White:Sanofi: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Chen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Kotb:Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Research Funding. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Schiller:MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding.
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Sehn, Laurie H., Matthew J. Matasar, Christopher R. Flowers, Manali Kamdar, Andrew K. McMillan, Mark Hertzberg, Sarit Assouline, et al. "Polatuzumab Vedotin Plus Bendamustine with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study." Blood 134, Supplement_1 (November 13, 2019): 4081. http://dx.doi.org/10.1182/blood-2019-123449.
Full textAbstract:
Introduction: Antibody-drug conjugate polatuzumab vedotin (pola) targets CD79b on B-cell non-Hodgkin lymphoma. Cytopenias and peripheral neuropathy (PN) are typical pola-associated adverse events (AEs). We reported significantly higher positron emission tomography-complete response (PET-CR) rates and improved duration of response (DOR), progression-free survival (PFS) and overall survival (OS) with pola + bendamustine-rituximab (BR) vs BR in patients (pts) with R/R DLBCL (Sehn et al. ASH 2018). With an additional year of follow up, we report updated results for the Ph Ib/II DLBCL cohorts (NCT02257567). Methods: Methods were previously reported (Sehn et al. ASH 2018). Safety-evaluable population combined Ph Ib and randomized (RAN) Ph II pola + BR arms (N=45) vs RAN BR (N=39) arm. Longer-term safety outcomes for PN and second malignancies were evaluated. Efficacy reported separately for Ph Ib/II RAN DLBCL arms per investigator (INV) assessment. Additional outcomes including DOR for pts with confirmed responses (defined as having two consecutive responses) were assessed. Results: As of March 15 2019, median follow up for pts with R/R DLBCL in the Ph Ib (N=6) and Ph II RAN arms (N=80) was 46 and 30 months (mo), respectively. In the RAN Ph II (pola + BR [N=40]; BR [N=40]; 39 treated per arm), baseline characteristics were largely balanced with median 2 prior lines of therapy; 28% vs 30% of pts had 1 prior line, 28% vs 23% had 2, 45% vs 48% had ≥3 in the pola + BR vs BR arms, respectively. Most pts (75% vs 85%) were refractory to last prior treatment. PN events occurred in 40% (18/45) of pts treated with pola + BR (all grade [Gr] 1-2). At clinical cutoff, median time to PN resolution was approx. 8 days (range 0-69) with 56% (10/18) of pts experiencing complete resolution of PN. Eight pts had ongoing PN: 4 discontinued study early due to death from disease progression or AE (further follow up for PN resolution not possible), 3 had unresolved Gr 1 PN, and 1 had improving PN (max. Gr 1). Second malignancies occurred in 4% (2/45) of pts treated with pola + BR (1 prostate cancer; 1 squamous cell carcinoma and myelodysplastic syndrome [MDS]) and 5% (2/39) of pts in the BR arm (1 epiglottic carcinoma and MDS; 1 papillary thyroid cancer). In the Ph II RAN arms (pola + BR vs BR) updated median INV-assessed PFS (95% confidence interval [CI]) was 7.5 (4.9, 17.0) vs 2.0 (1.5, 3.7) mo (hazard ratio [HR] 0.33; 95% CI 0.20, 0.56); median OS (95% CI) was 12.4 (9.0, 32.0) vs 4.7 (3.7, 8.3) mo (HR 0.41; 95% CI 0.24, 0.71), respectively (Figure). Median time to first response was 2 mo (range 1.8-5.3). Median DOR (95% CI) for all responding pts in the pola + BR (N=28) vs BR (N=13) arms was 12.7 (5.8, 27.9) vs 4.1 (2.6, 12.7) mo (HR 0.42; 95% CI 0.19, 0.91). Median DOR (95% CI) for confirmed responders in the pola + BR (N=19) vs BR (N=7) arms was 27.9 (10.3, NE) vs 12.7 (7.7, NE) mo (HR 0.44; 95% CI 0.14, 1.32). Nearly half (47%, 9/19) of pts with confirmed responses to pola + BR remained event free at clinical cutoff with 8 pts in CR and 1 pt in partial response (downgraded from CR due to missing bone marrow biopsy based on modified Lugano Criteria). Of these 9 pts, 8 had DORs ranging from 22+ to 34+ mo (1 pt consolidated with allogeneic transplant) and 1 pt withdrew early from study after 14.5 mo of response. In the BR arm, 2 pts maintained responses without events; both had consolidative therapy (1 radiation, 1 allogeneic transplant). Baseline characteristics of pts with confirmed responses in the pola + BR arm are shown in the Table. In the Ph Ib cohort, 3/6 pts were confirmed responders: 1 pt progressed at 45 mo, 2 pts had ongoing responses of 29+ and 44+ mo, respectively. Conclusions: No new safety signals were identified with longer follow-up. PN events were low grade, manageable and mostly reversible. Adding pola to BR did not increase risk of second malignancies. While median time-to-event endpoints have not changed significantly since the last data cut, longer follow-up demonstrates notable durability of response in a proportion of pts treated with pola + BR, many of whom had refractory disease and received multiple lines of prior therapy. Pola + BR represents a promising new treatment for pts with transplant-ineligible R/R DLBCL. Disclosures Sehn: Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Acerta: Consultancy, Honoraria. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other. Flowers:BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Karyopharm: Consultancy; Optimum Rx: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Gilead: Consultancy, Research Funding; Spectrum: Consultancy; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; Acerta: Research Funding; Burroughs Wellcome Fund: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Millenium/Takeda: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy. Kamdar:Seattle Genetics: Speakers Bureau; Genentech: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. McMillan:Pfizer: Honoraria, Research Funding; MSD: Honoraria; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Sandoz: Honoraria; Gilead: Honoraria; Novartis: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau. Hertzberg:Pfizer: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Novartis: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Bayer: Consultancy. Kim:F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding. Ozcan:F. Hoffmann-La Roche Ltd: Other: Travel, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria; Jazz: Other: Travel; Sanofi: Other: Travel; BMS: Other: Travel; MSD: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Abdi Ibrahim: Other: Travel; Janssen: Research Funding, Travel; Celgene: Research Funding; Bayer: Research Funding; Archigen: Research Funding. Croft:Genentech, Inc.: Employment. Hirata:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Cheng:F. Hoffmann-La Roche Ltd: Employment. Ku:Genentech, Inc.: Employment. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. OffLabel Disclosure: GO29365 (pola + BR vs BR in relapsed/refractory DLBCL). Rituximab (Rituxan) is approved for use in relapsed/refractory low-grade NHL and in previously untreated DLBCL with CHOP, but is not approved for use in relapsed/refractory DLBCL. Bendamustine (Levact) is approved for use in relapsed indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Polatuzumab vedotin (Polivy) is approved for use in third-line or later treatment of R/R DLBCL in the USA.
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Daver, Naval G., Pau Montesinos, Daniel J. DeAngelo, Eunice S. Wang, Nikolaos Papadantonakis, Eric Deconinck, Harry P. Erba, et al. "A Phase I Study of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia, Blastic Plasmacytoid Dendritic Cell Neoplasm, and Other CD123-Positive Hematologic Malignancies." Blood 134, Supplement_1 (November 13, 2019): 1334. http://dx.doi.org/10.1182/blood-2019-128275.
Full textAbstract:
Background: Overexpression of CD123, the alpha subunit of the IL-3 receptor, occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others, thus making this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against AML, BPDCN and ALL models, with a wide therapeutic index in animal models, as well as a 150-fold differential cytotoxicity in AML patient samples compared to normal hematopoietic progenitors (PMIDs: 29661755, 30361418). Remarkable sensitivity of BPDCN patient derived xenografts to IMGN632 has been demonstrated (Blood 2018 132:3956). These findings suggest a potential profile of robust efficacy and favorable tolerability in multiple hematologic malignancies. Study Design and Methods: This open-label Phase 1 study comprises a dose escalation phase designed to establish the maximum tolerated dose (MTD) for IMGN632 administered using two dosing schedules, as well as subsequent dose expansion cohorts to further explore the safety and preliminary anti-leukemia activity of IMGN632 in relapsed AML and BPDCN. Adult patients with CD123-positive, relapsed or refractory AML or BPDCN, may be eligible to enroll. Additional inclusion criteria include up to 3 prior lines of therapy (which may include transplant) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Patients with active central nervous system disease, history of veno-occlusive disease of the liver, or history of grade 3-4 capillary leak syndrome or non-cardiac grade 3-4 edema are ineligible. Two schedules have been evaluated during dose escalation: Schedule A, IMGN632 administered intravenously on Day 1 of a 21-day cycle (Q3W); and Schedule B, fractionated dosing (i.e. one-third total dose) of IMGN632 administered on Days 1, 4, and 8 of a 21-day cycle. IMGN632 was escalated from 0.015 to 0.45 mg/kg on Schedule A in both AML and BPDCN patients, and from 0.015 to 0.06 mg/kg on schedule B in patients with AML. Escalation on both schedules is complete. Currently, two expansion cohorts have been opened, with patients receiving IMGN632 at 0.045 mg/kg IV Q3W. In cohort 1, a total of 50 relapsed/refractory BPDCN patients are planned to assess the activity of IMGN632 in this population; prior SL-401 is allowed. In cohort 2, 20 relapsed AML patients (1 or 2 prior lines of therapy, and who have previously achieved a complete response) will be enrolled to aid in the design of future monotherapy and combination studies. Given the rarity of BPDCN, and the lack of therapeutic options for relapsed/refractory patients, enrollment of these patients continues with high priority. Clinical results from this study and the design of the phase 1b/2 combination study are reported in separate abstracts. Clinical trial information: NCT03386513. Disclosures Daver: Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Celgene: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. DeAngelo:Abbvie: Research Funding; Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Papadantonakis:Agios: Consultancy, Honoraria. Erba:Pfizer: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy. Pemmaraju:mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding. Sloss:ImmunoGen: Employment. Culm-Merdek:ImmunoGen Inc: Employment. Wang:ImmunoGen Inc: Employment. Malcolm:ImmunoGen Inc: Employment. Zweidler-McKay:ImmunoGen: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding.
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Richardson, Paul G., Akshanth R. Polepally, Monica Motwani, Yunming Mu, Zeena Salman, Sudhir Penugonda, and Philippe Moreau. "A Phase 1b, Open-Label Study of Eftozanermin Alfa in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 16–17. http://dx.doi.org/10.1182/blood-2020-137037.
Full textAbstract:
Background Many patients (pts) with multiple myeloma (MM) will relapse after treatment or become refractory to all therapies currently available. For these pts, the prognosis is poor and there is a clear unmet need to identify agents with novel mechanisms of action. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has a distinct role in the induction of apoptosis in tumor cells, and activating this pathway could represent an attractive therapeutic approach. Early generation TRAIL receptor agonists had minimal efficacy in pts with MM, which may be due to suboptimal TRAIL receptor clustering. Eftozanermin alfa (formerly ABBV-621) is a next-generation TRAIL receptor agonist specifically designed to optimize receptor clustering. The ongoing first-in-human study of eftozanermin alfa (NCT03082209) demonstrated a tolerable safety profile in pts with previously treated solid tumors and hematologic malignancies. Preclinical ex vivo and in vivo models of MM indicate combinatorial activity of eftozanermin alfa with proteasome inhibitors (PIs) resulting in enhanced efficacy. The addition of eftozanermin alfa to the well-established regimen of the PI bortezomib and dexamethasone may improve efficacy outcomes in pts with relapsed/refractory (R/R) MM. Study Design and Methods This is a phase 1b, open-label, nonrandomized, multicenter study enrolling pts (≥18 years, Eastern Cooperative Oncology Group score 0-1) with R/R MM. Approximately 40 pts are planned for enrollment. The primary objectives of the study are to determine the recommended phase 2 dose (RP2D) of eftozanermin alfa when given in combination with bortezomib and dexamethasone, and to assess the efficacy of this combination on the basis of overall response rate (ORR). Secondary objectives include assessing the safety and tolerability of eftozanermin alfa with bortezomib and dexamethasone and evaluating the rate of very good partial response (VGPR) or better, the duration of response (DOR), and pharmacokinetics (PK). Key inclusion criteria are pts with R/R MM who have received at least 3 but no more than 6 prior lines of therapy (including an immunomodulatory agent, a PI, and an anti-CD38 antibody) and have documented disease progression during or after the most recent therapy. Pts must also have measurable disease per standard International Myeloma Working Group (IMWG) criteria at baseline and adequate hematologic, hepatic, and renal function. Pts will be excluded if they have primary refractory disease, received bortezomib in the most recent prior therapy, or have peripheral neuropathy grade ≥2 or grade 1 with pain. The study consists of a screening period, a treatment period, and a follow-up period; dosing schedule details are presented in Figure. After screening, pts will receive eftozanermin alfa with bortezomib and dexamethasone until unacceptable toxicity, confirmed progressive disease, or other protocol-specified reasons for discontinuation are met. Treatment may continue for maximum 12 cycles. A safety lead-in will be performed to determine the RP2D of eftozanermin alfa when combined with bortezomib and dexamethasone. Dose escalation during the safety lead-in will be guided using a Bayesian optimal interval design with a target toxicity rate of 33%. The primary efficacy endpoint is the ORR, defined as the proportion of pts with partial response or better per IMWG criteria. Other efficacy endpoints include DOR, VGPR or better rate, and progression-free and overall survival. For all binary endpoints, the estimated proportion and associated 2-sided 90% Clopper-Pearson exact confidence intervals will be provided. The time-to-event endpoints will be summarized using the Kaplan-Meier method. Safety evaluations will include assessment of dose-limiting toxicities during cycle 1 of the safety lead-in, and monitoring of adverse events, vital signs, and clinical laboratory measures throughout the study. Samples for PK analysis, biomarker assessments, and assays for antidrug and neutralizing antidrug antibodies will be obtained at protocol-specified visits. Biomarker analyses may include evaluation of death receptor 4/5 expression, chromosomal abnormalities, and minimal residual disease status. Approximately 20 sites in 6 countries are planned to be involved in the study, which is anticipated to start in September 2020. Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Polepally:AbbVie: Current Employment, Other: may hold stock or stock options.. Motwani:AbbVie: Current Employment, Current equity holder in publicly-traded company. Mu:AbbVie: Current Employment, Other: may hold stock or stock options.. Salman:AbbVie: Current Employment, Other: may hold stock or stock options.. Penugonda:AbbVie: Current Employment, Other: may hold stock or stock options.. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.
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Karmali, Reem, Hagop Youssoufian, Kam Sprott, David T. Weaver, Narayana Narasimhan, Stephanie Lustgarten, Gloria Patrick, Alena Zalutskaya, and Leo I. Gordon. "A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)." Blood 134, Supplement_1 (November 13, 2019): 5251. http://dx.doi.org/10.1182/blood-2019-124406.
Full textAbstract:
Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.
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Fowler, Nathan H., Judith Trotman, Rebecca Auer, Christopher R. Flowers, William F. Reed, Elena Ivanova, Jane Huang, and Pier Luigi Zinzani. "Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)." Blood 134, Supplement_1 (November 13, 2019): 5252. http://dx.doi.org/10.1182/blood-2019-122628.
Full textAbstract:
Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. First generation BTK inhibitor ibrutinib has limited activity as monotherapy in R/R FL (Gopal et al. J Clin Oncol 2018). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. In preclinical studies, zanubrutinib had minimal inhibitory effects against ITK and did not inhibit ITK-mediated anti-CD20-induced antibody-dependent cell-mediated cytotoxicity (Li et al. Cancer Res 2015). Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma (NHL), Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib was generally well tolerated amongst pts with B cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1b dose-escalation study including 36 pts with R/R FL (median 2 [range, 1-9] prior lines of therapy) treated with the combination of zanubrutinib with anti-CD20 antibody obinutuzumab reported an overall response rate (ORR) of 72.2% including complete response in 14 pts (38.9%); median progression-free survival was 24.9 mo (Tam et al. ICML 2019). Study Design and Methods: This ongoing phase 2, global, randomized, open-label, active-controlled study (ROSEWOOD; NCT03332017) is examining zanubrutinib + obinutuzumab vs. obinutuzumab monotherapy in pts with R/R FL who have received ≥2 prior lines of therapy (Figure). Eligible pts must have histologically-confirmed grade 1-3a B-cell FL and measurable disease, and have received prior anti-CD20 antibody and alkylator-based combination therapy. Pts are randomized 2:1 to receive oral zanubrutinib 160 mg twice daily + obinutuzumab or obinutuzumab alone (both arms in 28-day cycles, at 1000 mg IV on days 1, 8, and 15 of cycle 1; day 1 of cycles 2-6; and then once every 8 weeks) until progressive disease (PD), toxicity or a maximum of 30 mo of obinutuzumab. Pts receiving zanubrutinib should remain on study treatment until PD. Randomization is stratified by prior therapies (2-3 vs >3) and rituximab-refractory status. Disease response is assessed per the 2014 Lugano Classification for NHL. The primary endpoint is ORR by independent review committee (IRC). Response rates will be compared between groups in an intent-to-treat analysis. Key secondary endpoints include ORR by investigator assessment, rate of complete response or complete metabolic response, time to and duration of response, progression-free survival (all IRC and investigator assessments), overall survival, and safety. At the investigator's discretion, pts in the obinutuzumab arm can cross over to the combination arm if they have PD at any time or less than partial response after 12 mo. Recruitment is ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trotman:Celgene: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Janssen: Research Funding. Auer:Hartley Taylor: Honoraria; Janssen: Honoraria, Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees; Celgene: Other: personal fees. Flowers:TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; Eastern Cooperative Oncology Group: Research Funding. Reed:BeiGene: Employment, Equity Ownership, Other: Travel & Accommodations. Ivanova:BeiGene: Employment. Huang:BeiGene: Employment, Equity Ownership. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US
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Ball, Brian J., Anthony S. Stein, Gautam Borthakur, Crystal Murray, Karin Kook, Kyle WH Chan, and Eytan M. Stein. "Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS." Blood 136, Supplement 1 (November 5, 2020): 18–19. http://dx.doi.org/10.1182/blood-2020-142557.
Full textAbstract:
Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), low response rates and poor overall survival remain unmet clinical needs. AML cells evade apoptosis through overexpression of antiapoptotic genes and inactivation of p53. The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax. Similarly, the sensitivity of AML patients' samples to venetoclax inversely correlates with the presence of a TP53 mutation or low expression of p53. In AML, p53 inactivation more commonly results from overexpression of its negative regulators, Mdmx and Mdm2. BTX-A51 is a novel, oral, direct inhibitor of Casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CK1α phosphorylates Mdmx and Mdm2 leading to enhanced binding and degradation of p53. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1a inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc andMcl1, enabling selective apoptosis of leukemia cells. The combination of CK1α, CDK7, and CDK9 inhibition was synergistic and prolonged survival in multiple genetic and patient-derived xenograft AML models. Study Design and Methods: This is an open-label, multi-center, first-in-human Phase 1 study evaluating the safety of BTX-A51 in patients with R/R AML or high-risk MDS. The trial will be performed in two phases, a dose escalation (phase 1a) and dose expansion (phase 1b). Phase 1a utilizes a hybrid accelerated titration with single patient cohorts and a Bayesian optimal interval (BOIN) design to assess 8 potential dosing cohorts. The maximum tolerated dose (MTD) will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. Up to a maximum of 35 patients will be enrolled in the dose escalation phase of the study at Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and City of Hope Cancer Center. Following determination of the MTD, 15 patients will be enrolled in the dose expansion phase for further evaluation of dose-limiting toxicities (DLTs) and for preliminary evidence of efficacy. BTX-A51 will be dosed 3 weeks on drug, followed by 1 week off drug over a 28-day cycle. For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored. Key inclusion criteria are age ³ 18 years, R/R AML or R/R high-risk MDS, Eastern Cooperative Oncology Group (ECOG) £ 2 and life expectancy of ³ 6 weeks, and adequate kidney and liver function. Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L. The primary objective for the Phase 1 study is to determine the MTD and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating overall response (complete remission, complete remission with incomplete blood count recovery, and partial remission) according to the European LeukemiaNet (ELN) 2017 criteria (Döhner et al. Blood. 2017), survival (overall survival and event-free survival) and pharmacokinetics. Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785 Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Borthakur:BioLine Rx: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Polaris: Research Funding; PTC Therapeutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Murray:Salamandra: Current Employment. Kook:Salamandra: Current Employment. Chan:BioTheryx: Current Employment. Stein:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.