Academic literature on the topic 'Kevin m. weeks'

Abstract Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is FDA approved for pts with mTNBC who received ≥2 prior chemotherapies (≥1 in the metastatic setting). The confirmatory phase 3 ASCENT study (NCT02574455) in pts treated in second line or greater (2L+) mTNBC demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit of SG over single-agent chemotherapy treatment of physician’s choice (median PFS: 4.8 vs 1.7 months, HR 0.43, P<0.001; median OS: 11.8 vs 6.9 months, HR 0.51) in the full trial population, with a manageable safety profile. However, outcomes and patterns of subsequent therapy for pts who discontinue SG following progressive disease (PD) are not well characterized. This post hoc subgroup analysis investigates post-progression treatment and OS of pts who discontinued SG due to PD during the ASCENT trial. Methods: In ASCENT, pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity or progression. Post-progression outcomes were assessed in pts who discontinued SG due to progressive disease (PD). Pts were followed every 4 weeks for OS, including documentation of further therapy for breast cancer. Time to post-progression therapy was defined as the number of months from time of randomization until the initiation of subsequent anticancer therapy. OS was analyzed in pts who received post-progression therapy vs those who did not and defined as the number of months from randomization or from end of SG treatment, using Kaplan Meier estimates and Cox regression. Results: 222/267 (83%) pts who were randomized to receive SG discontinued SG due to PD. In these patients median age was 53 years (range, 27-82), median number of prior anticancer regimens was 4, and 7% had known germline BRCA1/2 mutations. Pts received SG for a median duration of 4.2 months (range, 0.0-18.7). Following SG discontinuation, post-progression therapy was received by 73% (n=163) of pts; common post-SG therapies included eribulin (n=70; 32%), carboplatin (n=34; 15%), capecitabine (n=34; 15%), and atezolizumab, (n=15; 7%). The median time to receipt of post-progression therapy was 5.4 months (range, 1.0-19.8). Median OS in pts who received any post PD treatment vs those who did not receive post PD treatment following SG was 13.4 vs 7.3 months (HR, 0.46; 95% CI, 0.32-0.67; P<0.0001) from time of randomization and 7.9 vs 2.0 months (HR, 0.14; 95% CI, 0.09-0.22; P<0.0001) from end of SG treatment, respectively. In pts who received eribulin, carboplatin, atezolizumab, or capecitabine, median OS was 14.1 (95% CI, 10.9-14.9), 13.6 (95% CI, 10.6-15.9), 16.5 (95% CI, 8.7 to not evaluable), and 14.9 (95% CI, 10.9-16.8) months from time of randomization and 8.4 (95% CI, 6.8-9.2), 8.9 (95% CI, 6.7-10.8), 8.6 (95% CI, 4.3 to not evaluable), and 8.9 (95% CI, 6.6-10.3) months from end of SG treatment, respectively. Conclusions: In ASCENT, the majority of pts who discontinued SG due to PD were able to receive subsequent therapy post-progression. Pts who received post PD therapy following SG had significantly improved median OS over those who did not receive further therapy. Pts who received eribulin, carboplatin, atezolizumab, or capecitabine, as post PD therapy had similar median OS. These results indicate that treatment with SG does not prevent receipt of further systemic therapy. Citation Format: Javier Cortés, Aditya Bardia, Delphine Loirat, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Sara A. Hurvitz, Adam Brufsky, Sagar Sardesai, Kevin M Kalinsky, Tiffany Traina, Erika Hamilton, Joyce O’Shaughnessy, Véronique Diéras, Lisa A. Carey, Martine Piccart, Sibylle Loibl, Hope S. Rugo, Yanni Zhu, See Phan, Luca Gianni. Post-progression therapy outcomes in patients (pts) from the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-15.

Abstract Background: Optical-based imaging modalities play an important role in assessing breast tissue composition by measuring optical property contrast from endogenous chromophores. The advantages of optical techniques are the use of non-ionizing radiation, ease of use, and relatively low cost. The primary objective of this study is to examine changes in optically derived parameters (i.e., deoxy-hemoglobin concentration, ctHHb) from different breast cancer subtypes under neoadjuvant chemotherapy (NAC), and correlate with tumor pathologic complete response (pCR). Methods: This retrospective study evaluated 89 tumors in total divided into three distinct subtypes: HR+/HER2- (n=34), HER2+ (n=27), and TNBC (n=28). All patients were imaged at baseline, before starting NAC (TP0), and two weeks after receiving one cycle of taxane-based chemotherapy (TP1). HER2+ breast cancer patients also received HER2-target therapy. pCR was defined as complete absence of invasive carcinoma in the breast and lymph node(s) (ypT0/is ypN0 Mx) at the time of surgery. Whole breast volume was imaged by a diffuse optical tomography breast imaging system (DOTBIS) using low-intensity near-infrared light. ctHHb tumor volume concentration was normalized by the non-affected health tissue ctHHb mean value (ctHHbN). For each molecular subgroup, we conducted an independent-samples t-test to determine if there was a difference in ctHHbN levels at TP1 compared to TP0 between patients with a pCR and non-pCR. Significance was assumed at a confidence interval of 95% (α = 0.05). Results: In total, 69 patients were imaged with DOTIBS at both time points, TP0 and TP1. HR+/HER2-, TNBC and HER2+ accounted for 32% (n=23), 37% (n=22) and 30% (n=22), respectively. The ratio between ctHHbN levels measured at TP1 and TP0 was statistically significantly lower in the pCR group than non-pCR for the HER2+ and HR+/HER2- molecular subgroups, Table 1. Conclusion: Aligned to the current practices in breast cancer management based on the characterization of breast cancer subtypes, our work evaluated changes in DOTBIS optically derived features and pCR status for different subtypes. We observed that ctHHbN levels change after two weeks of NAC and these changes are modifiable according to pCR status and are dependent on immunophenotype. Table 1.Ratio between ctHHbN levels measured at TP1 and TP0 between pCR and non-pCR according to different molecular subtypes.Molecular SubtypepCR (mean ± SD )non-pCR (mean ± SD )p-valueHR+/HER2- (n=23)0.77 ± 0.22 (n=6)1.14 ± 0.24 (n=17).01HER2+ (n=24)0.74 ± 0.30 (n=15)1.54 ± 0.98 (n=9).04TNBC (n=22)0.96 ± 0.38 (n=4)1.29 ± 0.37 (n=18).18Bold values indicate statistical significance at p<.05 level. Citation Format: Mirella L Altoe, Kevin M Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Prediction of breast cancer response to neoadjuvant chemotherapy in different biological breast cancer subtypes using diffuse optical tomography [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-04.

Abstract Background: Taxane-induced peripheral neuropathy (TIPN) is one of the most common and debilitating adverse effects of taxane therapy for early-stage breast cancer (ESBC). TIPN is difficult to treat, and there are no known effective prevention strategies. Small non-randomized studies in patients with ESBC, have suggested both cryotherapy and compression therapy to the hands and feet may be effective for TIPN prevention. However, is unknown which therapy, if either, is more effective at prevention of TIPN compared to placebo. Methods: We conducted a randomized phase IIB adaptive sequential selection trial of cryotherapy vs. compression therapy vs. placebo among participants with ESBC during taxane chemotherapy (NCT03873272). Participants were randomized in triplets to either frozen gloves/socks [NatraCure] refrigerated for at least 3 hours to -25 to -30°C prior to use (cryotherapy); compression gloves/socks [Sigvaris] with a pressure of 20-30 mmHg on the upper extremity, 20-30 mmHg on the lower leger, and 15 mmHg on the toes/feet (compression therapy); or “loose” gloves/socks [Sigvaris] with a maximum pressure of 3 mmHg on the upper/lower extremities (placebo arm). All garments were worn for a total of 90-120 minutes, beginning 15 minutes prior to the start of taxane infusion and until 15 minutes after completion of the taxane infusion. The primary goal was to select the best intervention to be carried forward to a larger phase III trial, with a high probability of correct selection if one intervention is truly superior using a novel sequential design based on the Levin-Robbins-Leu family of sequential selection procedures. The primary endpoint was change in Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12-weeks; success was defined as <5-point decrease from baseline (minimal TIPN). The tally of success was compared starting from the 15th triplet. An arm would be eliminated if it had ≥4 successes less than the leading arm. The trial stopped the first time two arms were eliminated. Secondary endpoints included staff assessed adherence (defined as wearing study garments for ≥80% of infusions) and patient reported comfort (4-point Likert scale) to the study intervention. Results: Between 4/2019-4/2021 64 patients were randomized (n=20 cryotherapy; n=22 compression therapy; n=22 placebo). The stopping criterion was met after the 17th triplet (51 patients) had been evaluated for the primary endpoint. For the 51 patients, the median age was 50 years (range, 28-78), and the majority of patients (58.8%) were treated with docetaxel every 3-weeks, whereas 41.2% were treated with weekly paclitaxel. Success (i.e., minimal TIPN) at 12-weeks occurred in 11 (64.7%) patients treated with compression therapy, 7 (41.1%) patients treated with cryotherapy, and 7 (41.1%) patients treated with placebo. Adherence to the study intervention occurred in 82.4% of patients treated with compression therapy, 29.4% of patients treated with cryotherapy, and 76.5% treated with placebo. In regards to comfort, 87.4% of patients treated with compression therapy reported being satisfied/very satisfied with the study garments, compared to 56.3% treated with cryotherapy, and 73.3% treated with placebo. Conclusion: Compression therapy was found to be the most effective and tolerable intervention in this phase IIB selection trial to prevent TIPN, and has the greatest probability of being a successful intervention to prevent TIPN in a future randomized phase III study. Cryotherapy was not successful, which is likely related to poor tolerability due to the cold, which resulted in poor adherence to the study garments. Compression therapy for the prevention of TIPN should be further evaluated in a larger randomized phase III study. Citation Format: Melissa K Accordino, Shing Lee, Cheng-Shiun Leu, Meghna S Trivedi, Katherine D Crew, Kevin M Kalinsky, Rohit Rajhunathan, Alessandra Taboada, Lauren Franks, Erin Honan, Erik Harden, Cynthia Law, Dawn L Hershman. A randomized adaptive sequential selection trial of cryotherapy, compression therapy, and placebo to prevent taxane inducted peripheral neuropathy in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-04.

Abstract The combination of chimeric antigen receptor (CAR) T cell therapy, which delivers large numbers of tumor reactive T cells, and oncolytic viral therapy, causing activation of host immune responses, is an attractive approach for improving outcomes for patients with glioblastoma (GBM). Here we present data from two independent phase I clinical trials evaluating IL13Rα2-targeted CAR therapy (NCT02208362) and C134 oncolytic viral (OV) therapy (NCT03657576) for the treatment of recurrent GBM (rGBM), along with preclinical studies supporting the utility of combining these two therapies. For NCT02208362, locoregional delivery of IL13Rα2-targeted CAR T cells were evaluated in heavily pretreated patients with rGBM. Interrogating biomarkers of clinical response revealed that levels of intratumoral T cells prior to treatment were positively associated with overall survival; furthermore, two patients who achieved a complete response had the highest levels of intratumoral CD3+ T cells pre-therapy. These findings suggest that therapeutic strategies which increase endogenous immune infiltrates could augment CAR T cell mediated responses. For NCT03657576, intratumoral delivery of C134, a herpes simplex virus (HSV-1) that has been genetically engineered to safely replicate and kill glioma tumor cells, is also being evaluated for treatment of rGBM. We report findings from a patient treated intratumorally with 1 × 106 pfu of C134. At 6-7 weeks post treatment this patient had MRI changes that suggested possible recurrence or pseudoprogression, and therefore underwent resection with biopsy assessment. Evaluation of virus-treated areas showed increased immune infiltrates as compared to untreated tumor sites, suggesting that C134 activated host immune responses. These clinical findings provide the rationale for evaluating a combination therapy of C134 OV and IL13Rα2-CAR T cells to potentially reshape the tumor microenvironment (TME) and enhance CAR therapy. In orthotopic GBM models in nude mice, we show that co-treatment with the two agents gave no adverse reaction, and more notably pre-treatment with C134 re-shaped the TME by increasing immune cell infiltrates and enhanced the efficacy of sub-therapeutic doses of CAR T cell therapy delivered either intraventricularly or intratumorally. Ongoing preclinical studies aim to provide detailed phenotypic analysis, as well as a mechanistic understanding of this combination approach to support the potential benefit of a soon to be opened combination trial evaluating C134 and IL13Rα2-CAR T cells. In this clinical trial in patients with IL13Rα2+ rGBM and anaplastic astrocytoma, increasing doses of intratumorally administered C134 will be followed by dual intracranial intratumoral and intraventricular administration of IL13Rα2-targeted CAR T cell therapy. Citation Format: Christine E. Brown, Agata Xella, Jonathan C. Hibbard, Vanessa Salvary, Brenda Aguilar, Jamie Wagner, Bruce Dezube, Knut Niss, Lynn Bayless, James Edinger, Jianmei Leavenworth, Stephen J. Forman, Behnam Badie, James M. Markert, Kevin A. Cassady. Oncolytic viral reshaping of the tumor microenvironment to promote CAR T cell therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT541A.

-Bridget Brereton, Emilia Viotti Da Costa, Crowns of glory, tears of blood: The Demerara slave rebellion of 1823. New York: Oxford University Press, 1994. xix + 378 pp.-Grant D. Jones, Assad Shoman, 13 Chapters of a history of Belize. Belize city: Angelus, 1994. xviii + 344 pp.-Donald Wood, K.O. Laurence, Tobago in wartime 1793-1815. Kingston: The Press, University of the West Indies, 1995. viii + 280 pp.-Trevor Burnard, Howard A. Fergus, Montserrat: History of a Caribbean colony. London: Macmillan Caribbean, 1994. x + 294 pp.-John L. Offner, Joseph Smith, The Spanish-American War: Conflict in the Caribbean and the Pacific, 1895-1902. London: Longman, 1994. ix + 262 pp.-Louis Allaire, John M. Weeks ,Ancient Caribbean. New York: Garland, 1994. lxxi + 325 pp., Peter J. Ferbel (eds)-Aaron Segal, Hilbourne A. Watson, The Caribbean in the global political economy. Boulder CO: Lynne Rienner, 1994. ix + 261 pp.-Aaron Segal, Anthony P. Maingot, The United States and the Caribbean. London: Macmillan Caribbean, 1994. xi + 260 pp.-Bill Maurer, Helen I. Safa, The myth of the male breadwinner: Women and industrialization in the Caribbean. Boulder CO: Westview, 1995. xvi + 208 pp.-Peter Meel, Edward M. Dew, The trouble in Suriname, 1975-1993. Westport CT: Praeger, 1994. xv + 243 pp.-Henry Wells, Jorge Heine, The last Cacique: Leadership and politics in a Puerto Rican city. Pittsburgh PA: University of Pittsburgh Press, 1993. ix + 310 pp.-Susan Eckstein, Jorge F. Pérez-López, Cuba at a crossroads: Politics and economics after the fourth party congress. Gainesville: University Press of Florida, 1994. xviii + 282 pp.-David A.B. Murray, Marvin Leiner, Sexual politics in Cuba: Machismo, homosexuality, and AIDS. Boulder CO: Westview, 1994. xv + 184 pp.-Kevin A. Yelvington, Selwyn Ryan ,Sharks and sardines: Blacks in business in Trinidad and Tobago. St. Augustine, Trinidad: Institute of social and economic studies, University of the West Indies, 1992. xiv + 217 pp., Lou Anne Barclay (eds)-Catherine Levesque, Allison Blakely, Blacks in the Dutch world: The evolution of racial imagery in a modern society. Bloomington: Indiana University Press, 1993. xix + 327 pp.-Dennis J. Gayle, Frank Fonda Taylor, 'To hell with paradise': A history of the Jamaican tourist industry. Pittsburgh: University of Pittsburgh Press, 1993. ix + 239 pp.-John P. Homiak, Frank Jan van Dijk, Jahmaica: Rastafari and Jamaican society, 1930-1990. Utrecht: ISOR, 1993. 483 pp.-Peter Mason, Arthur MacGregor, Sir Hans Sloane: Collector, scientist, antiquary, founding Father of the British Museum. London: British Museum Press, 1994.-Philip Morgan, James Walvin, The life and times of Henry Clarke of Jamaica, 1828-1907. London: Frank Cass, 1994. xvi + 155 pp.-Werner Zips, E. Kofi Agorsah, Maroon heritage: Archaeological, ethnographic and historical perspectives. Kingston: Canoe Press, 1994. xx + 210 pp.-Michael Hoenisch, Werner Zips, Schwarze Rebellen: Afrikanisch-karibischer Freiheitskampf in Jamaica. Vienna Promedia, 1993. 301 pp.-Elizabeth McAlister, Paul Farmer, The uses of Haiti. Monroe ME: Common Courage Press, 1994. 432 pp.-Robert Lawless, James Ridgeway, The Haiti files: Decoding the crisis. Washington DC: Essential Books, 1994. 243 pp.-Bernadette Cailler, Michael Dash, Edouard Glissant. Cambridge: Cambridge University Press, 1995. xii + 202 pp.-Peter Hulme, Veronica Marie Gregg, Jean Rhys's historical imagination: Reading and writing the Creole. Chapel Hill: University of North Carolina Press, 1995. xi + 228 pp.-Silvia Kouwenberg, Francis Byrne ,Focus and grammatical relations in Creole languages. Amsterdam/Philadelphia: John Benjamins, 1993. xvi + 329 pp., Donald Winford (eds)-John H. McWhorter, Ingo Plag, Sentential complementation in Sranan: On the formation of an English-based Creole language. Tübingen: Max Niemeyer, 1993. ix + 174 pp.-Percy C. Hintzen, Madan M. Gopal, Politics, race, and youth in Guyana. San Francisco: Mellen Research University Press, 1992. xvi + 289 pp.-W.C.J. Koot, Hans van Hulst ,Pan i rèspèt: Criminaliteit van geïmmigreerde Curacaose jongeren. Utrecht: OKU. 1994. 226 pp., Jeanette Bos (eds)-Han Jordaan, Cornelis Ch. Goslinga, Een zweem van weemoed: Verhalen uit de Antilliaanse slaventijd. Curacao: Caribbean Publishing, 1993. 175 pp.-Han Jordaan, Ingvar Kristensen, Plantage Savonet: Verleden en toekomst. Curacao: STINAPA, 1993, 73 pp.-Gerrit Noort, Hesdie Stuart Zamuel, Johannes King: Profeet en apostel in het Surinaamse bosland. Zoetermeer: Boekencentrum, 1994. vi + 241 pp.

Abstract Recent works have demonstrated that eastward-propagating features smaller than zonal wavenumber 3 but with spatial structures similar to those of the Madden–Julian oscillation (MJO) frequently develop over the Indo-Pacific warm pool. These signals are characterized by periods shorter than 4 weeks, but since they occur as part of a spectral peak of the MJO, they might be characterized by similar physics. These zonally narrow features occur at any phase of traditionally defined 30–60-day MJO events, but they occur most frequently in its active convective phase. This work presents a linear regression analysis based on filtering in the wavenumber–frequency domain to compare such signals with traditionally defined MJOs and 15–30 m s−1, convectively coupled Kelvin waves. Results show that the trough collocated with the easterly wind anomaly extends westward into the region of lower-tropospheric westerly wind and deep convection in the zonally narrow slow signals and MJOs. The fast Kelvin waves have a ridge anomaly collocated with the westerly wind anomaly. The zonally narrow slow signals and MJOs include a warm anomaly in the boundary layer west of the deep convection that is absent in fast Kelvin waves. Results suggest that MJO dynamics are not confined to the 30–60-day band and that time scales as short as 2 weeks could be considered in wavenumber–frequency diagnostics for the MJO.

Abstract Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-02.

Abstract Introduction: Hepatoblastoma (HB) is the most common pediatric primary liver tumor and has the fastest rising incidence of all pediatric solid tumors. Patients with high-risk, treatment refractory, or relapse disease have a survival rate of less than 50%. The development of clinically relevant models of these aggressive tumors will facilitate studies to identify drugs that target these cells.Methods: Fresh, whole primary tumor samples were implanted into the livers of immunocompromised mice. Tumor growth was monitored with MRI and ELISA to measure serum human Alpha-fetoprotein (AFP), which is detectable in the blood of tumor-bearing animals. Tumors were validated with immunohistochemistry (IHC) for HB markers Glypican-3 (GPC3) and Beta-catenin; short tandem repeat (STR) DNA validation; next generation sequencing-based mutation profiling of 124 genes involved in pediatric solid tumors; RNA sequencing (RNA-seq), and single cell RNA-seq (scRNA-seq). Lung metastasis was also detected in models with serial sectioning and H&E staining. Cells derived from tumors were grown in vitro in adherent and spheroid conditions and used for high throughput drug screening of candidate agents. Tumors were serially passaged in animals for further in vivo drug testing of novel targeted agents.Results: Nine patient-derived xenograft (PDX) models were generated that represent low- and high-risk tumors, treatment refractory cases, and relapsed tumors. Passaging of these models showed consistent implantation rates at or above 80% with tumors detectable in 2 to 4 weeks. Eight of nine models secrete human serum AFP. All models mimic gene expression and histological patterns of their primary tumor counterparts as well as identical STR DNA profiles. The models also show gene expression consistent with an HB2/high-risk profile according to the Sumazin HB expression signature. Interestingly, two models represent unique sub-clones of a very aggressive HB relapse with different AFP secretion and transcriptomic expression. scRNA-seq of these two models indicated outgrowth of disparate disease sub-clones. The nine models also demonstrate a range of DNA mutations with three or four mutations per tumor; all variants present in the original clinical samples were conserved in the PDX models. Lung metastasis was evident in six of nine models. Two stable patient-derived cell lines (PDCLs) were developed from models, and these cell lines show expression of HB markers and secrete AFP with growth in culture. Drug screening of adherent and spheroid tumor cells support the efficacy of novel targeted agents and indicate a spectrum of sensitivity to cisplatin, a frontline standard chemotherapy agent. Importantly, the models replicate the chemotherapy responses of the corresponding patients. Additional in vitro and in vivo work showed the efficacy of a histone deacetylase inhibitor, panobinostat.Conclusions: These novel orthotopic PDX models of HB fully recapitulate the primary tumors and represent a platform for clinically relevant drug screening and testing. Citation Format: Sarah E Woodfield, Roma H Patel, Andres F Espinoza, Richard S Whitlock, Jessica Epps, Andrew Badachhape, Samuel R Larson, Rohit K Srivastava, Aayushi P Shah, Saiabhiroop R Govindu, Barry Zorman, Brandon J Mistretta, Kevin E Fisher, Ilavarasi Gandhi, Jacquelyn Reuther, Martin Urbicain, Aryana M Ibarra, Sakuni Rankothgedera, Kimberly R Holloway, Stephen F Sarabia, Andras Heczey, Ketan B Ghaghada, Kalyani R Patel, Dolores Lopez-Terrada, Angshumoy Roy, Preethi H Gunaratne, Pavel Sumazin, Sanjeev A Vasudevan. Patient-derived xenograft mouse models of hepatoblastoma for a personalized medicine pipeline [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO013.

Abstract Background: Hormone receptor+/HER2- breast cancer is the most common subtype of breast cancer. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. ZN-c5 is a novel, orally bioavailable SERD with high potency and has demonstrated activity in estrogen-dependent tumor models. Methods: This Phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics and preliminary anti-tumor activity of ZN-c5 as monotherapy or in combination with palbociclib. In the Phase 1 portion evaluating ZN-c5 as monotherapy, participants were adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast, ER+/HER2- disease, and sensitive to endocrine therapy for metastatic disease (partial response [PR], complete response or stable disease [SD] lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment). ZN-c5 was administered orally and continuously in 28-day cycles until disease progression or unacceptable toxicity. Dose escalation cohorts of subjects were enrolled at several dose levels of ZN-c5, based on a modified 3+3 design. Enrollment in the Phase 1 ZN-c5 monotherapy dose escalation and expansion has been completed and results are presented. Phase 1 testing of ZN-c5 in combination with palbociclib and Phase 2 testing in monotherapy are ongoing and will be presented at a future meeting. Results: In Phase 1 monotherapy, a total of 56 female subjects were enrolled to receive ZN-c5 at dose levels of 50 mg once daily (QD, n=16), 75 mg QD (n=3), 100 mg QD (n=3), 75 mg twice daily (BID, n=6), 150 mg QD (n=15), 150 mg BID (n=3), or 300 mg QD (n=10). Median age was 58.5 years (range, 38 - 89) and ECOG performance status was 0 (55%) or 1 (45%). Subjects had a median of 2 prior therapies for advanced/metastatic disease (range, 0 - 9), with a median of 2 prior hormonal-based therapies (range, 0 - 6) and a median of 0 prior chemotherapies (range, 0 - 3). Twenty-six subjects (46%) received prior fulvestrant and 38 (68%) received a prior CDK4/6 inhibitor. Twenty subjects (38%) had a baseline ESR1 mutation. The cut-off date for this analysis was 11 May 2021. There was no increase in severity of treatment-emergent adverse events (TEAEs) with increase in dose level. No dose-limiting toxicities were reported. The most common TEAEs were nausea (30%), fatigue (25%), and arthralgia (20%). Grade 3 TEAEs reported in > 1 subject were gamma-glutamyltransferase (GGT) increased and hyponatremia (2 subjects each); no Grade 4 TEAEs were reported. Among treatment-related events, the most common were hot flushes and nausea (14% each); the only Grade 3 events were GGT increased and hypersensitivity in 1 subject each. ZN-c5 was rapidly absorbed, with a median Tmax of 2 to 4 hours. AUC and Cmax on Days 1 and 15 were less than dose proportional. No ZN-c5 accumulation after 15 days of dosing was observed. Confirmed PRs have been observed in 2 subjects (at 150 and 300 mg QD, respectively), and 14/45 (31%) evaluable subjects have experienced clinical benefit (PR or SD ≥ 24 weeks). Five of the 14 subjects with long SD received prior fulvestrant. Median progression-free survival (PFS) was 3.8 months (95% CI: 3.2, 5.3). Conclusions: In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib. Citation Format: Kevin Kalinksy, Vandana Abramson, Pavani Chalasani, Hannah M. Linden, Jasmina Alidzanovic, Rachel M. Layman, Živko Vranješ, Julie R. Nangia, Katherine D. Crew, Zoran Andric, Marijana Milovic-Kovacevic, Jasna Trifunovic, Jose Suarez, Matt Suster, Mieke Ptaszynski, Joanne Mortimer. ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-02.