Journal articles: 'Weak key-IV combinations'

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Rugo, H. S., M. Campone, D. Amadori, A. Wardley, E. Villa, P. F. Conte, B. Mudenda, B. McHenry, and X. Pivot. "Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 1029. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1029.

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1029 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8 & 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev. [Table: see text] [Table: see text]

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Sands, B. E., B. G. Feagan, W. J. Sandborn, N. Shipitofsky, M. Marko, S. Sheng, J. Johanns, M. Germinaro, M. Vetter, and J. Panés. "OP36 Efficacy and safety of combination induction therapy with guselkumab and golimumab in participants with moderately-to-severely active Ulcerative Colitis: Results through week 12 of a phase 2a randomized, double-blind, active-controlled, parallel-group, multicenter, proof-of-concept study." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i042—i043. http://dx.doi.org/10.1093/ecco-jcc/jjab232.035.

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Abstract Background Preclinical data from a murine model of acute colitis suggest that dual blockade of interleukin(IL)-23 and TNFα more effectively prevented the development of colonic inflammation than each monotherapy. Guselkumab(GUS), an IL-23p19 subunit antagonist, is being studied in inflammatory bowel disease. Golimumab(GOL), a TNFα antagonist, is approved for ulcerative colitis(UC). The objective of this study was to evaluate the efficacy and safety of combination induction therapy with GUS+GOL vs GUS or GOL alone in adults with moderately-to-severely active UC. Methods 214 patients(pts) naïve to TNFα antagonists and refractory or intolerant to conventional therapy(ie, immunomodulators and/or corticosteroids) were randomly assigned to receive GUS 200mg intravenous(IV) at weeks(wks) 0, 4, and 8(n=71); GOL 200mg subcutaneous(SC) at wk0 then 100mg SC at wks2, 6, and 10(n=72); or combination with GUS 200mg IV+GOL 200mg SC at wk0, GOL 100mg SC at wks2, 6, and 10, and GUS 200mg IV at wks4 and 8(n=71). The primary endpoint was clinical response at wk12; the major secondary endpoint was clinical remission at wk12. Other key endpoints were clinical remission based on the modified Mayo score (mMayo), symptomatic remission, endoscopic improvement, endoscopic normalization, histologic remission, composite histologic-endoscopic endpoints, and biomarker outcomes. Results Baseline disease characteristics were similar among groups(Table 1), however a greater proportion of pts in both monotherapy groups had pancolitis vs the combination group. A greater proportion of pts who received combination therapy achieved clinical response at wk12(83.1%) vs GUS(74.6%) or GOL(61.1%)(Table 2). Similarly, the proportion of pts who achieved clinical remission in the combination group(36.6%) was greater than that of monotherapy groups(21.1% and 22.2%, respectively). Clinical remission by mMayo score, endoscopic improvement, histologic remission, both histologic remission and endoscopic improvement, and biomarker normalization (calprotectin, CRP) rates at wk12 were also greater in the combination group vs GUS or GOL. Percentages of pts with endoscopic normalization and both histologic remission and endoscopic normalization were nearly double with combination therapy vs either monotherapy. Adverse event(AE), serious AE, and infection rates were comparable among treatment groups. One pt receiving combination therapy experienced a serious infection of influenza and sepsis. No deaths, malignancies, or TB cases were reported through wk12. Conclusion Combination induction treatment with GUS+GOL more effectively induced clinical response, clinical remission, and endoscopic improvement at wk12 than either monotherapy alone. AE rates were comparable among the treatment groups.

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Kubota, Kaoru, Hiroshige Yoshioka, Fumihiro Oshita, Toyoaki Hida, Kiyotaka Yoh, Hidetoshi Hayashi, Terufumi Kato, et al. "Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 35, no. 32 (November 10, 2017): 3662–70. http://dx.doi.org/10.1200/jco.2017.72.7297.

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Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer.

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Xi, Jing, Jingqing Luo, Ciara O’Sullivan, Nan Chen, Erica Stringer-Reasor, Cynthia Ma, and Jian Campian. "SYST-13 PHASE II STUDY OF THE COMBINATION OF LIPOSOMAL IRINOTECAN AND PEMBROLIZUMAB FOR TRIPLE-NEGATIVE BREAST CANCER (TNBC) WITH BRAIN METASTASES (BM)." Neuro-Oncology Advances 4, Supplement_1 (August 1, 2022): i24. http://dx.doi.org/10.1093/noajnl/vdac078.092.

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Abstract BACKGROUND Breast cancer is one of the most common cancers associated with brain metastases (BM). Up to 50% of patients with metastatic triple-negative breast cancer (TNBC) develop BM which portends a poor prognosis, with a median survival of 4.4-7.3 months. There is a lack of effective systemic therapy. Irinotecan is a topoisomerase-1 inhibitor with a response rate of 5-23% in advanced breast cancer. Nal-IRI is an intravenous liposomal formulation of irinotecan, with greater efficacy in tumor growth inhibition and the ability to cross the blood brain barrier (BBB) than irinotecan, resulting in a prolonged survival in preclinical TNBC BM models. Additionally, Nal-IRI has demonstrated promising anti-tumor activity in patients with TNBC- BM in a phase-I trial (NCT01770353). Pembrolizumab is a humanized anti-PD-1 monoclonal antibody which has shown efficacy in TNBC. The purpose of this study is to evaluate whether the combination of Nal-IRI and pembrolizumab can provide a synergic effect to control the CNS disease and prolong survival in TNBC with progressive BM. METHODS This is a phase II, single arm trial with a safety lead-in to evaluate the efficacy of nal-IRI (50-70mg/m2 IV Q2W) in combination with pembrolizumab (400mg IV Q6W). Simon’s 2-stage design is used, with 18 patients in the 1st stage and additional 24 at 2nd stage for a total of 42. The first 6 patients will serve as a safety lead-in. Key eligibilities include: histologically/cytologically confirmed TNBC with new or progressive BM; prior immunotherapy is allowed but not prior nal-IRI/irinotecan; prior sacituzumab-govitecan is permitted if disease stable for ≥16-week while on therapy and ≥24-week washout prior to starting trial; measurable disease; and ≤4 prior lines of therapy in the metastatic setting. The primary endpoint is CNS disease control rate (DCR) at 6 months using RANO-BM criteria. Secondary endpoints include CNS and non-CNS ORR, PFS and OS. (ClinicalTrials.gov: NCT05255666)

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Kus, Julianne V., John Kelly, Luc Tessier, Hanjeong Harvey, Dennis G. Cvitkovitch, and Lori L. Burrows. "Modification of Pseudomonas aeruginosa Pa5196 Type IV Pilins at Multiple Sites with d-Araf by a Novel GT-C Family Arabinosyltransferase, TfpW." Journal of Bacteriology 190, no. 22 (September 19, 2008): 7464–78. http://dx.doi.org/10.1128/jb.01075-08.

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ABSTRACT Pseudomonas aeruginosa Pa5196 produces type IV pilins modified with unusual α1,5-linked d-arabinofuranose (α1,5-d-Araf) glycans, identical to those in the lipoarabinomannan and arabinogalactan cell wall polymers from Mycobacterium spp. In this work, we identify a second strain of P. aeruginosa, PA7, capable of expressing arabinosylated pilins and use a combination of site-directed mutagenesis, electrospray ionization mass spectrometry (MS), and electron transfer dissociation MS to identify the exact sites and extent of pilin modification in strain Pa5196. Unlike previously characterized type IV pilins that are glycosylated at a single position, those from strain Pa5196 were modified at multiple sites, with modifications of αβ-loop residues Thr64 and Thr66 being important for normal pilus assembly. Trisaccharides of α1,5-d-Araf were the principal modifications at Thr64 and Thr66, with additional mono- and disaccharides identified on Ser residues within the antiparallel beta sheet region of the pilin. TfpW was hypothesized to encode the pilin glycosyltransferase based on its genetic linkage to the pilin, weak similarity to membrane-bound GT-C family glycosyltransferases (which include the Mycobacterium arabinosyltransferases EmbA/B/C), and the presence of characteristic motifs. Loss of TfpW or mutation of key residues within the signature GT-C glycosyltransferase motif completely abrogated pilin glycosylation, confirming its involvement in this process. A Pa5196 pilA mutant complemented with other Pseudomonas pilins containing potential sites of modification expressed nonglycosylated pilins, showing that TfpW's pilin substrate specificity is restricted. TfpW is the prototype of a new type IV pilin posttranslational modification system and the first reported gram-negative member of the GT-C glycosyltransferase family.

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Hammel, Pascal, Rossana Berardi, Geert-Yan Creemers, Antonio Cubillo, Eric Van Cutsem, Richard Greil, Teresa Macarulla, et al. "TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS4666. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps4666.

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TPS4666 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC is established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial in October 2019 and suggested the trial continue as planned. Clinical trial information: NCT03665441 .

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Hammel, Pascal, Rossana Berardi, Eric Van Cutsem, Jaime Feliu, Richard Greil, Harpreet Singh Wasan, Jean-Philippe Metges, et al. "TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): TPS783. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.tps783.

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TPS783 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

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Hammel, Pascal, Rossana Berardi, Eric Van Cutsem, Jaime Feliu, Richard Greil, Harpreet Singh Wasan, Jean-Philippe Metges, et al. "Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): TPS471. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.tps471.

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TPS471 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. An HR in OS of 0.725 is being targeted representing a conservative estimate based on the P2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

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García-García, Carlos, David Alonso, Pedro G. Ferreira, Boryana Hadzhiyska, Andrina Nicola, Carles Sánchez, and Anže Slosar. "Combining cosmic shear data with correlated photo-z uncertainties: constraints from DESY1 and HSC-DR1." Journal of Cosmology and Astroparticle Physics 2023, no. 01 (January 1, 2023): 025. http://dx.doi.org/10.1088/1475-7516/2023/01/025.

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Abstract An accurate calibration of the source redshift distribution p(z) is a key aspect in the analysis of cosmic shear data. This, one way or another, requires the use of spectroscopic or high-quality photometric samples. However, the difficulty to obtain colour-complete spectroscopic samples matching the depth of weak lensing catalogs means that the analyses of different cosmic shear datasets often use the same samples for redshift calibration. This introduces a source of statistical and systematic uncertainty that is highly correlated across different weak lensing datasets, and which must be accurately characterised and propagated in order to obtain robust cosmological constraints from their combination. In this paper we introduce a method to quantify and propagate the uncertainties on the source redshift distribution in two different surveys sharing the same calibrating sample. The method is based on an approximate analytical marginalisation of the p(z) statistical uncertainties and the correlated marginalisation of residual systematics. We apply this method to the combined analysis of cosmic shear data from the DESY1 data release and the HSC-DR1 data, using the COSMOS 30-band catalog as a common redshift calibration sample. We find that, although there is significant correlation in the uncertainties on the redshift distributions of both samples, this does not change the final constraints on cosmological parameters significantly. The same is true also for the impact of residual systematic uncertainties from the errors in the COSMOS 30-band photometric redshifts. Additionally, we show that these effects will still be negligible in Stage-IV datasets. Finally, the combination of DESY1 and HSC-DR1 allows us to constrain the “clumpiness” parameter to S 8 = 0.768+0.021 -0.017. This corresponds to a ∼√(2) improvement in uncertainties with respect to either DES or HSC alone.

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Arance Fernandez, ANA Maria, Paolo Antonio Ascierto, Matteo S. Carlino, Adil Daud, Alexander M. Eggermont, Axel Hauschild, Harriet M. Kluger, et al. "Lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with advanced melanoma previously exposed to anti–PD-1/PD-L1 agents: Phase 2 LEAP-004 study." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS9594. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps9594.

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TPS9594 Background: Pembro, a PD-1 inhibitor, has shown effective antitumor activity, deep and durable responses, and survival benefit in treatment-naive pts and those with previously treated metastatic melanoma. Len, a potent inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, combined with a PD-1 inhibitor showed antitumor activity superior to either agent alone in preclinical models of colorectal and lung cancer. Additionally, len plus pembro showed anti-tumor activity and was well-tolerated (24-wk ORR, 47.6%; TRAE: gr 3/4, 67%; gr 5, 0%) in pts with advanced melanoma previously treated with 0-2 therapies in the phase 1b/2 KEYNOTE-146 trial. The efficacy and safety of len plus pembro combination therapy will be evaluated in an open-label, phase 2 trial of pts with advanced melanoma that progressed on PD-1/PD-L1 inhibitor therapy (NCT03776136). Methods: Key inclusion criteria: age ≥18 years, histologically/cytologically confirmed unresectable stage III-IV melanoma that progressed (per iRECIST) within 12 weeks of last dose of an approved PD-1/PD-L1 inhibitor therapy (≥2 doses as monotherapy or combined with other therapies), measurable disease, ECOG PS 0/1, no active autoimmune disease, and adequate organ function. Pts must provide a baseline tumor sample. Pts will receive len 20 mg/day orally plus pembro 200 mg IV Q3W for approximately 2 years (35 doses of pembro), after which they may receive len alone until PD or unacceptable toxicity. Response will be assessed per RECIST v1.1 based on blinded independent central review (BICR) Q9W until week 54, Q12W until week 102, and Q24W thereafter. Pts with CR may discontinue treatment after ≥24 weeks of therapy; eligible pts may continue treatment beyond initial RECIST- or iRECIST-defined PD. AEs will be assessed throughout treatment and for 90 days (120 days for serious AEs) after last dose and graded per NCI CTCAE v4.0. Pts will be followed-up for survival status Q12W. The primary efficacy end point is ORR per modified RECIST v1.1 (BICR). Key secondary end points are PFS and DOR per modified RECIST v1.1 (BICR), OS, and safety; an exploratory biomarker analysis is planned. Clinical trial information: NCT03776136.

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Schwartz, Rayna L., Claudia Espitia, Dan O. Persky, Steffan T. Nawrocki, and Jennifer S. Carew. "The Clinical Oncolytic Reovirus Formulation Reolysin Synergistically Augments the Anti-Leukemic Activity of Azacitidine." Blood 138, Supplement 1 (November 5, 2021): 3337. http://dx.doi.org/10.1182/blood-2021-151575.

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Abstract Despite the recent development of new agents for acute myeloid leukemia (AML) therapy, novel approaches are still needed for patients that do not benefit sufficiently from existing regimens. Reolysin (Pelareorep) is a proprietary clinical formulation of the naturally occurring oncolytic reovirus that is non-pathogenic and preferentially replicates in cancer cells, but not in normal tissue. Although Reolysin has been investigated in over 30 adult clinical trials and is very well tolerated when given alone and in combination with chemotherapy, it has never been evaluated for AML therapy. Our major goal was to determine the efficacy and mechanism of action of Reolysin alone and in combination with azacitidine in AML models and primary patient specimens. Reolysin exhibited dose-dependent effects against AML cells with respect to the reduction in leukemia cell viability and induction of apoptosis in all 8 cell lines evaluated. The combination of Reolysin with azacitidine yielded synergistic benefit across all cell lines that was dramatically superior to single agent treatments (p<0.001). The benefit of combination treatment was confirmed in primary AML specimens (N=14 to date). RNASeq-based transcriptome and gene ontology (GO) analyses of the pharmacodynamic effects of each agent and the combination revealed that the Reolysin and azacitidine combination potently altered multiple genes in the immune response pathway (p<0.001). qRT-PCR analyses and ELISA assays confirmed the broad immunomodulatory effects of the Reolysin plus azacitidine combination. Immune priming strategies that can turn "immune cold" cancers to "immune hot" may significantly augment the benefit of many therapeutic approaches. Basic leucine zipper transcription factor ATF-like 2 (BATF2) is a key tumor suppressor that is absent in AML and certain other malignancies. Its deficiency promotes immune escape of cancer cells. BATF2 exhibits anticancer activity through upregulation of interleukin-12 and the activation of CD8+ T cells and therefore represents a novel new target in anticancer treatment with immune checkpoint inhibitors. Our transcriptome analyses identified BATF2 as one of the most significantly upregulated genes in AML cells following treatment with the Reolysin plus azacitidine combination (p<0.0001). Additional mechanistic studies confirmed that BATF2 induction was a key driver of the anti-leukemic effects of combination treatment. Finally, Reolysin (5 x 10 8 TCID50 IV 1x per week), azacitidine (5 mg/kg SC 2x per week), and the combination were administered to mice bearing MOLM-13 FLT3-ITD+ xenografts for 19 days to assess the efficacy and tolerability of each treatment. Combination treatment was well tolerated and antagonized disease progression significantly more effectively than either monotherapy (p<0.01). Additional in vivo studies more rigorously assessing the immunomodulatory effects of Reolysin and azacitidine in immune competent mice are underway. Our collective data demonstrate that Reolysin is a safe and well tolerated agent with potent immunomodulatory effects that synergistically augments the anti-AML effects of azacitidine. A phase I investigator-initiated clinical trial further investigating the safety and preliminary efficacy of this combination in patients with AML is currently being planned. Disclosures No relevant conflicts of interest to declare.

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Burris III, Howard A., Susanna Varkey Ulahannan, Eric B. Haura, Sai-Hong Ignatius Ou, Anna Capasso, Pamela N. Munster, Hidenori Kitai, et al. "The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3098. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3098.

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3098 Background: RMC-5552 is a potent bi-steric mTORC1-selective inhibitor that activates the downstream tumor suppressor 4EBP1, thereby inhibiting initiation of protein translation. This novel therapeutic moiety addresses a key limitation of rapalogs, which do not effectively inhibit phosphorylation of 4EBP1. RMC-5552 has previously demonstrated significant anti-tumor activity in preclinical models of human cancers with mTOR pathway activation. Additionally, mTOR signaling plays a key role in therapeutic response and resistance in RAS-addicted cancers, which represent a significant unmet medical need. Methods: We examined the combination of bi-steric mTORC1 inhibitors (RMC-5552 and the research tool compound RMC-6272) with direct inhibitors of active RAS (RAS(ON) inhibitors) in mutant KRAS-driven models. To enable the clinical testing of RMC-5552 as a companion inhibitor for RAS(ON) inhibitors, a Phase 1/1b dose-escalation trial of RMC-5552 monotherapy is currently testing a once-a-week IV schedule. Results: RMC-5552 and RMC-6272 demonstrated marked combinatorial anti-tumor activity with RAS(ON) inhibitors across a series of preclinical models of KRAS mutated non-small cell lung cancer. The combination enhanced tumor apoptosis and resulted in durable tumor regressions as compared to tumor growth inhibition resulting from single agents alone. As of 13 January 2022, a total of 14 patients with solid tumors have been evaluated in an ongoing Phase 1/1b trial over 5 dose levels ranging from 1.6 to 12 mg IV weekly. Median age was 62 years and the majority received ≥3 prior therapies. The most common (> 25%) drug-related adverse events were mucositis/stomatitis (43%) and decreased appetite (29%). The most common grade 3 drug-related adverse events were mucositis/stomatitis observed in 3 patients in dose levels ≥ 10 mg (21%) and were dose-limiting. The dose of 6 mg IV weekly was well tolerated. Plasma exposures of RMC-5552 were dose-proportionate at lower dose levels up to 6 mg but increased above dose proportionality with higher dose levels. Plasma exposures at 6 mg and above were consistent with those resulting in inhibition of tumor p4EBP1 in preclinical models. Of 5 patients evaluable for efficacy at doses of 6 mg and higher, one confirmed PR was observed in a patient with head and neck cancer with a pathogenic mutation in PTEN (ORR 20%) and 3 patients had a best response of SD. Dose-optimization is ongoing. Conclusions: RMC-5552 is clinically active in tumors with mTORC1 signaling activation at a tolerable dose and schedule and has the potential to be a companion inhibitor of choice for RAS(ON) inhibitors in RAS-addicted tumors. Clinical trial information: NCT04774952.

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Burris III, Howard A., Susanna Varkey Ulahannan, Eric B. Haura, Sai-Hong Ignatius Ou, Anna Capasso, Pamela N. Munster, Hidenori Kitai, et al. "The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3098. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3098.

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3098 Background: RMC-5552 is a potent bi-steric mTORC1-selective inhibitor that activates the downstream tumor suppressor 4EBP1, thereby inhibiting initiation of protein translation. This novel therapeutic moiety addresses a key limitation of rapalogs, which do not effectively inhibit phosphorylation of 4EBP1. RMC-5552 has previously demonstrated significant anti-tumor activity in preclinical models of human cancers with mTOR pathway activation. Additionally, mTOR signaling plays a key role in therapeutic response and resistance in RAS-addicted cancers, which represent a significant unmet medical need. Methods: We examined the combination of bi-steric mTORC1 inhibitors (RMC-5552 and the research tool compound RMC-6272) with direct inhibitors of active RAS (RAS(ON) inhibitors) in mutant KRAS-driven models. To enable the clinical testing of RMC-5552 as a companion inhibitor for RAS(ON) inhibitors, a Phase 1/1b dose-escalation trial of RMC-5552 monotherapy is currently testing a once-a-week IV schedule. Results: RMC-5552 and RMC-6272 demonstrated marked combinatorial anti-tumor activity with RAS(ON) inhibitors across a series of preclinical models of KRAS mutated non-small cell lung cancer. The combination enhanced tumor apoptosis and resulted in durable tumor regressions as compared to tumor growth inhibition resulting from single agents alone. As of 13 January 2022, a total of 14 patients with solid tumors have been evaluated in an ongoing Phase 1/1b trial over 5 dose levels ranging from 1.6 to 12 mg IV weekly. Median age was 62 years and the majority received ≥3 prior therapies. The most common (> 25%) drug-related adverse events were mucositis/stomatitis (43%) and decreased appetite (29%). The most common grade 3 drug-related adverse events were mucositis/stomatitis observed in 3 patients in dose levels ≥ 10 mg (21%) and were dose-limiting. The dose of 6 mg IV weekly was well tolerated. Plasma exposures of RMC-5552 were dose-proportionate at lower dose levels up to 6 mg but increased above dose proportionality with higher dose levels. Plasma exposures at 6 mg and above were consistent with those resulting in inhibition of tumor p4EBP1 in preclinical models. Of 5 patients evaluable for efficacy at doses of 6 mg and higher, one confirmed PR was observed in a patient with head and neck cancer with a pathogenic mutation in PTEN (ORR 20%) and 3 patients had a best response of SD. Dose-optimization is ongoing. Conclusions: RMC-5552 is clinically active in tumors with mTORC1 signaling activation at a tolerable dose and schedule and has the potential to be a companion inhibitor of choice for RAS(ON) inhibitors in RAS-addicted tumors. Clinical trial information: NCT04774952.

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Puzanov, Igor, Jason Chesney, Frances Collichio, Parminder Singh, Mohammed Milhem, John Glaspy, Omid Hamid, et al. "433 Talimogene laherparepvec (T-VEC) in combination with ipilimumab (IPI) versus IPI alone for advanced melanoma: 4-year interim analysis of a randomized, open-label, phase 2 trial." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A459. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0433.

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BackgroundThis is the first randomized trial evaluating an oncolytic virus with an immune checkpoint inhibitor in advanced melanoma. Improved objective response rate (ORR) was observed for T-VEC plus IPI compared to IPI alone (39% vs. 18%; OR 2.9; 95% Cl, 1.5–5.5; P=0.002).1 At 3-year follow-up, median OS was not reached in either arm (HR, 0.85; 95% CI, 0.55–1.32; P=0.480).2 Here we present 4-year interim analysis results including BRAF V600 mutation subgroup analysis.MethodsPatients with unresectable or metastatic (IIIB-IV) melanoma were randomized 1:1 to receive T-VEC plus IPI or IPI alone. T-VEC was injected day 1, week 1, at 106 PFU/mL, followed by 108 PFU/mL on day 1, week 4, and Q2W thereafter. IPI (3 mg/kg) was given Q3W starting day 1, week 6, up to 4 doses, for T-VEC arm; day 1, week 1 for IPI alone. Response was assessed per immune-related response criteria (irRC) Q12W until disease progression. The primary endpoint was ORR; key secondary endpoints were overall survival (OS), progression-free survival (PFS), durable response rate (DRR), and safety (NCT01740297).ResultsA total of 198 patients (98 combination, 100 IPI alone) were randomized. As of February 25, 2020, median follow-up was 48.3 months for combination and 35.7 months for IPI alone. DRR improved for combination vs. IPI (33.7% vs. 13.0%; OR 3.4; 95% CI, 1.7–7.0; P=0.001). Median PFS was 13.5 months with combination and 6.4 months with IPI (HR 0.81; 95% Cl, 0.57–1.15; P=0.23). Median OS was not reached for combination and was 50.1 months for IPI (HR 0.82; 95% CI, 0.54–1.25; P=0.36). For combination, 47 (48.0%) patients received subsequent anti-cancer therapy vs. 64 (64.0%) for IPI; median time from randomization to first subsequent therapy was 27.7 months and 8.3 months, respectively. In subgroup analysis, patients without BRAF V600 mutation (63% combination, 60% IPI) improved DRR and PFS for combination vs. IPI alone (DRR: 33.9% vs. 5.0%; median PFS: 18.0 months vs. 4.5 months); BRAF V600 mutation positive patients (36% combination, 34% IPI) were similar between arms (DRR: 34.3% vs. 26.5%; median PFS: 4.2 months vs. 6.4 months). No additional safety signals observed in follow-up.ConclusionsThe improved PFS and DRR for the combination arm at 4-year follow-up indicates continued benefit of combination therapy. Patients receiving IPI alone were more likely to receive subsequent anti-cancer therapy in a shorter time. Subsequent anticancer therapies may confound OS analysis. The BRAF mutant post-hoc analysis requires further mechanistic investigation.Acknowledgements• The authors thank the investigators, patients, and study staff who contributed to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT01740297Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesChesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol 2018;36:1658–1667.Chesney JA, Puzanov I, Collichio F, et al. Talimogene laherparepvec (T-VEC) in combination (combo) with ipilimumab (ipi) versus ipi alone for advanced melanoma: 3-year landmark analysis of a randomized, open-label, phase 2 trial. Ann Oncol 2019;30:mdz394-067.

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Goss, Glenwood D., Christian Manegold, Rafael Rosell, Dean Anthony Fennell, Vojislav M. Vukovic, Iman El-Hariry, Florentina Teofilovici, Aaron S. Enke, and Suresh S. Ramalingam. "The GALAXY Trial(NCT01348126): A randomized IIB/III study of ganetespib (STA-9090) in combination with docetaxel versus docetaxel alone in subjects with stage IIIB or IV NSCLC." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS7613. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps7613.

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TPS7613^ Background: Hsp90 is a molecular chaperone required for proper folding and activation of many cancer-promoting proteins and is recognized as a key facilitator of cancer cell growth and survival. In pre-clinical models, Hsp90 inhibition causes degradation of multiple client proteins and leads to cancer cell death. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown potent anti-tumor activity in patients with lung, breast, and other cancers that had progressed on standard treatment agents. Moreover, combination of ganetespib with docetaxel results in synergistic antiproliferative effects in several human non-small cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and is devoid of severe liver or common ocular toxicities that have been observed with some other Hsp90 inhibitors. Diarrhea is the most common adverse event and is manageable with appropriate supportive care. In a recent report, ganetespib administered at 200 mg/m2 weekly showed activity in pretreated patients with advanced NSCLC patients with ELM4-ALK translocation and KRAS mutations. Methods: Stage 1 (240 subjects): randomized, international open-label Phase 2B study in subjects that progressed on or after one prior systemic therapy for stage IIIB or IV NSCLC: patients are prospectively stratified for ECOG performance status, histology, total LDH, interval since diagnosis, and smoking status. Co-primary endpoints are PFS in the ITT population, and PFS in patients with KRAS mutations. Main secondary endpoints include ORR, disease control rate, OS and clinical activity in different molecular subtypes, including BRAF, HER2, EGFR, EML4-ALK. Patients on the control arm are treated with docetaxel 75 mg/m2 on day 1 of a three-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on day 1 (with docetaxel) and day 15 of a three-week cycle. At the time of submission 90 subjects had been enrolled in Stage 1.

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Stanciu, Silviu, Alexandru Burcin, Diana Iancu, Maria Magdalena Gurzun, Alexandru Croitoru, and Lucian Ciobîcă. "Prosthetic Heart Valves Thrombosis with Infectious Endocarditis - A Practical Review." Internal Medicine 17, no. 6 (December 1, 2020): 55–64. http://dx.doi.org/10.2478/inmed-2020-0143.

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Abstract Simultaneous or sequential combination of prosthetic valve (PV) thrombosis and infectious endocarditis is a rare clinical finding. The management of these patients involves a complex multidisciplinary strategy using clinical judgment and imaging techniques. Transesophageal echocardiography (TEE) and especially 3D transesophageal echocardiography is essential. Moreover, positron emission tomography with fluorodeoxyglucose (F18-FDG PET/CT) can be a valuable tool to diagnose and manage these complicated clinical scenarios. We present the case of a 65-year-old patient who was admitted in our clinic for paroxysmal nocturnal dyspnea and chills for one week. He had multiple surgical interventions for rheumatic mitral valve disease (percutaneous mitral valvuloplasty in 2008, and mitral valve replacement and tricuspid annuloplasty in October 2019). At admission, the diagnosis of prosthetic valve thrombosis was established taking into account the clinical context (low INR values for the last two months), the patient symptoms and the echocardiographic findings. IV unfractionated heparin was administered. One week after admission the patient’s clinical status further deteriorated. TEE reevaluation showed partial thrombus regression with elements suggestive for concomitant infectious endocarditis. The diagnosis key is the clinical evolution and repeated TEE evaluations. In our case, they enabled the probable diagnosis of a sequential association of thrombosis and infectious endocarditis on mechanical PV. The therapeutic approach requires a high clinical suspicion and a prompt management, emergent surgery being the only lifesaving strategy in unstable patients with obstructive mechanical pathology.

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Azzoli, C. G., L. Krug, V. Miller, S. Bekele, L. Tyson, M. Dunne, M. Huntington, M. Saunders, and M. G. Kris. "Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients (pts) with advanced non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 13006. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.13006.

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13006 Background: Pralatrexate is a novel antifolate that has shown promising activity in the treatment of pts with previously- treated NSCLC at doses of 135–150 mg/m2 IV every other week (q2w). [Krug, Clin Cancer Res 9(6), 2003; 6(9), 2000] The addition of vitamin B12 and folic acid supplementation may mitigate toxicity from pralatrexate and improve efficacy by allowing higher doses to be delivered. Methods: This study is designed to determine the maximum tolerated dose (MTD) of pralatrexate in combination with vitamin B12 and folic acid supplementation in pts with NSCLC. Key eligibility criteria include confirmed stage IIIB or IV NSCLC; at least 1 prior chemotherapy regimen; Karnofsky performance status (KPS) = 70%; and no other active concurrent malignancy. Using a rapid escalation design, pralatrexate was initially administered at a dose of 150 mg/m2 IV q2w, escalating by 40 mg/m2 increments in successive cohorts, with one patient per cohort if no dose limiting toxicity (DLT) is encountered. All pts receive vitamin B12 1 mg intramuscular q 8–10 weeks and folic acid 1 mg by mouth once a day beginning at least 7 days prior to pralatrexate. All patients undergo pharmacokinetic testing following their first and second dose of pralatrexate. Results: Between 1/05–12/06, a total of 9 pts have been treated at the following dose levels: 150 (n=1), 190 (n=1), 230 (n=1), and 270 (n=6). Patient characteristics include: 2 male/7 female; median age 63 (range 52–73); KPS 80–90%; all pts had stage 4 NSCLC; 5 pts received 1 prior regimen and 4 pts received 2 or more prior regimens. Grade 3 esophagitis was a DLT in one patient at the 270 mg/m2 dose. Three other patients experienced grade 1–2 mucositis at this dose level without limiting drug delivery. The trial is ongoing, and enrollment is planned at 310 mg/m2 q2w to determine the MTD. Conclusions: When given in combination with vitamin B12 and folic acid supplementation, pralatrexate has been well tolerated in this pt population, with an MTD at least twice as high as achieved in previous phase 1 testing without supplementation. We plan to conduct a phase 2 trial of pralatrexate with vitamin B12 and folic acid supplementation to see if a higher dose will improve efficacy. No significant financial relationships to disclose.

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Mariette, X., C. Baldini, F. Barone, H. Bootsma, K. Clark, S. De Vita, K. Lerang, et al. "OP0135 SAFETY AND EFFICACY OF SUBCUTANEOUS BELIMUMAB AND INTRAVENOUS RITUXIMAB COMBINATION IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME: A PHASE 2, RANDOMISED, PLACEBO-CONTROLLED 68-WEEK STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 78.2–79. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2170.

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Background:B-lymphocyte stimulator (BLyS) is increased in primary Sjögren’s syndrome (pSS) and plays a role in the B-cell hyperactivity thought to contribute to pSS. Belimumab (BEL, anti-BLyS) and rituximab (RTX, anti-CD20) target B cells through distinct and potentially complementary mechanisms.Objectives:To evaluate the safety and efficacy of subcutaneous (SC) BEL/intravenous (IV) RTX combination (BEL/RTX) in patients with pSS.Methods:This Phase 2, double-blind study (GSK Study 201842; NCT02631538) randomised 86 adults with active pSS to 4 treatment arms stratified for baseline EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores 5-12 or >12: placebo (PBO; N=13), BEL/RTX (N=24; BEL 200 mg SC weekly to Week [Wk] 24 followed by weekly PBO SC to Wk 52 + RTX 1000 mg IV, Wk 8 + 10), BEL monotherapy (N=24; BEL 200 mg SC weekly to Wk 52) or RTX monotherapy (N=25; RTX 1000 mg IV, Wk 8 + 10). Follow-up was at Wk 68. Safety to Wk 68 was the primary endpoint (safety population; patients received ≥1 dose of study treatment). Secondary/other endpoints (completer population; patients completed treatment and follow-up phase) were ESSDAI score, stimulated salivary flow, CD20+ B-cell count within salivary gland biopsies, patient-reported oral dryness, and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score.Results:Baseline demographics and disease characteristics were similar among arms. Adverse events (AEs) were balanced across arms. Serious AEs were infrequent but occurred only in active treatment arms (Table). No unexpected safety issues were identified with BEL/RTX relative to BEL or RTX. Treatment phase and follow-up were completed by 60/86 patients. ESSDAI reductions with BEL/RTX were numerically greater over time than PBO, with greatest difference at Wk 68 (Table), but were not differentiated from monotherapy. Stimulated salivary flow showed a trend favouring BEL/RTX vs PBO over later time points (Table). In contrast with PBO, BEL, and RTX, salivary gland biopsies from BEL/RTX showed almost complete B-cell depletion (Wk 24). There was no clear evidence for a positive effect of BEL/RTX on patient-reported oral dryness or ESSPRI score.Table 1.Key safety endpoints and selected efficacy endpointsAEs – safety populationPBO(N=13)BEL/RTX (N=24)BEL(N=24)RTX(N=25)AEs, n (%)13 (100)24 (100)23 (96)24 (96)Drug-related AEs, n (%)10 (77)17 (71)16 (67)14 (56)AEs leading to discontinuation/withdrawal, n (%)1 (8)5 (21)3 (13)5 (20)SAEs, n (%)03 (13)2 (8)4 (16)Number of SAEs0427Deaths, n (%)01 (4)*00Infections and Infestations, n (%)†11 (85)19 (79)21 (88)18 (72)Efficacy – completer populationPBO (N=8)BEL/RTX (N=17)BEL (N=19)RTX (N=16)ESSDAI change, LS mean (SE) from BL over time‡Wk 12-2.00 (1.449)-4.85 (0.996)-3.87 (0.949)-4.22 (1.048)§Wk 24-2.87 (1.324)-5.32 (0.911)-3.87 (0.869)-5.25 (0.940)Wk 52-2.87 (1.294)-5.67 (0.890)-4.76 (0.850)-4.32 (0.919)Wk 68-1.75 (1.400)-5.73 (0.962)-3.87 (0.918)-4.38 (0.994)Stimulated salivary flow (ml/min), mean (SD)BL0.47 (0.247)0.71 (0.629)0.43 (0.329)0.62 (0.621)Wk 120.49 (0.205)0.75 (0.834)0.49 (0.373)0.58 (0.527)Wk 240.55 (0.305)0.78 (0.790)0.45 (0.411)0.72 (0.890)Wk 520.53 (0.378)1.00 (1.146)0.58 (0.608)0.69 (0.781)Wk 680.36 (0.163)0.88 (0.817)0.52 (0.450)0.73 (0.785)§*Aspiration (n=1); not considered related to treatment; patient died of food aspiration; †System organ class with the highest percent of AEs; ‡Analysis was performed using mixed model repeated measures; §n=15.BL, baseline; LS, Least square; SAEs, serious AEs; SD, standard deviation; SE, standard errorConclusion:No unexpected safety issues were identified with BEL/RTX relative to BEL or RTX. BEL/RTX showed a trend towards improvement in ESSDAI and stimulated salivary flow over time, which was sustained post treatment. BEL/RTX depleted B cells in minor salivary gland biopsies.Funding: GSKAcknowledgements:Medical writing assistance was provided by Katalin Bartus, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Xavier Mariette Consultant of: BMS, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier, UCB, Grant/research support from: Servier, Chiara Baldini: None declared, Francesca Barone Consultant of: GSK, UCB, Roche, Actelion, Grant/research support from: GSK, UCB, Roche, Actelion, Employee of: Kintai therapeutics, Candel Therapeutics, Hendrika Bootsma Speakers bureau: BMS, Novartis, Consultant of: BMS, Roche, Novartis, MedImmune, UCB, Servier, Grant/research support from: BMS, Roche, Ken Clark Shareholder of: GSK, Employee of: GSK, Salvatore De Vita Consultant of: GSK, Roche, Karoline Lerang: None declared, Prafull Mistry Shareholder of: GSK, Employee of: GSK, Frederic Morin: None declared, Rajesh Punwaney Shareholder of: GSK, Employee of: GSK, Raphaèle Seror Consultant of: GSK, BMS, Fresenius Kabi, Boehringer, Jansen, Amgen, Pfizer, Roche, Paul LA van Daele: None declared, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Nicolas Wisniacki Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

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Campbell, Matthew T., Tian Zhang, Lynda Chin, Allison Betof Warner, and Matthen Mathew. "ApricityRx companion digital therapeutic for evidence-based mitigation and phenotype-linked molecular characterization of irAEs in patients receiving immune checkpoint therapy (ICT)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS2089. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps2089.

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TPS2089 Background: Presentation of immune-related adverse events (irAEs) is heterogeneous and unpredictable in patients receiving immune checkpoint therapy (ICT). ICT has been approved for cancer patients as single agent, combination of dual ICT, ICT plus chemotherapy, and ICT plus targeted therapy. Given the ever increasing complexity in recognizing and managing irAEs, coupled with the lack of skilled resources and clinical experience in real world practice, there is increasing demand for digital solutions that can detect early toxicity and support evidence-based interventions in real world practice. To this end, we have developed ApricityRx, a companion digital therapeutic for end-to-end irAE management. In addition to (i) teaching patients about immune-related toxicities and (ii) empowering them to monitor key symptoms and vital signs, ApricityRx continuously analyzes the combined patient-reported data and longitudinal EMR data to (iii) detect symptom-triggers and lab test-triggers of irAEs, and (iv) activate the clinical team to triage, evaluate and treat in a timely fashion, while (v) providing access to synthesized longitudinal patient information and expert guidance on evidence-based management and care. In a feasibility trial conducted in a community setting, we demonstrated two-thirds of the study participants completed on average 5 eCheck-ins per calendar week (overall average 4 times per week), with 5% of the check-ins resulting in notifications alerting the clinical team to evaluate for the early signs of an irAE. Methods: To accelerate translational research in irAEs and to develop predictive biomarkers for risk stratification, we are launching a single-arm, open-label study that utilizes ApricityRx in patients receiving ICT alone or in combination. The objectives of the study will include (i) defining the operative characteristics of ApricityRx as an irAE mitigation strategy; (ii) identifying patients and time points for phenotype-triggered biospecimen collection and molecular characterization. The study aims to enroll initially up to 100 participants per site, with a total target of 1,000.

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Wendtner, Clemens-Martin, John C. Byrd, Robin Foà, Richard Greil, Peter Hillmen, Ulrich Jäger, Wojciech Jurczak, et al. "COSMOS: MOR208 plus idelalisib or venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton's tyrosine kinase inhibitor (BTKi)—A two-cohort phase II study." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS7567. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps7567.

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TPS7567 Background: Patients (pts) with R/R CLL who discontinue treatment with the BTKi ibrutinib due to progression have a particularly dismal prognosis. A phase I study showed that the Fc-enhanced, humanized, CD19 antibody MOR208 was well tolerated with encouraging single-agent activity in pts with R/R CLL/SLL. In preclinical models, MOR208 showed synergy with idelalisib (an inhibitor of PI3K delta) and venetoclax (an inhibitor of BCL-2), both approved for the treatment of CLL. Methods: This two-cohort, phase II study will investigate MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in pts with R/R CLL or R/R SLL and includes a safety run-in phase for each cohort, to be evaluated by an Independent Data Monitoring Committee. Key inclusion criteria: aged ≥18 years, R/R CLL/SLL while receiving a BTKi therapy or intolerance of such therapy, BTKi administered as a single-agent or in combination for at least 1 month as the most recent prior anticancer therapy, ECOG performance status of 0–2, and adequate organ function. Key exclusion criteria: transformed CLL/SLL or Richter’s syndrome, BTKi treatment within 5 days prior to study drug dosing, prior treatment with a CD19-targeted therapy, a PI3K inhibitor (cohort A) or a BCL-2 inhibitor (cohort B). Pts will be treated for a maximum of 24 (28-day) cycles or until disease progression. Treatment will be MOR208 12 mg/kg IV (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice-daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Primary endpoint: overall response rate based on independent review; secondary and exploratory endpoints include: progression-free and overall survival, duration of response, safety, pharmacokinetics, MOR208 immunogenicity, quality of life and minimal residual disease negativity. 120 pts per cohort are planned. Clinical trial information: 2015-002915-14.

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Lee, Michael Sangmin, Patrick J. Loehrer, Iman Imanirad, Stacey Cohen, Kristen Keon Ciombor, Dominic T. Moore, Cheryl Ann Carlson, Hanna Kelly Sanoff, and Autumn Jackson McRee. "Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 7. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.7.

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7 Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.

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Dunne, Richard Francis, Nicholas A. Ullman, Brian A. Belt, Luis I. Ruffolo, Paul Burchard, Aram F. Hezel, Jason Zittel, et al. "A phase I study to evaluate the safety and tolerability of SX-682 in combination with PD-1 inhibitor as maintenance therapy for unresectable pancreatic adenocarcinoma." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): TPS631. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.tps631.

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TPS631 Background: Survival outcomes for advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal despite improvements in systemic therapy regimens developed over the past decade. In addition, current first-line therapies result in cumulative cytopenias and neuropathy, highlighting the need for more effective, less toxic maintenance treatment strategies. There are currently no standard approved maintenance treatments for patients with PDAC not associated with BRCA or DNA-repair mutations. Pre-clinical data suggest a potential synergistic effect of combining blockade of CXC chemokine receptors (CXCR) with immunotherapy or chemotherapy in pancreatic cancer1,2. We are currently conducting a Phase I study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and Nivolumab as maintenance treatment for advanced PDAC. Methods: This is an open-label, dose escalation Phase I clinical trial evaluating the combination of SX-682 and Nivolumab. Patients must have histologically confirmed unresectable PDAC and have completed at least 16 weeks of first-line chemotherapy with disease stability or treatment response at time of enrollment. Radiographically measurable disease must be present per iRECIST criteria. Patients receive a 3-week run-in phase of twice-daily dosing of SX-682, followed by combination of twice-daily dosed SX-682 and every 2-week Nivolumab (240 mg IV). Dose finding of SX-682 is performed using Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD) when combined with Nivolumab. Pre-treatment and one on treatment (Day 28-35) biopsies are required for enrollment to evaluate change in tumor microenvironment immune cell composition by single cell-RNA sequencing, flow cytometry, RNA RT-qPCR, and IHC. The primary endpoint is to determine MTD; the key secondary endpoint is progression-free survival (PFS), defined as the time from enrollment to progression via iRECIST criteria or death. Nine of a planned 20 patients have been enrolled. Dose-level 1 (SX-682 50 mg BID) completed enrollment without dose-limiting toxicity (DLT). Dose-level 2, which commenced in June 2021, (SX-682 100 mg BID) is without DLTs, but has not completed enrollment at time of abstract submission. Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. 1) Gut. 2018;67(6):1112-1123. Steele CW, Karim SA, Leach JDG, et al. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. 2) Cancer Cell. 2016;29(6):832-845. Clinical trial information: NCT04477343.

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Song, Yuqin, Jun Zhu, Ningjing Lin, Chen Zhang, Xiaoping Jin, Shuping Xu, Baiyong Li, and Yu Xia. "A phase I/II study of the anti-programmed cell death-1 (PD-1) antibody AK105 in patients with relapsed or refractory classic Hodgkin lymphoma (cHL)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e19017-e19017. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e19017.

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e19017 Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy. These features were designed to offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I/II, single-arm study in relapsed/refractory cHL (NCT03722147) began in July, 2018, evaluating the safety and efficacy of AK105 administered IV q2w till disease progression (response assessed by Lugano 2014 criteria). Eligible pts had relapsed/refractory cHL after most recent therapy with progression after autologous hematopoietic stem cell transplantation, or at least 2 lines of prior chemotherapy. Enrollment for Phase I part of the study was completed, and Phase II at the RP2D of AK105 200 mg q2w is ongoing. Results: As of 1 Feb, 2019, in the Phase I part, 6 Chinese patients (pts) median age 26.5 years [19–38], female 33%, ECOG 0/1 ([67%/33%]), had received a median of 7 (3–12) doses of AK105 200mg q2w. No DLT and SAE were reported. No immune-related grade 2 (G2) or higher adverse reactions were reported. Treatment-related adverse events (TRAEs) occurred in 83% (5/6) of pts (G3 in 17% [1/6], no G4, none leading to treatment interruption or discontinuation). Most frequent TRAEs (≥2 pts) were hypothyroidism (33%, 2/6) and ALT increased (33%, 2/6). PK profile for Chinse pts is consistent with that in Caucasian pts. Of 5 evaluable heavily pretreated pts, ORR was 100% (5/5, 3 CR and 2 PR). All 3 pts achieved CR at the first tumor assessment (i.e., week 8) and remained in CR at the last assessment (i.e., week 24) prior to data cutoff. The other 2 pts achieved PR at week 8 and the responses are still ongoing. Conclusions: The reported safety profile and encouraging early antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in relapsed/refractory cHL and metastatic nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in hepatocellular carcinoma. Clinical trial information: NCT03722147.

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Hammel, Pascal, Iman El-Hariry, Teresa Macarulla, Rocio Garcia-Carbonero, Jean-Philippe Metges, Olivier Bouché, Fabienne Portales, et al. "Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with advanced pancreatic adenocarcinoma (NCT03665441)." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 518. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.518.

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518 Background: Eryaspase, asparaginase encapsulated in red blood cells is an investigational product under development. The encapsulated asparaginase induces the degradation of asparagine and glutamine, crucial for cancer cell growth and survival. An earlier Phase 2b study in patients with advanced pancreatic cancer showed an improvement in overall survival (OS) and progression free survival (PFS) with eryaspase plus chemotherapy. Methods: TRYbeCA-1 was a randomized, open-label Phase 3 trial of eryaspase combined with chemotherapy in patients with advanced adenocarcinoma of the pancreas who have progressed on only one prior line of systemic anti-cancer therapy. Patients were randomized in a 1:1 ratio to gemcitabine/nab-paclitaxel or irinotecan/fluorouracil (5FU) therapy (depending on first-line received) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria included progression on or following first-line systemic treatment, ECOG performance status 0 or 1, stage III-IV disease, documented evidence of disease progression, available tumor tissue and adequate organ function. The primary endpoint was OS. A total of 412 events were required for 90% power to detect a treatment effect hazard ratio (HR) of 0.725 at a two-sided significance level of 5%. Results: A total of 512 patients were included. Baseline characteristics were well balanced between the treatment arms. The study did not meet the OS primary endpoint [HR: 0.92 (95% confidence interval (CI), 0.76-1.11), p-value 0.375]. The median OS for patients treated with eryaspase plus chemotherapy was 7.5 mo (95% CI, 6.5-8.3), compared to 6.7 mo (95% CI, 5.4-7.5) for chemotherapy alone. There was a trend of nominal OS benefit in 107 patients treated with eryaspase and irinotecan-5FU compared to 109 patients in control subgroup, with a median OS of 8.0 mo versus 5.7 mo, respectively [HR: 0.81 (95% CI: 0.60- 1.09)]. Treatment effect was consistent across various prognosis factors. Median PFS was 3.7 mo vs. 3.5 mo in the eryaspase and control arms, respectively [HR: 0.89 (95% CI: 0.73-1.07), p-value 0.215]. Disease control rate was 57.6% and 49.0% (p-value 0.047) in the eryaspase and control arms, respectively. The most common adverse events were in the eryaspase arm were asthenia, diarrhea, and anemia (Grade 3-4: 16.9%, 7.66% and 17.3%, respectively). Eryaspase did not appear to enhance toxicity of chemotherapy. Conclusion: This large prospective study did not meet it primary endpoint of improving OS in patients treated with eryaspase. The addition of eryaspase demonstrated nevertheless a well-tolerated profile and an encouraging survival benefit in the irinotecan/5FU subgroup, warranting further investigation. Clinical trial information: NCT03665441.

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Lacy, M., M. Alsina, C. L. Melvin, L. Roberts, D. Yin, J. F. Petersen, A. Birgin, S. Poutney, A. Sharma, and A. Gualberto. "Phase 1 first-in-human dose escalation study of cp-751,871, a specific monoclonal antibody against the insulin like growth factor 1 receptor." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7609. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7609.

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7609 Background: Multiple lines of evidence indicate that the Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in the progression of multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes survival to the cytotoxic effects of chemotherapy in animal models of MM and its blood levels has been shown to correlate with those of paraprotein in MM patients. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. Methods: Based on its mechanism of action and the potential relevance of IGF-1R in MM, a Phase 1 First-in-Human dose escalation study was initiated with the objective to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic properties of CP-751,871 in this patient population. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase and/or less than complete remission following autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 10 dose-escalation cohorts of patients received from 0.025 to 10 mg/kg of CP-751,871 by iv infusion on Day 1 of 4-week cycles. In patients with a suboptimal response to CP-751,871 alone, oral dexamethasone was added to the treatment regimen. Patients received up to 14 cycles of CP-751,871 therapy, alone or in combination with dexamethasone. No dose limiting toxicities have been identified to date. Plasma CP-751,871 exposure increases with dose, and the pharmacokinetic characteristics are consistent with target-mediated disposition. Pharmacodynamic measurements indicate complete target saturation by CP-751,871 for the complete length of the dosing period. One near CR and 2 PR in combination with dexamethasone have been reported. Conclusions: These data indicate that CP-751,871 is well tolerated and may constitute a therapeutic approach for patients with multiple myeloma. [Table: see text]

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Flood, W. A., and L. D. Lewis. "A phase I study of intravenous (IV) milataxel in combination with carboplatin in adult patients with advanced malignant solid tumors." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e13525-e13525. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e13525.

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e13525 Background: Milataxel (MXL) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The primary objective of this study was to determine the MTD when MXL was given intravenously in combination with a fixed dose (AUC=6) of carboplatin (C) every 21 days in subjects with advanced malignant solid tumors. Secondary objectives were to (i) assess the safety and tolerability of the combination (ii) define the pharmacokinetics of MXL and C when given in combination (iii) obtain preliminary information on the antitumor activity of MXL+C. Methods: Key subject eligibility criteria included: adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. PK data was obtained on day 1 for MXL and both free and bound platinum. Results: 11 pts (median age 60; 2 F,9 M) were treated. MXL was dose escalated in three cohorts (15, 20 and 25 mg/m2). Three patients were treated at 15 mg/m2 of MXL without a DLT. At the 25 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose (1 pt - grade 3 febrile neutropenia, grade 4 thrombocytopenia; 1 pt - grade 4 ANC, grade 4 thrombocytopenia). At the 20 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose with both pts having grade 4 ANC. The MTD and the recommended Phase II dose of MXL was 15 mg/m2 plus C (AUC= 6). The median number of cycles administered was 3 (range 1–16). The most frequent grade 3 or 4 treatment emergent adverse events were neutropenia (82%), leukopenia (55%), pancytopenia (27%), asthenia (18%), generalized edema (18%), thrombocytopenia (18%), anemia (18%), confusion (18%), and dyspnea (18%). One pt in the MTD cohort with cholangiocarcinoma had a PR. This patient received 16 cycles of therapy and had a response duration of 378 days and a TTP of 406 days. PK data (n=9) showed the elimination half-life of MXL ranged from 26 to 110 h, and that for free and total platinum were as would be predicted for C monotherapy. Conclusions: The MTD of MXL was 15 mg/m2 IV per three week cycle when combined with carboplatin (AUC= 6). One patient with a cholangiocarcinoma had a sustained PR for 378 days. No significant financial relationships to disclose.

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Odia, Yazmin, Ludimila Cavalcante, Howard Safran, Steven Francis Powell, Pamela N. Munster, Wen Wee Ma, Benedito A. Carneiro, Bruno R. Bastos, Francis J. Giles, and Solmaz Sahebjam. "Malignant glioma subset from Actuate 1801: A phase 1/2 study of 9-ING-41, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory hematologic malignancies or solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2051. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2051.

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2051 Background: GSK-3β, a serine/threonine kinase, is a key regulator of metabolism and glycogen biosynthesis. GSK-3β aberrant overexpression promotes tumor progression and chemotherapy resistance through NF-κB and p53-mediated apoptotic pathways. GSK-3β inhibition impacts immunomodulation through downregulation of checkpoints, such as PD-L1 and LAG-3, and increasing NK and T-cell mediated killing of tumor cells. 9-ING-41 is a small-molecule potent selective GSK-3β inhibitor with preclinical antitumor activity against several tumor types. In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11. Methods: In the first-in-human study (NCT03678883), patients (pts) with refractory malignancies received 9-ING-41 monotherapy (n = 65) or in combination with one of 8 cytotoxic regimens after prior treatment with the same chemotherapy (n = 162). We report the subset of pts with recurrent gliomas treated with 9-ING-41 monotherapy IV twice a week in 21-day cycles at different dose levels (3.3, 5, 9.3, 15mg/kg), or in combination with lomustine 30 mg/m² orally once weekly in 84-day cycles. Primary objective was safety and tolerability. Results: An RP2D of 15mg/kg IV was confirmed across all 9 regimens, no accentuation of chemotherapy-related toxicity noted. Of 18 glioma patients enrolled, 13 were GBM, 2 anaplastic astrocytomas, 1 diffuse astrocytoma, and 1 anaplastic oligodendroglioma. Four patients received single agent 9-ING-41, 14 treated concurrently with lomustine. Demographics: 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18). Median recurrences 3 (1-6). Genomic alterations from available NGS reports included: IDH WT (11), IDH mutation (3), MGMT promoter unmethylated (11), MGMT promoter methylated (1), 1p19q co-deletion (10), EGFR amplification (6), EGFR v3 mutation (3), TERT promoter mutation (6), PTEN loss (3), NF1 rearrangement (2), ATRX loss (2), TP53 mutated (4), CDKN2A deletion (2), RB1 loss (1), PALB-2 mutation (10). No SAEs or grade 3/4 AEs attributed to 9-ING-41 were noted; AEs included G1/2 transient vision changes (9/18, 50%), infusion reactions (4/18, 22%). Side effects from lomustine included: G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine. Median days on therapy was 55 (4-305), 4/18 (22%) were stable for 20 weeks or longer. Conclusions: These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients. Clinical trial information: NCT03678883.

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Menon, Nandini Sharrel, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Atanu Bhattacharjee, Devanshi Kalra, Vijayalakshmi Mathrudev, Arti Bhelekar, and Kumar Prabhash. "Quality of life in patients with locally advanced head and neck cancer undergoing chemoradiation with once-a-week versus once-every-three-weeks cisplatin." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 12092. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.12092.

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12092 Background: This trial was conducted to compare the efficacy of low dose once-a-week cisplatin with once-every-3-weeks cisplatin with radiation in locally advanced head and neck squamous cell carcinoma (LAHNSCC). The current analysis focuses on the quality of life (QoL) of patients in this trial. Methods: In this phase III randomized trial, patients with stage III or IV non-metastatic LAHNSCC were randomized to receive cisplatin 30 mg/m2 once a week or cisplatin 100 mg/m2 once every 3 weeks concurrently with curative intent radiotherapy. The primary endpoint was locoregional control. QoL was a key secondary endpoint. QoL was assessed using the EORTC QLQ-C30 (v.3) and EORTC QLQ-H&N35 (v.1). QoL data were assessed at baseline and days 22 and 43 during treatment; at the end of chemoradiation and at each follow-up. The linear mixed effects model was used for longitudinal analysis of QoL domains to determine the impact of treatment (arm) and time on QoL scores. Results: Three hundred patients were enrolled, 150 in each arm. QoL data from 283 patients with at least one assessable questionnaire were analyzed. The pretreatment QoL scores were similar in both the arms in all domains. There was no significant difference in the global health status/QoL with respect to the treatment arm ( P =0.608) or time ( P=0.0544 ). There was no significant difference in the longitudinal QoL scores between the two treatment arms in all domains except the physical function ( P= .0074), constipation ( P= .0326), trouble with social contact ( P= .0321) and sexuality ( P= .0004). There was a decline in the QoL scores in all domains in both arms during treatment. After completion of treatment, the QoL scores started improving steadily up to 1 year and plateaued thereafter in both arms. Conclusions: The use of once-every-three weeks cisplatin significantly improved the locoregional control without adversely impacting the quality of life as compared to once-a-week cisplatin in combination with radical radiotherapy in locally advanced HNSCC. Clinical trial information: CTRI/2012/10/ 003062. .

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Molyneaux, Michael, John Xu, David M. Evans, and Patrick Lu. "Effect on tumor growth by TGF-β1/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14652-e14652. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14652.

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e14652 Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.

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Shu, Catherine A., Koichi Goto, Byoung Chul Cho, Frank Griesinger, James Chih-Hsin Yang, Enriqueta Felip, John Xie, et al. "CHRYSALIS-2: A phase 1/1b study of lazertinib as monotherapy and in combination with amivantamab in patients with EGFR-mutant NSCLC." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS9132. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps9132.

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TPS9132 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved clinical outcomes for patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC); however, patients will inevitably progress due to acquired resistance mutations. Lazertinib is a potent, brain-penetrant, 3rd-generation EGFR TKI with efficacy against activating EGFR and resistance T790M mutations. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating EGFR and MET mutations. Synergistic inhibition of the EGFR by targeting the receptor’s extracellular domain with amivantamab and the kinase domain with lazertinib, may lead to more potent inhibition of the EGFR pathway and potentially delay resistance. In the ongoing CHRYSALIS phase 1 study (NCT02609776), preliminary antitumor activity has been demonstrated with the combination of lazertinib and amivantamab in patients with treatment-naïve and osimertinib-relapsed EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). Methods: CHRYSALIS-2 is an ongoing phase 1/1b open-label study of lazertinib as monotherapy and in combination with amivantamab in patients with advanced EGFRm NSCLC (NCT04077463; https://clinicaltrials.gov/ct2/show/NCT04077463 ). Phase 1 of the study has confirmed the safety and tolerability of lazertinib monotherapy in Japanese patients. The objective of phase 1b is to characterize the preliminary efficacy of lazertinib in combination with amivantamab in subpopulations of patients with EGFRm NSCLC (Phase 1b Expansion Cohorts) at the recommended combination dose of 1050 mg (1400 mg, ≥80 kg) IV amivantamab dosed weekly in cycle 1 (28-day cycle), every other week thereafter, and 240 mg oral lazertinib QD. Global enrollment in Phase 1b Expansion Cohorts is currently ongoing. Expansion Cohort A is enrolling patients who have progressed on 1st or 2nd-line osimertinib followed by platinum chemotherapy; Expansion Cohort B is enrolling patients with EGFR exon 20 insertion (Exon20ins) mutation who have progressed on prior therapy; and Expansion Cohort C is enrolling patients with uncommon non-Exon20ins EGFR mutations (i.e., S768I, L861Q, G719X) who are treatment-naïve or received 1st or 2nd-generation EGFR TKI as last therapy. The primary endpoints of the study are frequency of dose-limiting toxicity for phase 1 and 1b combination cohorts, and overall response rate for phase 1b expansion cohorts. Key secondary endpoints include safety (adverse events), pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, and overall survival. Safety assessments will include monitoring AEs, clinical laboratory tests, ophthalmologic examination, ECG, and ECHO/MUGA. Blood samples will be collected to access PK. Tumor response will be assessed every 6 weeks by the investigator using RECIST, v1.1. Clinical trial information: NCT04077463.

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Hauschild, A., U. Trefzer, C. Garbe, K. Kaehler, S. Ugurel, F. Kiecker, T. Eigentler, H. Krissel, and D. Schadendorf. "A phase II multicenter study on the histone deacetylase (HDAC) inhibitor MS-275, comparing two dosage schedules in metastatic melanoma." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 8044. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.8044.

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8044 Background: The acetylation of histones is a key component of gene regulation, which plays an important role in tumor initiation and progression. MS-275, an inhibitor of the benzamide series, is a synthetic orally available inhibitor of HDACs which showed anti-tumor activity in 3 phase 1 trials. Methods: A phase II, multicenter, randomized, parallel-group study of oral MS-275 evaluated the efficacy and toxicity in patients with non-resectable metastatic melanoma. Patients should have received at least one, but not more than two previous systemic therapies (chemo- and/or immunotherapy) for stage IV melanoma. Patients were stratified to receive either 3 mg MS-275 biweekly (days 1+15 of a 4-week cycle) or 7 mg MS-275 weekly (days 1+8+15 of a 4-week cycle) until disease progression or unacceptable toxicity. Study endpoints were the assessment of tumor response and toxicity. Results: A total of 28 patients have been randomized equally to the two dosing groups. Patients were classified as belonging to AJCC stage IVa (n=0), IVb (n=9; 32%), and IVc (n=19; 68%). In general, MS-275 was very well tolerated. No treatment-related SAEs have been observed. Most frequently reported side effects were nausea (CTC Grade 1+2, 32%) hypophosphatemia (CTC Grade 1–3, 29%), and diarrhea (CTC Grade 1+2, 18%). Stable diseases lasting from 8 wks to more than 48 wks have been observed in 4 pts (29%) in the 3 mg and 3 pts (21%) in the 7 mg dose group. Stabilizations occurred in these metastatic localizations: skin, peripheral and visceral lymph nodes, lung and bone, respectively. However, objective tumor responses were not observed. Conclusions: The results suggest that MS-275 is well tolerated and shows long-lasting tumor stabilizations in patients with pre-treated metastatic melanoma. The failure of objective tumor responses in the single-agent treatment with MS-275 warrants further evaluation also in combinational settings. [Table: see text]

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Miljkovic, Milos D., Kevin C. Conlon, Jennifer Hsu, Clare Sun, Adrian Wiestner, and Thomas A. Waldmann. "Phase 1 Trial of Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocytic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 3052. http://dx.doi.org/10.1182/blood-2019-130807.

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Background: Of the several drugs and drug combinations approved for treatment of relapsed and refractory chronic lymphocytic leukemia (CLL), the reported complete response rates are no greater than 30%. Obinutuzumab is a glycoengineered, humanized type 2 anti-CD20 monoclonal antibody thought to engage the immune system by directly activating antibody- dependent, cell-mediated cytotoxicity (ADCC); it is approved for treatment of chronic lymphocytic leukemia in combination with chlorambucil. The key mediators of ADCC are polymorphonuclear neutrophils, monocytes, and natural killer (NK) cells. Recombinant human Interleukin-15 (rhIL-15) is a stimulatory cytokine that promotes the differentiation and activation of NK cells, monocytes, and long-term CD8+ memory T-cells. In a Phase I trial, administration of rhIL-15 as a 5-day continuous intravenous infusion (civ) was associated with up to 45-fold increase in the number of NK cells at well- tolerated dose levels. Preclinical murine lymphoid malignancy models have shown increased efficacy of monoclonal antibodies when administered together with rhIL-15; BL/6 mice inoculated with EL4-CD20 cells (a syngeneic lymphoma line); including significant prolongation of survival with the IL-15/Rituximab combination compared to either drug given as single agent (90% v. 30% alive at 75 days). We hypothesized that rhIL-15-associated increase in NK cell number and activity would improve efficacy of obinutuzumab in treatment of relapsed and refractory CLL, and would increase the duration and depth of response; this phase I trial is testing the safety of the combination. Primary objective: determine the safety, toxicity profile, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of civ rhIL-15 administration in combination with obinutuzumab treatment Secondary objectives: 1) evaluate the potential antitumor activity of the combination of rhIL-15 and obinutuzumab by assessing the clinical response rate, minimal residual disease (MRD) status, progression-free survival, and overall survival in patients with relapsed and refractory CLL; 2) define the effects of rhIL-15 on the ADCC mediated by obinutuzumab using ex vivo peripheral blood mononuclear cells (PBMCs); 3) characterize the biological effects of rhIL-15 administered with obinutuzumab on the percentages and absolute numbers of circulating lymphocytes (T and NK cells) and the T- cell subsets (including naïve, central, and effector memory subsets) by flow cytometry Exploratory objectives: identify biomarkers predictive of response to rhIL-15 and obinutuzumab treatment, such as circulating tumor DNA (ctDNA) and baseline cytokine levels Eligibility criteria: 1) age ≥ 18 years; 2) ECOG ≤ 1; 3) Diagnosis of CLL or small lymphocytic lymphoma (SLL) with ≥ 50% of B cells expressing CD20; 4) measurable or evaluable disease that is refractory or relapsed following therapy with a BTK inhibitor OR have relapsed/refractory CLL and are intolerant to BTK inhibitor therapy; patients with del(17p) must also be refractory or relapsed after, or intolerant to, therapy with venetoclax; 5) adequate organ function parameters as defined within the protocol; 6) active disease requiring treatment, as defined within the protocol. Study design: a single institution non-randomized phase I dose escalation study evaluating increasing doses of civ rhIL-15 in combination with obinutuzumab using a 3 + 3 dose escalation design. On days 1-5 of each 4-week cycle, rhIL-15 will be administered by civ at dose levels 0.5, 1, and 2 mcg/kg/day. During the first cycle, obinutuzumab will be administered at a dose of 100 mg by IV on day 4, 900 mg on day 5, 1,000 mg on day 11, and 1,000 mg on day 18; then 1,000 mg on day 4 of each subsequent cycle. Infusion reaction, antimicrobial, and tumor lysis syndrome prophylaxis will be administered per manufacturer's recommendations. Treatment will continue up to 6 cycles, or until unacceptable toxicity or progressive disease. Up to 24 patients will be enrolled in the study. Correlative studies: 1) optional lymph node biopsy at baseline and after the first week of treatment (C1D8) for tissue immune cell subsets and quantifying antibody penetration; 2) lymphocyte subset testing, ctDNA, and cell and plasma banking on days 1, 4, 8, and 11 of cycle 1, and days 1 and 8 of cycles 2-6; 3) ADCC capacity of ex vivo NK cells on C1D1, 4, and 8. One patient has started treatment to date. Enrollment is ongoing. Figure Disclosures Wiestner: Acerta: Research Funding; Pharmayclics: Research Funding; Merck: Research Funding; Nurix: Research Funding. Waldmann:Bioniz: Membership on an entity's Board of Directors or advisory committees.

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Appleman, James Richard, and Stephen Evan Webber. "Discovery of a novel Toll-like Receptor 7 agonist for systemic immunotherapy of cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14246-e14246. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14246.

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e14246 Background: While ICPIs (immune checkpoint inhibitors) have fundamentally changed the practice of cancer therapy for tumors arising from many different tissues, ways to increase both response rate and durability are critically needed. On theoretical grounds, combining stimulators of innate immunity with activators of adaptive immunity should lead to better outcomes. We have therefore created a series of novel Toll-like receptor 7 (TLR7) agonists that are intended to be combined with activators of adaptive immunity for the treatment of cancer. We have previously reported a series of unusual properties that must be met for successful drug candidates targeting TLR7 intended for chronic and systemic administration for the treatment of cancer. Methods: Key assays in our testing cascade include: cellular reporter assays and hPBMC assays to evaluate selectivity and potency; characterization in cynomolgus monkeys: appropriate PK with active TLR7 agonist, efficient oral delivery into systemic circulation with prodrugs of the TLR7 agonist, and targeted pharmacodynamic response at relevant oral dose (gating for candidate selection); antitumor activity alone and in combination with other immunotherapeutics in syngeneic rodent tumor models. Results: Appropriate potency at and specificity for TLR7 was achieved early in this discovery program. Furthermore, the PK profile after IV administration met our previously defined criteria. However, oral absorption of candidate prodrugs of two lead molecules was limited. In one class of prodrugs this was due to insufficient lipophilicity; in another class this was a consequence of MDR1 activity. Next-generation candidates have been synthesized; these candidates are expected to have substantially better oral delivery in vivo based upon results in predictive in vitro models. Testing in advanced animal models is in progress. Conclusions: From our original starting point - a relatively weak TLR7 agonist with no oral bioavailability - we have invented a novel series of molecules that are designed to be dosed QOD continuously over a 24-month period to appropriately engage innate immunity at a level that is well-tolerated by the patient while increasing treatment response rate and durability.

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Gu, Zexian, Xiaoqing Zhao, Pei Huang, Junwei Pu, Xinyu Shi, and Yungang Li. "Identification of Multi-Dimensional Relative Poverty and Governance Path at the Village Scale in an Alpine-Gorge Region: A Case Study in Nujiang, China." International Journal of Environmental Research and Public Health 20, no. 2 (January 10, 2023): 1286. http://dx.doi.org/10.3390/ijerph20021286.

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Absolute poverty has historically been solved in China, and the focus on poor areas has shifted to addressing relative poverty. To realize the organic combination of the rural revitalization strategy and relative poverty governance, multi-dimensional relative poverty identification and governance path research at the village scale in an alpine-gorge region is required. For this study, the Nujiang Lisu Autonomous Prefecture’s research area in a typical alpine-gorge was chosen. This paper constructed an evaluation index system for the rural regional system based on location conditions, ecological environment, productive resources, economic base, and public service, based on the theory of multi-dimensional regional poverty and the human–land relationship. The level of poverty, types of poverty, and spatial distribution characteristics of 255 administrative villages were systematically analyzed, and poverty governance paths were proposed. The results show that: (1) There were 215 multi-dimensional relative poverty villages in Nujiang Prefecture, accounting for 84.31% of the total. The relatively poor villages with poverty grades I and II, which are classified as mild poverty, account for 77.21% of all poor villages; this demonstrated that the relatively poor villages in Nujiang Prefecture had a high potential for poverty alleviation. (2) There are 19 different types of constraints in poor villages. Grades III and IV poor villages were mostly found in high-altitude areas. The economic foundation was very weak, the infrastructure was imperfect, the land use type was relatively single, and traffic conditions were relatively backward. (3) The priority model accounted for 16.67% of relative poverty governance, the steady improvement accounted for 28.79%, and key support accounted for 54.54%. Relative poverty governance paths for various counties have been proposed, including rural revitalization priority demonstration, ecological environment governance, eco-tourism, modern agriculture + mountain agroforestry, and improved people’s livelihood and well-being. The findings provided scientific support and direction for future research on the mode and course of relative poverty governance in poor villages in the alpine-gorge area, as well as the rural revitalization strategy’s implementation.

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Armstrong, Andrew J., Tong Shen, Susan Halabi, Gabor Kemeny, Rhonda Lynn Bitting, Patricia Kartcheske, Elizabeth Embree, et al. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 105. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.105.

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105 Background: PTEN loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 Kinase pathway. Temsirolimus blocks mTOR/TORC1, a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer is unknown. Methods: We conducted a single arm trial of weekly IV temsirolimus in men with chemorefractory metastatic CRPC who had >=5 circulating tumor cells (CTCs) at baseline (Cellsearch). The primary endpoint was change in CTCs at 8 weeks; secondary endpoints were composite progression-free survival (excluding PSA), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely due to lack of efficacy/feasibility. Median age was 61, with 55% African-Americans and 36% Caucasians. Median baseline PSA was 390 ng/dl, median baseline CTC was 14 cells, 50% had significant pain, and 63% had >2 prior chemotherapy regimens. The median decline in CTC enumeration at week 8 was 48% and three patients experienced a decline in CTCs to <5. However, 73% of men had persistently unfavorable CTCs (>=5) over time and only 1 patient had a >=30% PSA decline. Median PFS was 1.9 months (95% CI 0.9-3.1) and median OS was 8.8 months (95% CI 3.1-15.6). Toxicities included grade 4 hypophosphatemia and grade 4 CNS hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Persistently high N-cadherin expression on longitudinal CTC analysis was observed as a marker of epithelial plasticity and treatment resistance. Conclusions: Temsirolimus lacked sufficient clinical activity in men with metastatic CRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. Clinical trial information: NCT00887640.

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Swanton, Charles, and Jamie Cromer. "Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS650. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps650.

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TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene ampliﬁcation (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.

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Yap, Timothy A., Minal A. Barve, Justin F. Gainor, Colin D. Weekes, Bruno Bockorny, Yawen Ju, Ryan Faucette, et al. "First-in-human phase 1 trial (DRAGON) of SRK-181, a potential first-in-class selective latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS3146. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps3146.

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TPS3146 Background: Transforming growth factor-beta 1 (TGFβ1) is a key mediator of primary resistance to programmed cell death protein 1 (PD-1) pathway blockade. SRK-181 is a fully human, highly potent and selective monoclonal antibody that inhibits latent TGFβ1 activation. SRK-181 has minimal or no binding to latent TGFβ2 and TGFβ3 isoforms or to active TGFβ growth factors. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 in combination with anti-PD1 therapy overcame primary anti-PD-1 resistance and showed survival benefit. No cardiotoxicities (valvulopathy) were observed with SRK-181 in 4-week GLP nonclinical toxicology studies. Thus, the potency and selectivity of SRK-181 may overcome PD-1 inhibitor resistance and toxicity of non-selective TGFβ pathway approaches. Methods: The DRAGON trial NCT04291079 is an ongoing multicenter, open-label, phase 1 study of SRK-181 administered by IV infusion every 3 weeks (Q3W) alone or in combination with anti-PD-(L)1 in patients (pts) with locally advanced or metastatic solid tumors. The study comprises 3 parts: Part A of the study follows a standard 3+3 dose escalation trial design to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of SRK-181 alone (Part A1) or in combination with the anti-PD-(L)1 agent that is approved for the respective tumor indication (Part A2). Part A1 and Part A2 will determine maximum tolerated dose (MTD) or maximum administered dose and Recommended Phase 2 Dose (RP2D) for Part B. Part B (expansion phase) will evaluate combination treatment of SRK-181 with anti-PD-(L)1 in pts with non-small cell lung cancer, urothelial carcinoma (UC), melanoma or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the antitumor activity of combination treatment. Pts in Part A2 and Part B must have previously received an anti-PD-(L)1 therapy approved in their tumor indication and considered non-responders (best response of stable disease or disease progression) to anti-PD-(L)1 monotherapy. Pts in Part B must have received the most recent dose of the prior anti-PD-(L)1 within 6 months of study enrollment (9 months for UC cohort). Safety, PK, PD and efficacy data will be collected and monitored throughout the study. Detailed translational PD and predictive biomarker studies for SRK-181 will include a novel digital pathology analysis of CD8 to assess the alteration of immune profile in tumor microenvironment and TGFb pathway biomarkers, such as quantitative analysis of tumor phospho-Smad2 and circulating levels of TGFb1 ligand. As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination). Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W. Clinical trial information: NCT04291079.

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Hong, David S., Shadia Ibrahim Jalal, Elena Elimova, Jaffer A. Ajani, Mariela A. Blum Murphy, Andres Cervantes, T. R. Jeffry Evans, et al. "SURPASS-2 trial design: A phase 2, open-label study of ADP-A2M4CD8 SPEAR T cells in advanced esophageal or esophagogastric junction cancers." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): TPS363. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.tps363.

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TPS363 Background: ADP-A2M4CD8 is an autologous specific peptide enhanced affinity receptor (SPEAR) mixed CD4 and CD8 T-cell product that expresses an engineered T-cell receptor (TCR) designed to target the MAGE-A4 antigen in HLA-A*02-positive patients. These SPEAR T-cells also express wild-type CD8α co-receptors, designed to provide additional functionality to CD4 T-cells. MAGE-A4 expression has been described in several solid tumors, including esophageal and esophagogastric junction (EGJ) cancers[1]. In an ongoing phase 1 study (NCT04044859) of ADP-A2M4CD8 in patients with different tumor types, most adverse events have been consistent with those typically experienced by patients undergoing chemotherapy and/or adoptive T-cell therapies, and as of 2 August 2021, among evaluable patients with esophageal and EGJ cancers, best overall responses were 1 partial response (EGJ), 4 stable disease (2 EGJ, 2 esophageal), and 1 progressive disease (EGJ)[2]. Methods: SURPASS-2 (NCT04752358) is a phase 2, open-label, single-arm trial to assess safety and efficacy of ADP-A2M4CD8 SPEAR T-cells in HLA-A*02–positive patients with advanced esophageal or EGJ cancers that express MAGE-A4 antigen. A total of 45 patients between the ages of 18 and 75 years old will be treated across sites in North America and Europe. Key eligibility criteria include measurable disease per RECIST v1.1; ECOG performance status of 0 or 1; no active autoimmune or immune-mediated disease; no leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases; and ≤2 prior lines of combination or single agent systemic treatment for advanced or metastatic disease before treatment with ADP-A2M4CD8 as the next therapy. Leukapheresis can be performed before initiating or at the end of second-line treatment. Collected T-cells will be transduced with a self-inactivating lentiviral vector expressing the high affinity MAGE-A4-specific TCR and the CD8α co-receptor. Lymphodepleting chemotherapy, consisting of intravenous (IV) cyclophosphamide 600 mg/m2/day for 3 days and IV fludarabine 30 mg/m2/day for 4 days, will be given approximately 1 week prior to treatment with ADP-A2M4CD8. ADP-A2M4CD8 dose will range between 1 x 109 to 10 x 109 transduced cells administered by a single IV infusion. The primary endpoint is overall response rate per RECIST v1.1 by an independent radiological assessment committee. Safety evaluations will include adverse events (AEs); serious AEs; incidence, severity, and duration of the AEs of special interest; replication competent lentivirus; and T-cell clonality and insertional oncogenesis. All patients receiving ADP-A2M4CD8 cellular therapy will be followed for 15 years from time of last T-cell infusion for observation of delayed AEs. To date, one site is activated. [1] Ishihara et al. BMC Cancer 20, 606 (2020). [2] Hong et al. E-poster 540P: ESMO (2021). Clinical trial information: NCT04752358.

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Isakoff, Steven J., Sara M. Tolaney, Nadine M. Tung, Sylvia Adams, Hatem Hussein Soliman, Elena F. Brachtel, Karleen R. Habin, et al. "A phase 1b study of safety and immune response to PVX-410 vaccine alone and in combination with durvalumab (MEDI4736) in HLA-A2+ patients following adjuvant therapy for stage 2/3 triple negative breast cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS1126. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps1126.

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TPS1126 Background: Stage 2-3 triple negative breast cancer (TNBC) remains at high risk for recurrence despite modern adjuvant therapy. An important role for the immune system in TNBC has recently emerged. Tumor infiltrating lymphocytes (TILs) are correlated with improved prognosis and several PD-1/PD-L1 checkpoint inhibitors, including Durvalumab (DUR), demonstrated activity in metastatic TNBC. Vaccines are a promising approach to further enhance the immune response in many cancers including TNBC. PVX-410 (PVX) is a novel tetra-peptide vaccine against XBP1 (2 splice variants), CD138 and CS1 that was safe and induced immune responses in a phase 1b study in smoldering myeloma. XBP1 and CD138 are also over-expressed in TNBC. Methods: This Phase 1b multi-center, single arm study will enroll 20 HLA-A2+ female patients (pts) following completion of all adjuvant therapy for stage 2-3 TNBC. Pts will receive 6 doses of 800ug PVX (emulsified in Montanide (SC) and co-administered with Hiltonol (IM)) at 2-week intervals, and 2 doses of DUR 1500mg IV at the 4th and 6th vaccine visits. Eligible pts must be between 1-6 months from completing adjuvant therapy, have no prior autoimmune disease, and have residual disease if neoadjuvant therapy was used. The primary objective is to determine the safety and tolerability of the combination, and the key secondary objective is to determine the immune response to PVX + DUR. If ≤1 pt in the first 6 has a protocol defined dose limiting toxicity within 4 weeks after the first DUR dose, accrual will continue to 20 pts. Immune response will be assessed at baseline, pre-dose 4 PVX/dose 1 DUR, and 4 weeks after completing protocol therapy. Paired data in 20 pts provides 90% power to see a shift of 0.75 standardized units from baseline to 4 weeks post treatment with the signed rank test. Immune response will be determined by a FACs based assay of antigen specific CD3+CD8+ T lymphocyte response and IFN-γ production (intracellular staining) in patient PBMCs. Additional correlative studies, including T-cell PD-1 and tissue PD-L1, XBP1, and CD138, are planned. Currently 4 pts are enrolled. Clinical trial information: NCT02826434.

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Hainsworth, John D., Dana S. Thompson, F. Anthony Greco, Eric Raefsky, Scott Lunin, James Reeves, and Ian W. Flinn. "Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute." Blood 120, no. 21 (November 16, 2012): 2749. http://dx.doi.org/10.1182/blood.v120.21.2749.2749.

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Abstract Abstract 2749 Background: Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods: Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results: Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion: The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures: Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

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Diaz, Adolfo E., Matthew James Butler, Anand Karnad, and Ricardo Aguiar. "Combination of Phosphodiesterase 4 (PDE4) Inhibitor Roflumilast and R-CHOP As First-Line Therapy for High-Risk Diffuse Large B Cell Lymphoma Patients." Blood 134, Supplement_1 (November 13, 2019): 1592. http://dx.doi.org/10.1182/blood-2019-124382.

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R-CHOP remains the standard therapy for diffuse large B cell lymphoma (DLBCL), even though long-term disease free survival is achieved in only ~60-70% of the patients. One approach to improve on this cure rate is to implement rationally devised therapeutic strategies that capitalize on a better understanding of lymphoma biology, and on robust pre-clinical data. Still, in many instances clinical translation is limited by the difficulty in inhibiting key lymphomagenic proteins (e.g., MYC), or by subpar clinical responses and/or toxicity associated with the use of inhibitors to well-validated targets (e.g., SYK, BTK, PI3K, VEGF, etc.). Using genome-wide studies, we identified high expression of phosphodiesterase 4B (PDE4B) in fatal DLBCLs (Nat Med. PMID: 11786909). PDE4 hydroxylases cyclic adenosine monophosphate (cAMP) thus terminating its inhibitory signals and promoting B lymphocytes survival. Using in vitro and in vivo models, we showed that PDE4 inhibition augments cAMP signals and suppresses PI3K-AKT activity in DLBCL (Blood, PMID: 15331441). We mapped these events to SYK inhibition downstream of the B cell receptor (BCR) (Blood, PMID: 19369227). PDE4 inhibitors also suppress the pro-angiogenic lymphoma microenvironment by directly inhibiting the endothelium, and by decreasing VEGF production/secretion by the lymphoma cells, as we showed in a mouse engineered to develop lymphoma in a Pde4b KO background (Leukemia, PMID: 26503641). Earlier, we built on these pre-clinical data to test the safety and pharmacodynamics of the PDE4 inhibitor roflumilast (FDA-approved for COPD) in patients with relapsed/refractory mature B cell malignancies. In that first-in-cancer drug-repurposing study (NCT01888952), we found that roflumilast was well tolerated, clinically active, and that it suppressed PI3K activity, which correlated with the degree of clinical response (Clin. Cancer Res PMID: 27542768). Aberrant BCR signaling and angiogenesis are integral to the pathogenesis of DLBCL. Yet, combination of either ibrutinib or bevacizumab with R-CHOP was not beneficial in this disease. Thus, considering the pleiotropic anti-lymphoma properties of PDE4 inhibitors (seeBloodPMID: 27756749), which includes BCR suppression and anti-angiogenesis, we opened a trial to test the combination of roflumilast with R-CHOP in treatment naïve DLBCLs (NCT03458546). This is a single center, phase Ib, open label, non-randomized single arm study of roflumilast + R-CHOP (RR-CHOP) aimed at untreated high-risk DLBCL patients. Key eligibility criteria include: non-GCB DLBCL (Han's algorithm), NCCN-IPI risk score of ≥ 2, Ann Arbor stage II-IV; key exclusion criteria include active CNS involvement and documented history of severe depression (a specific concern related to the use of roflumilast). Patients will receive R-CHOP every 21 days for 6 cycles, and roflumilast PO daily (500 mcg) throughout the 18-week treatment period. Given the anti-angiogenic properties of PDE4 inhibitors that we documented pre-clinically, and the prohibitive cardiotoxicity of bevacizumab + R-CHOP combination, we will monitor serum levels of troponin and B-type natriuretic peptide, as biomarkers for cardiac toxicity. In addition, PBMC, plasma and urine samples will be collected for measurement SYK/PI3K/AKT activity and VEGF levels at baseline and before cycles 3 and 6. Exome sequencing of germline and tumor DNA is to be performed too. Adverse events will be assessed and documented according to the CTCAE version 4.03 criteria. Eligible patients will be included in the intent-to-treat analysis. The primary objective of this study is to test safety and tolerability of RR-CHOP; the secondary objectives are to preliminarily assess anti-tumor efficacy of the combination and the biomarker potential of SYK/PI3K/AKT activity and VEGF levels. Given its exploratory nature, this study was designed for a cohort of 10 patients, in which no statistical assessment of response or sample size calculation was included. To date, we have met ~50% of the target accrual, with half of those patients being of Hispanics ethnicity. If RR-CHOP is proven safe, the next step will be to initiate a randomized trial that compares RR-CHOP to R-CHOP in untreated DLBCL patients, which should conclusively validate (or refute) our extensive, biologically-informed, pre-clinically data on the benefits of PDE4 inhibitors for the treatment of mature B cell malignancies. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: roflumilast - PDE4 inhibitor, FDA-approved for COPD patients.

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Markowski, Mark Christopher, Mary-Ellen Taplin, Rahul Raj Aggarwal, Hao Wang, Aliya Lalji, Channing Judith Paller, Catherine Handy Marshall, et al. "COMBAT-CRPC: Concurrent administration of bipolar androgen therapy (BAT) and nivolumab in men with metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5014. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5014.

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5014 Background: During BAT, intramuscular (IM) testosterone (T) is administered, which results in rapid cycling of serum T levels from supraphysiologic to near-castrate in men with metastatic castration resistant prostate cancer (mCRPC). We previously observed anecdotal clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT and hypothesized that that a BAT/ICB combination would be synergistic. Here we report a prospective phase 2 study of men with mCRPC treated with BAT in combination with nivolumab. Methods: This was a multi-center, single arm, open label phase 2 trial (NCT03554317) of men with mCRPC who received T cypionate 400mg IM (BAT) every 28 days and nivolumab 480mg IV every 28 days. LHRH agonist treatment was continued. All pts received BAT as single agent therapy for a 12-week lead-in prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue disease amenable to biopsy and progressed on at least one prior novel AR targeted therapy. Up to one line of chemotherapy was allowed for the treatment of mCRPC disease. The primary endpoint was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate (ORR), and radiographic progression-free survival (rPFS). The trial was designed to detect a 20% absolute increase in PSA50 response rate from the null of 25%. Results: 45 pts were enrolled on study and treated. The confirmed PSA50 response rate was 40.0% (N=18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis). For pts with measureable disease, the ORR was 23.8% (N=10/42). Median rPFS on BAT and nivolumab was estimated at 5.7 months (95% CI: 4.9-7.8 months). 11.1% (N=5/45) of pts were free from radiographic progression for 11 or more months. One patient achieved a complete radiographic response, which is ongoing (>13 months). The majority of adverse events (AE) were Grade <2. The most common AEs were edema (20%), nausea (20%), and back pain (13%). Immune related AE (irAE) were generally mild (Grade <2) with N=2 Grade 3 irAE observed (pericarditis, lipase elevation). Serial biopsies were obtained on trial for translational studies. Conclusions: BAT plus nivolumab was well tolerated without concerning safety signals. The combination met the pre-specified primary endpoint of confirmed PSA50 response in a heavily treated population. Durable responses were observed in a subset of pts. Biomarker analysis is ongoing to identify a molecular signature predictive of response. Clinical trial information: NCT03554317. [Table: see text]

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Hemmings, Alan D., Sanjay Chaturvedi, Elizabeth Leane, Daniela Liggett, and Juan Francisco Salazar. "Nationalism in Today’s Antarctic." Yearbook of Polar Law Online 7, no. 1 (December 5, 2015): 531–55. http://dx.doi.org/10.1163/2211-6427_020.

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Whilst nationalism is a recognised force globally, its framing is predicated on experience in conventionally occupied parts of the world. The familiar image of angry young men waving Kalashnikovs means that the idea that nationalism might be at play in Antarctica has to overcome much instinctive resistance, as well as the tactical opposition of the keepers of the present Antarctic political arrangements. The limited consideration of nationalism in Antarctica has generally been confined to the past, particularly “Heroic-Era” and 1930s–1940s expeditions. This article addresses the formations of nationalism in the Antarctic present. Antarctic nationalism need not present in the same shape as nationalisms elsewhere to justify being called nationalism. Here it occurs in a virtual or mediated form, remote from the conventional metropolitan territories of the states and interests concerned. The key aspect of Antarctic nationalism is its contemporary form and intensity. We argue that given the historic difficulties of Antarctic activities, and the geopolitical constraints of the Cold War, it has only been since the end of that Cold War that a more muscular nationalism has been able to flourish in Antarctica. Our assessment is that there at least 11 bases upon which Antarctic nationalism might arise: (i) formally declared claims to territorial sovereignty in Antarctica; (ii) relative proximity of Antarctica to one’s metropolitan territory; (iii) historic and institutional associations with Antarctica; (iv) social and cultural associations; (v) regional or global hegemonic inclinations; (vi) alleged need in relation to resources; (vii) contested uses or practices in Antarctica; (viii) carry-over from intense antipathies outside Antarctica; (ix) national pride in, and mobilisation through, national Antarctic programmes; (x) infrastructure and logistics arrangements; or (xi) denial or constraint of access by one’s strategic competitors or opponents. In practice of course, these are likely to be manifested in combination. The risks inherent in Antarctic nationalism are the risks inherent in unrestrained nationalism anywhere, compounded by its already weak juridical situation. In Antarctica, the intersection of nationalism with resources poses a particular challenge to the regional order and its commitments to shareable public goods such as scientific research and environmental protection.

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Andritsos, Leslie, John C. Byrd, Jeffrey A. Jones, Becker Hewes, Thomas J. Kipps, Frank J. Hsu, and Jan A. Burger. "Preliminary Results From A Phase I Dose Escalation Study to Determine the Maximum Tolerated Dose of Plerixafor In Combination with Rituximab In Patients with Relapsed Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 2450. http://dx.doi.org/10.1182/blood.v116.21.2450.2450.

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Abstract Abstract 2450 Background: Dose intense rituximab in previously-treated patients (pts) with CLL has demonstrated modest activity. Preclinical data indicate that the CXCR4/CXCL12 axis plays a key role in CLL cell homing and retention in tissue microenvironments, such as the bone marrow. Disruption of this axis using the small-molecule CXCR4-antagonist, plerixafor, may abrogate stroma-mediated drug resistance, and enhance sensitivity of CLL cells to rituximab. To test this hypothesis, we initiated a phase 1 trial of plerixafor + rituximab in previously-treated pts with CLL. Aims: The primary objective was to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with rituximab. Methods: Adult pts with WBC≤ 50×109/L, intermediate/high risk CLL not refractory to rituximab, and with active disease by NCI criteria were eligible in this ongoing study. Pts were treated with 3x/week rituximab, as a 100mg flat dose on Day 1, and subsequently 375mg/m2 IV for 12 total doses (i.e. for 4 weeks). Plerixafor was given SC prior to rituximab starting at the 4th rituximab dose (Day 8) for 9 total doses. Cohorts of pts were treated at 1 of 4 dose levels with plerixafor (0.08mg/kg, 0.16mg/kg, 0.24mg/kg and 0.32mg/kg). Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose (Day 8) through Day 29 and cohort advancement followed dose escalation rules using a 3+3 design. Peripheral blood (PB) CD34+ and CLL cells were enumerated on Days 8 and 26 by flow cytometry; PB samples were obtained at baseline pre-plerixafor treatment and at 2, 4, 6, 10, and 24 hours post-plerixafor. Responses were assessed as defined by Cheson et al (Blood, 1996). Results: 17 pts (median age 64 years; 88% male; Rai Stage IV: 53%) were enrolled, 3 pts each in the 0.08 and 0.24 mg/kg cohorts, 4 pts in the 0.16mg/kg cohort and 7 pts in the 0.32mg/kg cohort (Table 1). No DLTs were reported. Of 14 evaluable pts, 5 (36%) had partial response, 3 (21%) had stable disease for ≥2 months and 6 (43%) had progressive disease. Treatment-emergent, plerixafor-related adverse events (AEs) were seen in 5 pts and included diarrhea, vomiting, nausea, appetite loss, headache, hypoaesthesia and paraesthesia. All AEs were grade 1 except nausea (n=1) that was grade 2. Treatment-emergent serious AEs were seen in 2 pts (0.16mg/kg dose; grade 3 EBV infection, grade 2 gastrointestinal reflux disease and grade 2 dyspnea); all unrelated to plerixafor. On Day 8, there was a median 3.8-fold increase in PB CLL cells (range: 1.2 –15.0-fold), indicating CLL cell mobilization. On Day 26 fewer PB CLL cells were detected with a median fold increase of 1.5 (range, 0.9–8.0). Conclusions: The combination of plerixafor + rituximab in CLL pts with WBC < 50×109/L was well tolerated. CLL cells were mobilized following plerixafor, and partial remissions were seen in a proportion of pts. In some cases, maximum responses were seen several months after completion of rituximab, consistent with single agent therapy. This suggests that continued follow up may show additional responses in recently treated pts. Disclosures: Andritsos: Genzyme Corporation: Research Funding. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Byrd: Genzyme Corporation: Research Funding. Jones: Genzyme Corporation: Research Funding. Hewes: Genzyme Corporation: Employment. Kipps: Genzyme Corporation: Research Funding. Hsu: Genzyme Corporation: Employment, Equity Ownership. Burger: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Schwartz, Gary K., William D. Tap, Li-Xuan Qin, Michael B. Livingston, Samir D. Undevia, Bartosz Chmielowski, Mark Agulnik, et al. "A phase II multicenter study of the IGF-1 receptor antibody cixutumumab (A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with refractory IGF-1R positive (+) and negative (-) bone and soft tissue sarcomas (STS)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10003. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10003.

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10003 Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.

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Yeung, David T., Naranie Shanmuganathan, Andrew Grigg, Ilona Cunningham, Jake Shortt, Philip Rowling, John Reynolds, et al. "Combination of Nilotinib and Pegylated Interferon Alfa-2B Results in High Rates of MR4.5 at 24 Months - Primary Analysis of the ALLG CML 11 Pinnacle Study." Blood 134, Supplement_1 (November 13, 2019): 2926. http://dx.doi.org/10.1182/blood-2019-125740.

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Pegylated interferon (Peg-IFN) increases molecular response rates when used in combination with imatinib (IM) and dasatinib compared with tyrosine kinase inhibitor (TKI) monotherapy in de novo chronic phase chronic myeloid leukemia (CP-CML). (Preudhomme NEJM 2010, Hjorth-Hansen Leukemia 2016). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in CP-CML patients. Co-primary end points were MMR (BCR-ABL1 ≤ 0.1%) at 12 mths and MR4.5 (BCR-ABL1 ≤ 0.0032%) at 24 mths. Key secondary end points were survival and overall molecular response. Patients were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL. Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 34 mths (24-60). Data is presented on an intention to treat basis. Eight pts (13%) did not commence Pegintron (2 due to persistent haem toxicities, 4 from GI disturbance, liver/pancreatic enzyme derangements, and 2 from pt preference). Considering Pegintron as a product of protocol assigned dose and duration, adjusted for time from study entry, 21 pts (35%) received >85% of their assigned dose, 13 (22%) received between 50-84% and 18 pts (30%) received <50% (Fig 1A). There was no difference between patients who had >85% of their assigned dose versus those wwho took <85% with respect to age or sex. The median duration of Pegintron exposure was 15 mths (Range 1-21 months). Adverse events (AE) are reported at a similar frequency compared to the interim analysis. Grade III/IV AEs attributed to NIL were increased lipase and neutropenia (each 12%), pancreatitis (6%), thrombocytopenia and rash (each 5%). Grade III/IV AEs attributed to Pegintron were neutropenia (10%), atrial fibrillation (6%), and myalgia, depression and rash (4% each). Three vascular revents occurred: one case each of ischaemic colitis, femoral artery occlusion, coronary artery disease. The former occurred on imaitnib and the latter 2 occurred after 2.5 and 4 years of niloitnib respectively; both patient have since switched to imatinib. Eighteen pts (30%) have withdrawn from study: 2 withdrew consent, 6 due to intolerance (diarrhoea, pancreatitis, GI upset, rash, high amylase and LFT derangements), 4 for failing to consistently achieve BCR-ABL MMR, 2 for loss of response; 4 pts withdrew for other reasons. Fig 1B shows BCR-ABL1 transcript levels over time. At 3 mths, 22 (37%) have achieved MMR, 23 (38%) had BCR-ABL between 0.1-1%, and 6 (10%) had BCR-ABL between 1-10%; 3 have already withdrawn. Six pts (10%) had BCR-ABL1 ≥10%; 3 subsequently achieved and maintained MMR, 1 has BCR-ABL <1% at 24 mos, 1 transformed to AP after study withdrawal, and 1 was refractory to all TKIs and received an allograft. At 12 mths, MMR (BCR-ABL ≤ 0.1%) and MR4.5 (BCR-ABL ≤ 0.0032%) rates were 78.3% (95% CI 65.3-88.2; Fig 1C) and 43.3% (95% CI 30.1-57.3%; Fig 1D), respectively. At 24 mths, MR4.5 was 50% (95% CI 36.6-63.4%). No BCR-ABL mutations were reported on study. Three pts lost MMR - 2 were transient; the other was associated with non-compliance. Current TKI treatment for pts on study is NIL (n=37; 62%) and IM (n=5; 8%). Combination therapy with NIL and Peg-IFN leads to favourable rates of molecular responses that may be superior to NIL monotherapy (Table). While the majority of patients did not durably tolerate full dose Pegintron, there was minimal interference with TKI dose intensity. Such strategies may maximise achievement of deep molecular response, allowing a trial of TKI cessation and the benefit of treatment free remission to an increased number of patients. Disclosures Yeung: BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding. Shanmuganathan:Gilead: Other: Travel Support; Janssen: Other: Travel Support; Amgen: Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support; Novartis: Honoraria, Other: Travel Support. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Reynolds:AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership; Novartis Australia: Honoraria; Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.. Harrup:Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group; Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees. Ross:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mills:Novartis: Other: Speaker Fees; Specialised Therapeutics: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Conference Sponsorship; MSD: Membership on an entity's Board of Directors or advisory committees. Yong:BMS: Honoraria, Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. OffLabel Disclosure: Pegylated interferon is not registered for use in chronic phase CML

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Tapavički, Borislav, Tomislav Stantić, Stefan Glišić, Đurđa Cvjetković, Nebojša Janjić, Julijana Kostić, and Andrea Zubnar. "THE IMPACT OF WELL-PLANNED TRAINING ON CHANGING SEDENTARY LIFESTYLE HABITS." Revista Brasileira de Medicina do Esporte 28, no. 4 (August 2022): 337–41. http://dx.doi.org/10.1590/1517-8692202228042020_0071.

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ABSTRACT Introduction: A sedentary lifestyle is one of the biggest health problems of the 21st century. The role of the trainer in motivating the sedentary individual is crucial. Also, there is a growing accessibility to gyms today, especially outdoor gyms, as a novel way to motivate people to train. Objective: The aim of the study was to evaluate the impact of regular combined indoor and outdoor physical activity on anthropometric and functional parameters and the adoption of a more active lifestyle. Methods: The study included 45 participants between 18 and 56 years of age. They underwent 12 weeks of resistance training, focusing on chest presses and leg presses. Height, weight, bioelectrical impedance, chest and leg press one-repetition maximums, push-up and curl-up counts, and sit and reach were measured both before and after the 12-week training program. Results: After 12 weeks of training, male participants showed a significant increase in the percentage of skeletal muscle mass (p<0.05) and a significant decrease in the fat mass percentage (p<0.05). Female participants experienced a significant reduction in the fat mass percentage (p<0.05). Both groups were able to significantly increase their one-repetition maximums for the chest press (p<0.05) and leg press (p<0.05). Push-up and curl-up counts increased significantly after 12 weeks of training in both sexes, as did flexibility in both sexes. A year after the study, 80% of all participants were still training with a combination of indoor and outdoor physical activities. Conclusions: After 12 weeks of training, the body composition of both female and male participants had changed significantly. Twelve weeks of resistance training significantly increased strength and flexibility in both male and female participants. A well-thought-out training plan seems to be the key factor in motivating a beginner trainee to adopt a more active lifestyle. Level of Evidence IV; Case series.

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Llombart-Cussac, Antonio, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, et al. "Abstract OT2-19-06: Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT2–19–06—OT2–19–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot2-19-06.

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Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [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 OT2-19-06.

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Raitman, Irene, Joseph Gleason, Salvatore Rotondo, Shuyang He, Valentina Rousseva, Xuan Guo, Hemlata Rana, et al. "Human Placental CD34 +-Derived Natural Killer Cells with High Affinity and Cleavage Resistant CD16 (CYNK-101) in Combination with Daratumumab for Immunotherapy Against CD38 Expressing Hematological Malignancies." Blood 138, Supplement 1 (November 5, 2021): 2773. http://dx.doi.org/10.1182/blood-2021-148869.

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Abstract Natural Killer (NK) cells are key mediators of antibody dependent cellular cytotoxicity (ADCC) via the CD16 Fc receptor. NK cellular therapies can effectively be targeted to tumor antigens when combined with tumor specific antibodies. Celularity Inc. is developing human placental CD34 +-derived, cryopreserved, off-the-shelf, allogenic NK cells (CYNK-101) with a high IgG binding affinity and proteinase cleavage resistant CD16 variant (CD16VP) for cancer treatment. We hypothesize that expressing CD16VP augments anti-tumor ADCC activity. Reported here are the in vitro and in vivo results of evaluating CYNK-101 cytotoxicity against CD38 expressing multiple myeloma (MM) and lymphoma tumor cell lines when in combination with daratumumab, an anti-CD38 monoclonal antibody. Human placental CD34 + cells were transduced with lentivirus expressing CD16VP and cultured in the presence of cytokines to generate CYNK-101 cells. The in vitro cytotoxic activity of CYNK-101 against CD38 + MM (MOLP-8, LP-1, MM.1S) and lymphoma (Daudi) tumor cell lines, and normal B-cells was assessed in combination with daratumumab via flow cytometry based ADCC assays and cytokine secretion was assessed via multiplex Luminex analysis. In vivo ADCC activity of CYNK-101 was assessed using a disseminated B-cell lymphoma xenograft model in B-NDG-hIL15 mice. B-NDG-hIL15 mice lack T, B, and NK cells and are transgenic for human IL-15 to support CYNK-101 persistence and maturation. Luciferase expressing Daudi cells (3×10 6) were intravenously (IV) injected on Day 0 three days after preconditioning with a myeloablative dose of busulfan to allow for better tumor cell engraftment. CYNK-101 cells (1x10 7) and/or daratumumab (0.05 mg/kg) were IV injected on Days 7, 14 and 21. Tumor burden was assessed weekly by bioluminescence imaging (BLI) and the mice were followed for assessment of their survival (n=5 mice per group). In vitro ADCC studies indicate enhanced cytolysis of CYNK-101 in combination with daratumumab against both MM and lymphoma tumor cells compared to that of IgG control. At 24h at the effector to target (E:T) ratio of 5:1, CYNK-101 (n=5 donors) demonstrated a cytolysis of 87.6 ± 6.3% with daratumumab vs. 37.3 ± 9.5% with IgG control against MOLP-8 (p<0.001), 73.9 ± 2.5% vs. 32.1 ± 7.2% against LP-1 (p<0.001), 77.2 ± 11.5% vs. 67.4 ± 10.7% against MM.1S (p<0.001), and 54.7 ± 24.0% vs. 4.3 ± 2.6% against Daudi (p<0.01) tumor cells. Secretion of GM-CSF, IFN-γ, and TNF-α was increased in CYNK-101 co-cultured with the tumor cell lines in the presence of daratumumab for 24h (n=5 donors, p<0.05). When cocultured with mixed LP-1 and CD38 + normal B-cells, CYNK-101 in combination with daratumumab displayed specific cytotoxicity against LP-1, while sparing CD38 + normal B-cells even at an E:T ratio up to 100:1, demonstrating that CYNK-101 can distinguish CD38 + tumor cells from CD38 + normal cells. Additionally, despite expression of CD38 on CYNK-101 there was no NK fratricide observed when CYNK-101 were in combination with daratumumab. In vivo studies in the lymphoma xenograft model revealed a significant decrease in tumor burden as evidenced from bioluminescence imaging at day 28 (1 week after last CYNK-101 injection) for mice that received CYNK-101 in combination with daratumumab compared to vehicle control (p<0.001), CYNK-101 (p<0.05) and daratumumab (p<0.05). Furthermore, CYNK-101 in combination with daratumumab demonstrated an enhanced survival benefit with a median survival of 35 days versus a median survival of 28 days for the vehicle treated group (p<0.005). In summary, our results demonstrate enhanced in vitro and in vivo ADCC activities of CYNK-101 in combination with daratumumab against CD38 + hematological tumors and warrant further development of this combination therapy for these cancers. Disclosures Raitman: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Gleason: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rotondo: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. He: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rousseva: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Guo: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rana: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. van der Touw: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Ye: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Kang: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Hariri: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Celularity Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

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Ekanayake, Preethika Subashini, Johanna Elizabeth Gerwer, and Karen Clare McCowen. "Alpelisib-Induced Hyperglycemia- A Small Case Series." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A365—A366. http://dx.doi.org/10.1210/jendso/bvab048.744.

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Abstract The phosphoinositide-3-kinase (PI3K) family consists of highly conserved enzymes that are key intermediaries in signal transduction regulating cell survival and mitogenesis. This axis has been implicated in many types of cancers. In 2019 Alpelisib (Piqray), a reversible inhibitor specific to the PI3Kα subunit, in combination with fulvestrant, was approved to treat hormone receptor positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. This approval followed SOLAR-1 trial results showing a 35% risk reduction in cancer progression or death with alpelisib-fulvestrant compared to placebo in a cohort with PI3K mutated breast cancer. PI3K also plays a critical role in the insulin signaling pathway and alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and c-peptide. Here we present a case series of severe hyperglycemia induced by alpelisib. A 44-year-old woman with ER+/Her2(-)/PI3K positive metastatic breast cancer was started on alpelisib. Previously, HbA1C was 5.4%. Hyperglycemia developed and HbA1c rose to 9.0% within 6 months of alpelisib 300mg daily. She started metformin and empagliflozin, which she was unable to tolerate due to nausea and vomiting. Her self-monitored blood glucoses were 300-400mg/dL within hours after her morning alpelisib dose. We discontinued empagliflozin when she developed metabolic acidosis with an increased anion gap. However, prior to any dose reduction, oncology discontinued alpelisib due to evidence of cancer progression. A week later, her glucoses normalized. Second case is of a 64-year-old woman with stage IV ER+/Her2(-)/PI3K mutated breast cancer with bony metastases, who was started on alpelisib 250mg. Her prior HbA1C was 5.5%. Ten days after initiation of alpelisib, she developed grade 3 hyperglycemia (blood glucoses 200-500mg/dL). She was started on metformin 2000mg with alpelisib dosed at noon. However, she noted a marked rise in blood glucose in the afternoon, few hours following alpelisib dose. Thus, moving the alpelisib to bedtime allowed better control of glycemia by using overnight basal insulin. Similarly, a 37-year-old woman with a history of ER+/HER2(-) stage IV metastatic breast cancer to the liver, with PI3K mutation was found to have acute, severe hyperglycemia with blood glucose of 300mg/dL, despite HbA1C being only 4.7%. This was attributed to initiation of alpelisib 2 days prior to admission. Given the severity of her insulin resistance (requiring > 100 units of insulin daily), alpelisib dose was reduced from 300mg to 150mg/day. On discharge, she was placed on metformin, dulaglutide, and basal and prandial insulins. Her HbA1C rose to 9.4% within 3 months of alpelisib initiation. This case series demonstrate the unique challenges in managing alpelisib induced reversible hyperglycemia.

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