Peltz, Gerson

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

Abstract Background BMS-911543 is an oral, selective small-molecule inhibitor of JAK2 (IC50=1.1nM) with potent anti-proliferative and pharmacodynamic effects in cell lines and in vivo models dependent upon JAK2 signaling. In vitro, BMS-911543 demonstrates high selectivity within the JAK family (JAK1 [IC50=356nM], JAK3 [IC50=73nM] or TYK2 [IC50=66nM]) and across a large kinase panel (at 1 µM concentration of BMS-911543, only 8 of 451 kinases were markedly inhibited [≥67%]) It also has little activity in cells dependent on other JAK family pathways. Anti-proliferative responses were observed with BMS-911543 in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive polycythemia vera (PV) (Leukemia 2012;26:280). Methods In a multicenter phase 1/2a study, BMS-911543 was administered orally using a BID dosing schedule, in patients with high-, intermediate-2 or intermediate-1 risk symptomatic primary or secondary MF (JAK2 WT or mutant) with platelet counts ≥50,000/mm3. Patients were not required to have palpable splenomegaly. The aim of the study is to determine safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of BMS-911543. Safety was assessed using NCI-CTCAE version 4.0. Treatment effect was assessed using the International Working Group (IWG) response criteria, MF-SAF, BFI, physical examination, spleen and liver volume assessment by MRI, bone marrow morphology, karyotype, V617F mutant allele burden, plasma cytokine analysis, circulating CD34+ cells and other molecular parameters. Current status To date, 84 patients have been treated (dose escalation [n=42]; dose expansion [n=42]) and the maximum tolerated dose (MTD) was defined as 200mg BID. The summary below represents an interim data analysis of 36 patients from the dose escalation phase dosed at 5, 10, 20, 40, 80, 120, 160, and 200mg BID. Fifteen of 36 (42%) patients had received prior Jak inhibitors (Jaki) including 3 who had received ≥2 Jak inhibitors. PK, PD, Safety, Tolerability and Efficacy After repeat dosing, greater than dose-proportional increase in the Cmax and AUC, and drug accumulation was observed at doses ≥40mg BID. PD analysis indicated inhibition of JAK/STAT pathway signaling activity in peripheral blood mononuclear cells, and modulation of several soluble peripheral blood proteins including IL-6, EPO and Leptin. Eleven patients (31%) had drug-related AEs. The nine hematological AEs included 3 anemia (1 grade 3 and 2 grade 2); 3 neutropenia (grade 4); and single leukopenia (grade 4), thrombocytopenia (grade 4), and reduction in platelet count (grade 2). Nine non-hematological AEs included 3 nausea (grade1/2); amylase increased (grade 3) and lipase increased (grade 3) one each; and grade 1 fatigue, muscle spasms, insomnia, erectile dysfunction one each. Ten patients (28%) discontinued treatment: 4 were attributed to disease progression, 2 to lack of efficacy, 2 at patient’s request, 1 to poor compliance, and 1 to unrelated AE. Spleen volume reductions (SVR) by MRI were observed in Jaki failure and in Jaki naive patients. Of 11 patients treated at 160 and 200mg, 8 patients (73%) had SVR greater than 35% at 3 months. In contrast, 1 of 4 patients treated at 120mg and none treated below 120mg had SVR greater than 35%. Of the patients treated at 160mg and 200mg, more than 50% had MF-SAF reductions > 50%. Overall, 3 patients (8.3%; 2 treated at 10mg BID and 1 at 200mg BID) had an increase in hemoglobin of ≥2g/dL;. Other signs of clinical activity included reductions in V617F mutant allele burden, leukocytosis, leukoerythroblastosis, circulating CD34+ cells, and LDH. Conclusion BMS-911543 was generally well tolerated and has an acceptable safety and efficacy profile. BMS-911543 induced rapid control of constitutional symptoms, and splenomegaly in patients with symptomatic MF, including those previously treated with one or more Jak inhibitors. Updated data from all 84 patients who have been treated in the dose escalation and ongoing expansion phases, including MRI assessments of spleen and liver volume, V617F mutant allele burden and levels of select plasma cytokines, will be presented.</abstract> Disclosures: Pardanani: JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other; PharmaMar: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; Bristol Myers Squibb: Clinical trial support Other. Off Label Use: Use of BMS-911543, Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment. Seymour:Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Verstovsek:Incyte Corporation: Research Funding. Yoshitsugu:Bristol-Myers Squibb: Employment, Equity Ownership. Gestone:Bristol-Myers Squibb: Employment, Equity Ownership. Phillips:Bristol-Myers Squibb: Employment, Equity Ownership. Xing:Bristol-Myers Squibb: Employment, Equity Ownership. Peltz:Bristol-Myers Squibb: Employment, Equity Ownership. Lorenzi:Bristol-Myers Squibb: Equity Ownership, Former employment Other. Alland:Bristol-Myers Squibb: Employment, Equity Ownership. Woolfson:Bristol-Myers Squibb: Equity Ownership, Former employment Other.