Randomized phase II (RP2) study of ATR inhibitor M6620 in combination with gemcitabine versus gemcitabine alone in platinum-resistant high grade serous ovarian cancer (HGSOC)

Abstract Background HGSOCs exhibit genomic instability and high replication stress due to universal loss of the G1/S checkpoint (via TP53 mutations), presence of homologous recombination alterations and induction via amplification of MYC and CCNE1 oncogenes. Based on in vitro and in vivo data, we hypothesized that addition of the selective ATR inhibitor M6620 to gemcitabine (gem) would demonstrate acceptable toxicity and superior efficacy in HGSOC. Methods We conducted a multicenter, open-label, RP2 study of gem/M6620 versus gem alone (1:1 randomization) in platinum resistant HGSOC. Randomization was stratified based on platinum free interval (PFI), (PFI≤3 months vs > 3 months). Primary endpoint was progression-free survival (PFS) while secondary endpoints included safety, objective response and clinical benefit rate. Unlimited prior lines but ≤1 prior regimen in the platinum resistant setting were allowed. Patients (pts) received gem 1000 mg/m2 IV on Days 1 and 8 with or without M6620 210 mg/m2 IV on Days 2 and 9 of a 21-day cycle until disease progression (PD) or intolerable toxicity. Pts on gem alone were allowed to crossover to gem/M6620 only if they developed PD by RECIST. In order to have 80% power to detect improvement of median PFS from 15 weeks with gem to 27.3 weeks with gem/M6620 (hazard ratio (HR) =0.55) with a one-sided alpha level of 0.1, 64 total pts were required. Results 70 pts were randomized, 36 to gem and 34 to gem/M6620 arms. Kaplan-Meier estimated median PFS was 14.7 weeks in the gem alone versus 22.9 weeks in the gem/M6620 arm; gem/M6620 HR was 0.57 (90% CI, 0.33-0.997; 1-sided log-rank test p = 0.047). The benefit of addition of M6620 was observed mainly among pts stratified into the PFI≤3 months group (HR = 0.31; 90% CI, 0.13-0.77; 1-sided p = 0.013); insignificant PFS difference between the two arms was observed among pts with PFI>3 months (HR = 0.95; 90% CI, 0.46-1.97; 1-sided p = 0.45). No increase in treatment-related toxic effects was observed in the gem/M6620 arm. Conclusions Addition of the ATR inhibitor M6620 to gem in platinum resistant HGSOC met the primary endpoint of this RP2 trial without increasing toxicity. Further evaluation of gem/M6620 in this setting is warranted. Clinical trial identification NCI CTEP: 9944; NCT02595892. Legal entity responsible for the study National Cancer Institute (NCI). Funding National Cancer Institute (NCI). Disclosure P.A. Konstantinopoulos: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Advisory Board: Vertex; Advisory / Consultancy, Advisory Board: Pfizer; Research grant / Funding (institution): Eli Lilly. R.T. Penson: Advisory / Consultancy, Advisory Board: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: AstraZeneca; Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eisai; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck & Co; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Genentech/Roche; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi Aventis; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Vascular Biogenics; Advisory / Consultancy, Advisory Board: Sutro Biopharma; Advisory / Consultancy, Advisory Board: Mersana Therapeutics; Research grant / Funding (institution): Array Biopharma. L.R. Duska: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline/Novartis; Research grant / Funding (institution): Morab; Honoraria (self), Research grant / Funding (institution): MorphoTek; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Aduro BioTech; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Ludwig; Research grant / Funding (institution): LEAP Therapeutics; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Inovio; Advisory / Consultancy: Cue Biopharma; Research grant / Funding (institution): Advaxis. M.A. Crispens: Advisory / Consultancy: AbbVie; Research grant / Funding (institution): AstraZeneca. A.B. Olawaiye: Advisory / Consultancy, Advisory Board: Clovis; Advisory / Consultancy, Advisory Board: Tesaro. M.T. McHale: Advisory / Consultancy: Eisai; Research grant / Funding (institution): Verastem. R.J. Schilder: Advisory / Consultancy, Consultant: Incyte; Advisory / Consultancy, Consultant: Immunogen; Advisory / Consultancy, Consultant: Celsion; Advisory / Consultancy, Consultant: Flatiron. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck KGaA/EMD-Serono; Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: Bicycle Therapeutics; Advisory / Consultancy: Fusion Pharmaceuticals; Advisory / Consultancy: Cybrexa Therapeutics; Advisory / Consultancy: Astex; Advisory / Consultancy: Almac; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Angiex; Advisory / Consultancy: Daiichi Sankyo; Research grant / Funding (institution): Array Biopharma. U.A. Matulonis: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Myriad Genetics; Advisory / Consultancy: Clovis; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Mersana; Advisory / Consultancy: Geneos; Advisory / Consultancy: Fuji Firm; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Cerulean; Advisory / Consultancy: 2X Oncology. All other authors have declared no conflicts of interest.