Phase I Trial Of The Triplet Berzosertib (M6620, Vx-970), Veliparib And Cisplatin (Bvp) In Patients With Advanced Solid Tumors.

Abstract Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway. We conducted a phase I trial of cisplatin in combination with the ataxia-telangiectasia-related (ATR) protein kinase inhibitor berzosertib (M6620) and the poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor veliparib, postulating that simultaneous PARP and ATR inhibition impairs DNA repair and induces a “BRCA null”-like phenotype which could potentiate the antitumor activity of cisplatin. We evaluated the safety, maximal tolerated dose (MTD) and preliminary anti-tumor activity of this treatment triplet. The study was conducted through the Experimental Therapeutics Clinical Trials Network (ETCTN). Methods: This open label trial used a 3+3 design. Cisplatin and berzosertib were each administered intravenously on separate, sequential days for two continuous weeks [day (D) 1 and 8; D2 and 9 respectively], together with veliparib orally twice daily during IV therapy and for 24 hours after (D1-3 and 8-10) in 21-day cycles. Prior platinum and PARP inhibitor therapy were permitted. Tumor expression of DNA damage repair (DDR) biomarkers was assessed at the MTD using validated, quantitative immunofluorescence assays. Results: Fifty-three patients (pts) enrolled, 46 pts evaluable for response. The MTD and RP2D dose is cisplatin 40 mg/m2 D1 and D8, berzosertib 210 mg/m2 D2 and D9, and veliparib 200mg BID (D1-3, D8-10). Three patients achieved a confirmed partial response (PR; 5.6%). A further 2 patients had an unconfirmed PR (breast carcinoma, -30%; HGS carcinoma, -36%). Four responders (3 PR and 1 uPR) received prior platinum. Median time on study: 4 cycles (range 1-25). Genomic data was available on four pts achieving a response: ovarian cancer (BRCA-wildtype, ATM unknown; 25 cycles), breast carcinoma (ATM mutation; 14 cycles), SCC of the tongue (Chek2 mutation; 20 cycles), and HGS carcinoma (ATM/BRIP1 mutation; 4 cycles). Twenty-six pts (56.5%) had stable disease. Thirty-five patients (66.0%) required dose reduction in at least 1 agent, most commonly veliparib (25; 47.2%). Most common grade 3 and 4 adverse events were related to myelosuppression: anemia (20; 37.7%), thrombocytopenia (17; 32.1%), leukopenia (13; 24.5%), neutropenia (12; 22.6%), and lymphopenia (11; 20.8%). Ongoing pharmacodynamic analyses of tumor biopsies collected on C1D1 (post-veliparib/cisplatin) and C1D9 (post-veliparib/cisplatin/M6620) have demonstrated a combination-induced increase in RAD51, indicative of replication stress. Conclusions: The BVP combination shows anti-tumor activity in HR-compromised tumors and M6620 further increases the DDR response elicited by combination cisplatin/veliparib. Citation Format: Geraldine O'Sullivan Coyne, Khanh T. Do, Shivaani Kummar, Naoko Takebe, Sarina Piha-Paul, Richard Piekarz, Deborah Wilsker, Brandon Miller, Katherine Ferry-Galow, Ralph Parchment, Lamin Juwara DNP, Mary Jane Ong, Arjun Mittra, James H. Doroshow, Alice P. Chen. Phase I trial of the triplet berzosertib (M6620, VX-970), veliparib and cisplatin (BVP) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT115.