Phase I trial of the triplet M6620 (formerly VX970) + veliparib + cisplatin in patients with advanced solid tumors.

Abstract

2549 Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades that culminate in cell cycle arrest to allow time for DNA damage repair (DDR). M6620 is an ATR inhibitor with antitumor activity across a range of cell lines. Veliparib (ABT-888), an oral poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, plays a pivotal role in DDR response through the base excision repair pathway, with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers. As DNA damage and antitumor activity of platinum results from DNA cross-links that stall replication forks and halt transcription, this trial evaluates if veliparib together with M6620 impair DNA repair by inducing a “BRCA null”-like phenotype that potentiates the antitumor activity of cisplatin. Methods: Open label phase I trial of the M6620+veliparib+cisplatin combination; 3+3 design, 21-day cycle: cisplatin 40mg/m2 intravenously (IV) Day 1 [Day 8 added from dose level (DL)3]; M6620 (M) IV Days 2+9; Veliparib (V) orally twice daily Days 1-3 and 8-10. Prior platinum, PARPi therapy permitted. Response: RECIST 1.1. Results: 23 patients(pts) enrolled, 22pts evaluable for response. 3/22pts confirmed partial responses (PR) lasting > 4cycles (range 4-15): 1pt with BRCA-wildtype ovarian cancer (DL3), 1pt with esophageal cancer/biallelic loss of ATM (DL4); 1pt with NSCL cancer/ATM mutation (DL5); all remain on study. 12/22pts have stable disease: median time on study 5 cycles (range 3-10). DL3+4 expanded for dose limiting toxicity: grade 4 hypophosphatemia and thrombocytopenia respectively (1pt, 4%). Other adverse events: grade 3 thrombocytopenia (6pts, 27%), leucopenia (5pts, 22%), lymphopenia (4pts, 18%). Maximally tolerated dose (MTD) not reached for the combination, currently enrolling DL7: V 200mg, M 210mg/m2. Conclusions: combination is safe and shows anti-tumor activity in HR-compromised tumors. Planned biomarker assessment at MTD includes γH2AX, RAD51, pNbs1, and pATR in tumor biopsies and circulating tumor cells using a validated, quantitative immunofluorescence assay. Clinical trial information: NCT02723864.