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

Abstract Poster

Authors

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Geraldine Helen O'Sullivan Coyne

Early Clinical Trials Development Program, DCTD, National Cancer Institute at the National Institutes of Health, Bethesda, MD

Geraldine Helen O'Sullivan Coyne , Khanh Tu Do , Shivaani Kummar , Naoko Takebe , Mary Flanagan Quinn , Sarina Anne Piha-Paul , Ashley Bruns , Lamin Juwara , Elad Sharon , Richard Piekarz , Howard Streicher , Larry Rubinstein , Deborah Wilsker , Robert J. Kinders , Ralph E. Parchment , Elliot B Levy , Austin Doyle , James H. Doroshow , Alice P. Chen

Organizations

Early Clinical Trials Development Program, DCTD, National Cancer Institute at the National Institutes of Health, Bethesda, MD, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, NCI/ NIH, Elkridge, MD, Natoinal Naval Medical Center, Rockville, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, National Cancer Institute, Bethesda, MD, NCI at Frederick, Bethesda, MD, US, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, National Cancer Institute, Frederick, MD, 1050 Boyles Street, Frederick, MD, National Institutes of Health, Bethesda, MD, National Cancer Institute, Rockville, MD, Center for Cancer Research, Division of Cancer Treatment and Diagnosis, Bethesda, MD

Research Funding

NIH

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

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Abstract Details

Meeting

2018 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics

Track

Developmental Therapeutics and Translational Research

Sub Track

Other Novel Agents

Clinical Trial Registration Number

NCT02723864

Citation

J Clin Oncol 36, 2018 (suppl; abstr 2549)

DOI

10.1200/JCO.2018.36.15_suppl.2549

Abstract #

2549

Poster Bd #

375

Abstract Disclosures

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