First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Session Type and Session Title: 
General Poster Session, Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 2580)
Johann Sebastian De Bono, Lida A. Mina, Michael Gonzalez, Nicola J. Curtin, Evelyn Wang, Joshua W. Henshaw, Manpreet Chadha, Jasgit C. Sachdev, Daniela Matei, Gayle S. Jameson, Michael Ong, Bristi Basu, Zev A. Wainberg, Lauren Averett Byers, Rashmi Chugh, Andrew Dorr, Stanley B. Kaye, Ramesh K. Ramanathan; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Indiana University, Indianapolis, IN; Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, United Kingdom; BioMarin Pharmaceutical, Novato, CA; Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ; Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ; Indiana University School of Medicine, Indianapolis, IN; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Michigan, Ann Arbor, MI; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ

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Abstract Disclosures


Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.