Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.

Abstract

7522 Background: BMN 673 is the most potent inhibitor of PARP1/2 in clinical development (IC50<1nM), inducing synthetic lethality in tumors deficient in homologous recombination. Based on preclinical data showing high PARP expression in SCLC models and significant antitumor activity of BMN 673, an expansion cohort of SCLC patients was also studied. Methods: Safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of BMN 673 were evaluated in a 2-stage study. 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) recruited pts with tumors defective in DNA repair: Previously treated extensive stage SCLC (second line), Ewing’s sarcoma (ES), or tumors in germline (g) BRCA mutation (mut) carriers. Results: Stage 1: The MTD and Recommended Phase 2 Dose (RP2D) was established at 1 mg/d in 39 pts (33F/6M) treated at doses ranging from 25 to 1100 μg/d. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 μg/d, respectively. Stage 2: To date, 54 pts [38F/16M, median age 52 (range 18-78)] have been enrolled: 15 SCLC, 12 ES and 27 gBRCA mut. RECIST confirmed responses have been reported in 2/11 (18%) evaluable previously treated SCLC pts [Clinical Benefit Rate (PR+SD > 8 wks): 6/11 pts (55%); median PFS: 7.4 wks, 95% CI 4.3-19.4]; 12/26 (46%) gBRCA mut ovarian cancer pts (median PFS: 32.3 wks, 95%CI 28.2-38.6); and 8/18 (44%) gBRCA mut breast cancer pts (median PFS: 31 wks, 95% CI 13.1-45.4). No responses were seen in ES pts. Overall, the most frequent adverse events were mild to moderate and included fatigue (all grades=30%), nausea (26%), alopecia (25%), anemia (23%), thrombocytopenia (20%) and neutropenia (14%). Conclusions: BMN 673 is well tolerated at the RP2D of 1 mg/d. BMN 673 has antitumor activity in pts with advanced previously treated SCLC and significant activity in pts with gBRCA mut ovarian and breast cancer. A phase 3 trial in gBRCA mut breast cancer is ongoing. Clinical trial information: NCT01286987.