Presentation Abstract

Abstract Number: C295
Presentation Title: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors
Presentation Time: Tuesday, Oct 22, 2013, 12:30 PM - 3:00 PM
Location: Exhibit Hall C-D
Author Block: Zev A. Wainberg1, Johann S. de Bono2, Lida Mina3, Jasgit Sachdev4, Lauren Averett Byers5, Rashmi Chugh6, Charlie Zhang7, Joshua W. Henshaw7, Andrew Dorr7, John Glaspy1, Ramesh Ramanathan4. 1David Geffen School of Medicine at UCLA, Los Angeles, CA; 2The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; 3Indiana University, Indianapolis, IN; 4Virginia G. Piper Cancer Center at Scottsdale Healthcare/Tgen, Scottsdale, AZ; 5University of Texas MD Anderson Cancer Center, Houston, TX; 6University of Michigan, Ann Arbor, MI; 7BioMarin Pharmaceutical, Novato, CA
Abstract Body: 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. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly related to high PARP expression. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES). Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 µg/d with 1000 µg/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC’s was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively. Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet.Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway.
Clinicaltrial.gov ID: NCT01286987
BRCA Breast and Ovarian Cancer
NBRCA Tumor TypeResponse
18BreastCRPRCBR*
18Breast1 (6%)9 (50%)^14 (78%)
28OvarianResponse - 25 RECIST evaluable; 27 CA-125 evaluable
28OvarianCRPRCA-125CBR*
1 (4%)10 (40%)19 (70%)23 (82%)
2PancreasCRPRSD > 12 weeks
2Pancreas0 (0%)0 (0%)2 (100%)**

^3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient