Phase 1 Study of Veliparib With Concurrent Whole Brain Radiation Therapy (WBRT) in Patients (PTS) With Brain Metastases (METS)

ABSTRACT Background Veliparib, an oral PARP-1 and -2 inhibitor, potentiates the antitumor activity of DNA damaging agents including radiation therapy in vivo, and is shown to cross the blood-brain barrier. Updated data on safety and antitumor activity from an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts with brain mets are presented here. Methods Pts with brain mets (including leptomeningeal) from primary non-CNS metastatic solid tumors (except germ cell cancer), adequate organ function, and Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10–300 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety and exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1 dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates were calculated for all pts who had at least 1 measureable lesion at baseline. Median survival time was estimated using Kaplan-Meier methodology for all dosed pts. Results To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal (n = 3), renal (n = 1), and others (n = 8); 74.2% pts had multiple lesions, and 16.7% had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities were grade 3 hypokalemia and hyponatremia in 1 pt each at the 150 mg dose. Grade 3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration (6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8% and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer. Conclusion Addition of veliparib up to 200 mg BID was well tolerated with concurrent standard WBRT and dose escalation is ongoing. These encouraging safety and preliminary efficacy data suggest that veliparib requires further evaluation as a radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial. Disclosure M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure, Tomotherapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix; Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr. Curran had served on the advisory board of Lilly, BMS, and Plexxikon. There are no conflicts. D. Wang: As a clinical investigator, and the principle investigator at Henry Ford Health System, I have conducted this clinical trial that is financially supported by Abbott Oncology. I have no other conflict of interest to be disclosed, otherwise. L. Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B. Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott employee and stockholder. All other authors have declared no conflicts of interest.