Abstract CT325: Combination of the PARP inhibitor veliparib (ABT888) with irinotecan in patients with triple negative breast cancer: Preliminary activity and signature of response
Authors: Patricia M. LoRusso, Sara M. Tolaney, Shukmei Wong, Ralph E. Parchment, Robert J. Kinders, Lihua Wang, Jessica Aldrich, Alice Chen, Diane Durecki, Scott A. Boerner, Tina Guthrie, Adam Bowditch, Lance K. Heilbrun, Mary Jo Pilat, David Craig, Dongpo Cai, Tracy Bell, John Carpten, Geoffrey Shapiro
Journal: Cancer Research (2015)

Abstract Background: The nuclear enzyme PARP is essential in recognition and repair of DNA damage. Preclinical evidence suggests that PARP inhibitors work as sensitizing agents for DNA-damaging agents such as irinotecan. Veliparib is an orally bioavailable PARP 1 and 2 inhibitor. This expansion to a phase I study, which demonstrated veliparib reduces PAR levels in tumor after irinotecan exposure, was conducted to assess the safety, tolerability and preliminary anti-tumor activity of the combination of veliparib and irinotecan in triple negative breast cancer (TNBC) patients (pts), as well as to apply next generation sequencing technologies to define a signature of response. Methods: Pts were enrolled to two breast cancer cohorts: (1) TNBC, germline BRCA-mutant positive and (2) TNBC, non-BRCA mutated (wt). Eligibility included performance status 0-2; ≥ age 18; adequate bone marrow, hepatic and renal function. Cycles were 21 days. Irinotecan was given i.v. 100 mg/m2 over 90 min on Days 1 and 8. Twice daily (BID) oral dosing of 40 mg veliparib occurred Days 2-15 (Cycle 1) and Days 1-15 (subsequent cycles) followed by a 6-day rest. Tumor biopsies were collected at baseline, 4-6 hours after the first dose of irinotecan (day 1) and the combination (day 8) in cycle 1. Whole exome and transcriptome sequencing was performed using both normal and tumor tissue. Circulating tumor cells (CTC) were evaluated using the CellSearch platform. Results: 24 TNBC pts were enrolled, with 20 pts treated and evaluable for response (8 germline BRCA-mutation positive, 10 non-BRCA mutated, 2 suspected deleterious). Median age was 51 (range 31-63). Median number of prior treatments was 4 (range 1-7). Most frequent drug-related toxicities included: leukopenia (60%), neutropenia (60%), nausea (55%), diarrhea (40%), fatigue (40%), anemia (30%), and vomiting (30%). Best responses were as follows: Germline BRCA-mutant positive 7/8 PR (88%; median number of days on study = 330; range 148-594 days), 1/8 PD (12%); suspected deleterious 2/2 PD (100%); non-BRCA mutated 7/10 SD (70%; median number of days on study = 70; range 42-98 days), 3/10 PD (30%). Exploratory molecular profiling has been performed in a subset of these pts and the results will be presented. EpCAM+ CTC numbers were evaluable in 11 of 22 enrolled pts, and nuclear γH2Ax+, a pharmacodynamic biomarker of DNA damage, was identified in a fraction of CTCs from all 11 of these pts. Conclusions: Veliparib in combination with irinotecan was safe and tolerable in TNBC pts. Although the cohort in this trial is small, the preliminary response rate of 88% in pts with germline BRCA mutation is encouraging and higher than that historically reported with PARP inhibitor monotherapy in this population. Deep molecular profiling among BRCA mutant carriers will be validated in a larger, independent cohort to define potential biomarkers of response. Support: NCI U01-CA062487, NCI U01-CA062490, Komen KG120001, NCI R21-CA135572, and HHSN261200800001E. Citation Format: Patricia M. LoRusso, Sara M. Tolaney, Shukmei Wong, Ralph E. Parchment, Robert J. Kinders, Lihua Wang, Jessica Aldrich, Alice Chen, Diane Durecki, Scott A. Boerner, Tina Guthrie, Adam Bowditch, Lance K. Heilbrun, Mary Jo Pilat, David Craig, Dongpo Cai, Tracy Bell, John Carpten, Geoffrey Shapiro. Combination of the PARP inhibitor veliparib (ABT888) with irinotecan in patients with triple negative breast cancer: Preliminary activity and signature of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT325. doi:10.1158/1538-7445.AM2015-CT325