Table S1: Schedule of pharmacokinetic analysis; Table S2: Overview of study dose levels (N=50); Table S3. Adverse events reported at any time during study therapy: grade 3-4 adverse events; Table S4: Veliparib pharmacokinetic (PK) parameters by cohort; Table S5: Total and ultrafilterable platinum pharmacokinetic parameters by cohort; Table S6: Immunohistochemistry results for 28 pre-therapy samples; Figure S1: Veliparib Cmax (ng/mL, panel A) and veliparib AUC0-6 (hr*ng/mL, panel B) by dose Cohort; Figure S2: Veliparib pharmacokinetic parameters (A) Cmax and (B) AUC0-6 at cycles 1 and 4 by cohort; Figure S3: Ultrafilterable platinum pharmacokinetic parameters Cmax and AUC0-24 at cycles 1 and 4 by cohort; Figure S4: Consort 2010 flow diagram for exploratory efficacy analysis comparing germline BRCA mutation positive to wild type; Figure S5: PAR assay results (pg/mL) for 14 patients in dose cohorts 6-8 (120-200 mg)
Funding
National Cancer Institute
Fred Hutchinson Cancer Research Center; AbbVie Laboratories; Safeway Gift Fund; and Mullen Gift Fund
University of Pittsburgh Cancer Institute (UPCI) Biostatistics Shared Resource Facility and the (UPCI) Cancer PK and Pharmacodynamics Facility
ARTICLE ABSTRACT
Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.
