Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

Abstract

PURPOSE Cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry 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 BID. Maximum tolerated dose 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 (10 of 14 (71%) vs 8 of 27 (30%), mid-p=0.01). Median progression-free survival for all 50 patients was 5.5 months (95% confidence interval 4.1–6.7). CONCLUSION Veliparib at 300 mg BID 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. Translational Relevance We hypothesize that TNBC tumors have defects in homologous recombination DNA repair similar to BRCA mutation associated tumors, which will render them sensitive to platinum therapy and PARP inhibition. This report describes a phase I study that explored the safety and efficacy of cisplatin, vinorelbine and veliparib. This combination was tolerable and reached the highest dose of veliparib in combination with chemotherapy used in breast cancer to date. Antineoplastic activity was observed both in BRCA mutation associated breast cancer and in BRCA wild-type TNBC. We measured changes in PARP activity and performed gene expression profiling and immunohistochemistry studies. Based on promising results from this study, a randomized phase II study has been developed to evaluate the addition of veliparib to cisplatin chemotherapy for patients with advanced TNBC. This study will incorporate a multi-pronged biomarker approach to identify a homologous recombination repair deficiency (HRD) phenotype that derives benefit from PARP inhibition.

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083

“…While the median baseline PAR level was selected as the cut-point in this study, the intention is to motivate larger studies to examine the role of baseline PAR to possibly help select patients for PAR-directed therapy. Ongoing genomic analyses of archival tumor tissues may shed additional light on characteristics that predict CB, and in particular of exceptional responders (41). Further assessments of PARPis and combinations of agents that disrupt DNA repair—whether BRCA or other germline or somatic mutation associated—are needed, and are ongoing in MBC and other malignancies (42).…”

Increased centrosome number in BRCA‐related breast cancer specimens determined by immunofluorescence analysis

“…The ability to identify BRCA-related cancer patients among many breast cancer patients is important, because these patients are suitable for targeted therapy and prophylactic surgery as well as intensive follow-up to prevent breast cancer-related death. 4,[20][21][22][23] c-Tubulin immunodetection could be a useful pretest for patients who are considering BRCA genetic testing, as it is inexpensive and WATANABE ET AL. 9,24,25 These pretests that use clinicopathological information might be more affected by ethnic differences than our method.…”

“…Genetic tests for BRCA mutation are important for identifying suspected cases of BRCA ‐related breast and ovarian cancer syndrome so that prophylactic surgery and intensive follow‐up programs can be recommended to the patient. Furthermore, BRCA status predicts patient chemosensitivity to platinum or poly (ADP‐ribose) polymerase (PARP) inhibitor . Widespread use of PARP inhibitors, thus, necessitates BRCA genetic tests.…”

A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia

“…Other studies combining veliparib with chemotherapy in solid tumors have noted less than proportional increases in veliparib exposure at doses above 120 mg twice daily (43)(44). In contrast, we observed greater than proportionate increases in veliparib exposure above 80 mg (Table 5).…”