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Gray HJ , Bell-McGuinn K , Fleming GF , Cristea M , Xiong H , Sullivan D , Luo Y , McKee MD , Munasinghe W , Martin LP
Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies
Gynecol Oncol. 2018 Mar;148(3) :507-514
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OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and </=2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m(2) on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated. RESULTS: Seventy-five patients were enrolled (ovarian cancer, n=54; breast cancer, n=12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs; >/=60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (>/=40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250mg with carboplatin AUC 4 plus gemcitabine 800mg/m(2). Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310mg BID) for >34cycles. CONCLUSIONS: Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. Trial registration ID: NCT01063816.
1095-6859 Gray, Heidi J Bell-McGuinn, Katherine Fleming, Gini F Cristea, Mihaela Xiong, Hao Sullivan, Danielle Luo, Yan McKee, Mark D Munasinghe, Wijith Martin, Lainie P Journal Article Clinical Trial, Phase I Multicenter Study Research Support, Non-U.S. Gov't United StatesGynecol Oncol. 2018 Mar;148(3):507-514. doi: 10.1016/j.ygyno.2017.12.029. Epub 2018 Jan 17.