Leonard J Appleman1,2,3, Jan H Beumer4,5,6,7, Yixing Jiang8, Yan Lin4,5,9,10, Fei Ding4,5,9, Shannon Puhalla4,5,6, Leigh Swartz4, Taofeek K Owonikoko11, R Donald Harvey11, Ronald Stoller4,5, Daniel P Petro4,5, Hussein A Tawbi4,5, Athanassios Argiris4,5, Sandra Strychor4,5, Marie Pouquet4,5, Brian Kiesel4,5,6, Alice P Chen12, David Gandara13, Chandra P Belani8, Edward Chu4,5,6, Suresh S Ramalingam11. 1. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. applemanlj@upmc.edu. 2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. applemanlj@upmc.edu. 3. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. applemanlj@upmc.edu. 4. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 5. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 6. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 7. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA. 8. Penn State Hershey Cancer Institute, Hershey, PA, USA. 9. UPMC Hillman Cancer Center Biostatistics Facility, Pittsburgh, PA, USA. 10. Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. 11. Winship Cancer Institute, Emory University, Atlanta, GA, USA. 12. National Cancer Institute, Bethesda, MD, USA. 13. Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Davis, CA, USA.
Abstract
PURPOSE: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. METHODS: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2. RESULTS: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. CONCLUSION: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.
PURPOSE:Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. METHODS: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2. RESULTS: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. CONCLUSION:Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.
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