Ronald Stoller1,2, John C Schmitz1,2, Fei Ding3, Shannon Puhalla2, Chandra P Belani4, Leonard Appleman1,2, Yan Lin3,5, Yixing Jiang4, Salah Almokadem4, Daniel Petro2, Julianne Holleran1, Brian F Kiesel1, R Ken Czambel1, Benedito A Carneiro2, Emmanuel Kontopodis1,6, Pamela A Hershberger1,7,8, Madani Rachid1, Alice Chen9, Edward Chu1,2, Jan H Beumer10,11,12. 1. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. 2. Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 3. Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. 4. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA. 5. Biostatistics Department, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 6. Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece. 7. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 8. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA. 9. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA. 10. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. beumerj@gmail.com. 11. Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. beumerj@gmail.com. 12. Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.
Abstract
BACKGROUND: Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS: Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated. RESULTS: Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥ 3 adverse events were myelosuppression-related. The MTD was determined to be 750-mg/m2 gemcitabine IV on days 1 and 8- and 20-mg PO veliparib BID days 1-14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy. CONCLUSIONS: Gemcitabine at 750-mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20-mg PO BID days 1-14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting.
BACKGROUND:Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS:Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated. RESULTS: Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥ 3 adverse events were myelosuppression-related. The MTD was determined to be 750-mg/m2 gemcitabine IV on days 1 and 8- and 20-mg PO veliparibBID days 1-14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy. CONCLUSIONS:Gemcitabine at 750-mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20-mg PO BID days 1-14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting.
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