Lisa M Landrum1, William E Brady2, Deborah K Armstrong3, Kathleen N Moore4, Paul A DiSilvestro5, David M O'Malley6, Meaghan E Tenney7, Peter G Rose8, Paula M Fracasso9. 1. Department of OB/GYN, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States. Electronic address: lisa-landrum@ouhsc.edu. 2. NRG Oncology/Gynecologic Oncology Group Statistics & Data Center, Roswell Park Cancer Institute, Buffalo, NY, United States. Electronic address: wbrady@gogstats.org. 3. Department of Gynecology & Obstetrics, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, United States. Electronic address: armstde@jhmi.edu. 4. Department of OB/GYN, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States. Electronic address: Kathleen-Moore@ouhsc.edu. 5. Department of Gynecologic Oncology, Women and Infant's Hospital, Providence, RI, United States. Electronic address: pdisilvestro@wihri.org. 6. Department of Gynecologic Oncology, The Ohio State University, Columbus, OH, United States. Electronic address: omalley.46@osu.edu. 7. Department of Gynecologic Oncology, University of Chicago, Chicago, IL, United States. Electronic address: mtenney@babies.bsd.uchicago.edu. 8. Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Cleveland Clinic, Cleveland, OH, United States. Electronic address: rosep@ccf.org. 9. Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, United States; Bristol-Myers Squibb Company, Princeton, NJ, United States. Electronic address: fracasso@virginia.edu.
Abstract
OBJECTIVE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. METHODS: Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. RESULTS: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1). CONCLUSIONS: The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.
OBJECTIVE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. METHODS: Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. RESULTS: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1). CONCLUSIONS: The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.
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