Kathleen N Moore1, Austin Miller2, Katherine M Bell-McGuinn3, Russell J Schilder4, Joan L Walker5, Roisin E O'Cearbhaill6, Saketh R Guntupalli7, Deborah K Armstrong8, Andrea R Hagemann9, Heidi J Gray10, Linda R Duska11, Cara A Mathews12, Alice Chen13, David O'Malley14, Sarah Gordon15, Paula M Fracasso16, Carol Aghajanian17. 1. Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA. Electronic address: Kathleen-moore@ouhsc.edu. 2. NRG Oncology Statistics & Data Management Center, Roswell Park Cancer Institute. Electronic address: millerA@nrgoncology.org. 3. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: katherine.bell-mcguinn@lilly.com. 4. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: russell.schilder@jefferson.edu. 5. Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA. 6. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: ocearbhr@mskcc.org. 7. University of Colorado, Denver, CO, USA. Electronic address: saketh.guntupalli@UCDENVER.edu. 8. Johns Hopkins, Baltimore, MD, USA. Electronic address: armstde@jhmi.edu. 9. Washington University, St. Louis, MO, USA. Electronic address: hagemanna@wustl.edu. 10. University of Washington, Seattle, WA, USA. Electronic address: hgray@u.washington.edu. 11. University of Virginia School of Medicine, Charlottesville, VA, USA. Electronic address: lrd5d@hscmail.mcc.virginia.edu. 12. Women and Infants Hospital of Rhode Island, Providence, RI, USA. Electronic address: cmathews@wihri.org. 13. Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, USA. Electronic address: chenali@mail.nih.gov. 14. The Ohio State University, Columbus, OH, USA. Electronic address: omalley.46@osu.edu. 15. Virginia Commonwealth University, Richmond, VA, USA. Electronic address: sarah.gordon@vcuhealth.org. 16. University of Virginia School of Medicine, Charlottesville, VA, USA. Electronic address: paula.fracasso@adaptimmune.com. 17. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: aghajanc@mskcc.org.
Abstract
BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.
BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.
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