A phase I study of intravenous or intraperitoneal platinum based chemotherapy in combination with veliparib and bevacizumab in newly diagnosed ovarian, primary peritoneal and fallopian tube cancer Journal Article

Authors: Moore, K. N.; Miller, A.; Bell-McGuinn, K. M.; Schilder, R. J.; Walker, J. L.; O'Cearbhaill, R. E.; Guntupalli, S. R.; Armstrong, D. K.; Hagemann, A. R.; Gray, H. J.; Duska, L. R.; Mathews, C. A.; Chen, A.; O'Malley, D.; Gordon, S.; Fracasso, P. M.; Aghajanian, C.
Article Title: A phase I study of intravenous or intraperitoneal platinum based chemotherapy in combination with veliparib and bevacizumab in newly diagnosed ovarian, primary peritoneal and fallopian tube cancer
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. © 2019 Elsevier Inc.
Keywords: adult; aged; primary tumor; major clinical study; overall survival; constipation; drug tolerability; fatigue; neutropenia; bevacizumab; cisplatin; cancer combination chemotherapy; diarrhea; hypertension; side effect; paclitaxel; cancer staging; anorexia; ovarian cancer; carboplatin; progression free survival; infection; multiple cycle treatment; pain; peritoneum cancer; sensory neuropathy; anemia; mucosa inflammation; nausea; thrombocytopenia; vomiting; dehydration; myalgia; qt prolongation; maintenance therapy; cohort analysis; creatinine blood level; abdominal pain; dyspnea; febrile neutropenia; pneumonia; lung embolism; hyponatremia; insomnia; myelodysplastic syndrome; thromboembolism; ovary carcinoma; nausea and vomiting; suicide; sepsis; colon perforation; headache; maximum tolerated dose; phase 1 clinical trial; uterine tube carcinoma; drug dose increase; lung infection; dyspepsia; epistaxis; atrial fibrillation; proteinuria; heart arrest; small intestine obstruction; cerebrovascular accident; hypocalcemia; motor neuropathy; duodenum ulcer; muscle atrophy; mouth ulcer; vagina bleeding; hypertransaminasemia; perforation; acute myeloid leukemia; peritonitis; primary therapy; veliparib; faintness; very elderly; human; female; priority journal; article; parp inhibition
Journal Title: Gynecologic Oncology
Volume: 156
Issue: 1
ISSN: 0090-8258
Publisher: Elsevier Inc.  
Date Published: 2020-01-01
Start Page: 13
End Page: 22
Language: English
DOI: 10.1016/j.ygyno.2019.10.012
PUBMED: 31708167
PROVIDER: scopus
PMCID: PMC7048389
Notes: Article -- Export Date: 3 February 2020 -- Source: Scopus
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