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Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer.

AbstractPURPOSE:
Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).
EXPERIMENTAL DESIGN:
Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.
RESULTS:
Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.
CONCLUSION:
This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.
AuthorsShivaani Kummar, Amit M Oza, Gini F Fleming, Daniel M Sullivan, David R Gandara, Michael J Naughton, Miguel A Villalona-Calero, Robert J Morgan Jr, Peter M Szabo, Ahrim Youn, Alice P Chen, Jiuping Ji, Deborah E Allen, Chih-Jian Lih, Michele G Mehaffey, William D Walsh, Paul M McGregor 3rd, Seth M Steinberg, P Mickey Williams, Robert J Kinders, Barbara A Conley, Richard M Simon, James H Doroshow
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 7 Pg. 1574-82 (Apr 01 2015) ISSN: 1557-3265 [Electronic] United States
PMID25589624 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Copyright©2015 American Association for Cancer Research.
Chemical References
  • Antineoplastic Agents
  • Benzimidazoles
  • veliparib
  • Cyclophosphamide
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents (therapeutic use)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Benzimidazoles (administration & dosage, adverse effects)
  • Cyclophosphamide (administration & dosage, adverse effects)
  • Cystadenocarcinoma, Serous (drug therapy, genetics, mortality)
  • Disease-Free Survival
  • Fallopian Tube Neoplasms (drug therapy, genetics, mortality)
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Humans
  • Middle Aged
  • Ovarian Neoplasms (drug therapy, genetics, mortality)
  • Peritoneal Neoplasms (drug therapy, genetics, mortality)

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