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Randomized Trial of Oral Cyclophosphamide and Veliparib in High Published OnlineFirst January 14, 2015; DOI: 10.1158/1078-0432.CCR-14-2565 Cancer Therapy: Clinical Clinical Cancer Research Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer Shivaani Kummar1, Amit M. Oza2, Gini F. Fleming3, Daniel M. Sullivan4, David R. Gandara5, Michael J. Naughton6, Miguel A. Villalona-Calero7, Robert J. Morgan Jr8, Peter M. Szabo1, Ahrim Youn1, Alice P. Chen1, Jiuping Ji9, Deborah E. Allen1, Chih-Jian Lih9, Michele G. Mehaffey9, William D. Walsh9, Paul M. McGregor III9, Seth M. Steinberg1, P. Mickey Williams9, Robert J. Kinders9, Barbara A. Conley1, Richard M. Simon1, and James H. Doroshow1 Abstract Purpose: Veliparib, a PARP inhibitor, demonstrated clinical Results: Seventy-five patients were enrolled and 72 were evalu- activity in combination with oral cyclophosphamide in able for response; 38 received cyclophosphamide alone and 37 patients with BRCA-mutant solid tumors in a phase I trial. the combination as their initial treatment regimen. Treatment was To define the relative contribution of PARP inhibition to well tolerated. One complete response was observed in each arm, the observed clinical activity, we conducted a randomized with three partial responses (PR) in the combination arm and six phase II trial to determine the response rate of veliparib in PRs in the cyclophosphamide alone arm. Genetic sequence and combination with cyclophosphamide compared with cyclo- expression analyses were performed for 211 genes involved in phosphamide alone in patients with pretreated BRCA-mutant DNA repair; none of the detected genetic alterations were signif- ovarian cancer or in patients with pretreated primary perito- icantly associated with treatment benefit. neal, fallopian tube, or high-grade serous ovarian cancers Conclusion: This is the first trial that evaluated single-agent, (HGSOC). low-dose cyclophosphamide in HGSOC, peritoneal, fallopian Methods: Adult patients were randomized to receive cyclo- tube, and BRCA-mutant ovarian cancers. It was well tolerated phosphamide alone (50 mg orally once daily) or with veliparib and clinical activity was observed; the addition of veliparib at 60 (60 mg orally once daily) in 21-day cycles. Crossover to the mg daily did not improve either the response rate or the median combination was allowed at disease progression. progression-free survival. Clin Cancer Res; 1–9. Ó2015 AACR. Introduction small-molecule PARP inhibitors potentiates DNA damage caused by cytotoxic chemotherapies, including cyclophospha- PARP 1 and 2 enzymes regulate DNA damage repair and mide (1–3). Inhibition of PARP activity in the presence of maintain genomic stability in cells. Inhibition of DNA repair by deleterious mutations in the BRCA gene, which is involved in the homologous recombination pathway of DNA damage repair, can result in tumor cell death through the process 1 National Cancer Institute, National Institutes of Health, Bethesda, of synthetic lethality (4, 5). Clinical activity is observed with Maryland. 2Princess Margaret Hospital, University of Toronto, Ontario, Canada. 3The University of Chicago Medical Center, Chicago, Illinois. PARP inhibitors alone and in combination with cytotoxic 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. chemotherapy in patients with breast or ovarian cancers car- 5 University of California Davis Cancer Center, Davis, California. rying germline BRCA mutations (BRCA-mutant; refs. 6–8). 6Washington University School of Medicine, St. Louis, Missouri. 7The Ohio State University Comprehensive Cancer Center, James Cancer Clinical responses have also been observed with PARP inhibi- Hospital and Solove Research Institute, Columbus, Ohio. 8City of Hope tors in patients with high-grade serous ovarian cancer Comprehensive Cancer Center, Duarte, California. 9Leidos Biomedical (HGSOC), a disease known to have a high incidence of DNA Research, Inc., Frederick National Laboratory for Cancer Research, BRCA Frederick, Maryland. repair defects even in patients who do not carry germline mutations (9). Note: Supplementary data for this article are available at Clinical Cancer Low daily doses of oral cyclophosphamide (Cytoxan; Bristol- Research Online (http://clincancerres.aacrjournals.org/). Myers Squibb Company) in combination with other agents have Current address for A. Youn: Department of Biostatistics, Columbia University, demonstrated clinical activity in lymphomas and multiple solid New York, NY. tumors (10–13). Our phase I study of oral cyclophosphamide in Corresponding Author: James H. Doroshow, NIH/NCI, Bldg. 31, Room 3A44, 31 combination with veliparib was well tolerated and demonstrated Center Drive, Bethesda, MD 20814. Phone: 301-496-4291; Fax: 301-496-0826; activity in patients with BRCA-mutant tumors: 6 of 13 patients E-mail: [email protected] experienced a partial response (PR), and 3 additional patients had doi: 10.1158/1078-0432.CCR-14-2565 prolonged disease stabilization (14). Based on this promising Ó2015 American Association for Cancer Research. activity, we conducted a multicenter, randomized phase II trial to www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst January 14, 2015; DOI: 10.1158/1078-0432.CCR-14-2565 Kummar et al. creatinine <1.5Â ULN were also required. Prior exposure to PARP Translational Relevance inhibitors or cyclophosphamide was allowed unless previously Administration of PARP inhibitors has been shown to result administered in combination. in antitumor responses as single agents in BRCA-mutant Previous anticancer therapy or surgery must have been com- tumor models and in combination with DNA-damaging ther- pleted at least 4 weeks before enrollment. Patients with treated apies. Veliparib, a small-molecule PARP inhibitor, demon- brain metastases stable for greater than 4 weeks off steroids were strated clinical activity in combination with oral cyclophos- eligible. This trial was conducted under an NCI-sponsored phamide in patients with BRCA-mutant solid tumors in a IND with institutional review board approval at each participat- phase I trial. To define the relative contribution of PARP ing site. Protocol design and conduct followed all applicable inhibition to the observed clinical activity, we conducted a regulations, guidance, and local policies [ClinicalTrials.gov Iden- multicenter, randomized phase II study of low-dose, oral tifier: NCT01306032]. cyclophosphamide, alone and in combination with veliparib, in patients with BRCA-mutant ovarian cancer or in patients Trial design with pretreated primary peritoneal, fallopian tube, or high- This was an open-label, multicenter, randomized phase II study grade serous ovarian cancers. Clinical responses were of the combination of veliparib and oral cyclophosphamide observed; however, there was no difference in the response compared with oral cyclophosphamide alone in patients with rate between the arms. Genetic sequence and expression pretreated primary peritoneal cancer, fallopian tube cancer, analyses were performed for 211 genes involved in DNA HGSOC, or BRCA-mutant ovarian cancer. Veliparib (ABT-888) damage repair; mutations were detected but did not correlate was supplied by the Division of Cancer Treatment and Diagnosis, with clinical benefit on study. NCI, under a Collaborative Research and Development Agree- ment with AbbVie. Cyclophosphamide was obtained from com- mercial sources. Oral cyclophosphamide was administered at 50 mg once daily, compare the response rate (complete plus partial responses; alone or with oral veliparib at 60 mg once daily throughout a CRþPR) of veliparib in combination with oral cyclophospha- 21-day cycle, the same combination regimen studied in our prior mide with that of oral cyclophosphamide alone in patients with phase I trial (14). Patients were required to maintain a diary pretreated BRCA-mutant ovarian cancer or in patients with documenting when drugs were taken and any associated side pretreated HGSOC, primary peritoneal, or fallopian tube can- effects. There were no restrictions on food consumption. Adverse cers. This trial was designed to estimate the relative contribu- events were graded according to NCI Common Toxicity Criteria tion of PARP inhibition to the activity of this combination in version 4.0. Doses of both drugs were reduced for grade 2 patients with known BRCA mutations or in tumors known to nonhematologic and grade 4 hematologic toxicities. Nonhema- have a high incidence of DNA repair defects (9). Secondary tologic toxicities were required to have resolved to grade 1, and objectives were to evaluate archival tissue and blood samples hematologic toxicities to grade 2 (except lymphopenia) before for mutations in genes involved in DNA damage repair and continuing treatment. Radiographic evaluation was performed at determine poly(ADP-ribose) (PAR) levels in peripheral blood baseline and every three cycles to assess tumor response based on mononuclear cells (PBMC) and levels of phosphorylated his- the RECIST version 1.1 (18). tone H2AX (gH2AX), a marker of DNA damage response, in The trial was randomized and used a phase 2.5 design, intend- circulating tumor cells (CTC) before and during treatment (15, ing to enroll 65 patients per arm to have 80% power to permit a 16). Archival patient tumor samples were sequenced for 211 0.10 alpha level one-sided test to compare clinical responses of genes
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