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

Abstract

Purpose: 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.

Conflict of interest statement

Conflicts of Interest: none to report

©2015 American Association for Cancer Research.

Figures

Figure 1

Archival tumor tissue was assessed for tumor content, necrosis, and inflammation before sequencing. (A) The sample shown from patient 1039 was 90% tumor and did not require macrodissection. (B) The tissue from patient 1044 was 30% tumor, and macrodissection was carried out to enrich to >70% tumor in the circled areas.

Figure 2

Treatment cycles for the 72 evaluable patients. Each patient’s best response during each treatment is listed to the left of the patient number: complete or partial response (X) or stable disease (*). (A) Thirty-five patients received the combination of veliparib plus cyclophosphamide as their initial treatment, of whom 16 reported deleterious BRCA mutations (+). (B) Thirty-seven patients initially received cyclophosphamide alone, of whom 14 reported deleterious BRCA mutations (+) and 1 reported wildtype BRCA status (−). (C) Twenty-nine patients crossed over to the combination treatment after disease progression on cyclophosphamide-only treatment. (D) No difference in progression free survival (PFS; p=0.68) was observed between patients treated with cyclophosphamide alone (median PFS of 2.3 months) or in combination with veliparib (median PFS of 2.1 months).