Veliparib alone or in combination with mitomycin C in patients with solid tumors with functional deficiency in homologous recombination repair

Miguel A. Villalona-Calero, Wenrui Duan, Weiqiang Zhao, Konstantin Shilo, Larry J. Schaaf, Jennifer Thurmond, Judith A. Westman, John Marshall, Li Xiaobai, Jiuping Ji, Jeffrey Rose, Maryam Lustberg, Tanios Bekaii-Saab, Alice Chen, Cynthia Timmers

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNAbreaking agent. Methods: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC). Results: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400 mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300 mg BID veliparib and veliparib 200 mg BID for 21 days following 10 mg/m2 MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens. Conclusions: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.

Original languageEnglish (US)
Article numberdjv437
JournalJournal of the National Cancer Institute
Volume108
Issue number7
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Villalona-Calero, M. A., Duan, W., Zhao, W., Shilo, K., Schaaf, L. J., Thurmond, J., Westman, J. A., Marshall, J., Xiaobai, L., Ji, J., Rose, J., Lustberg, M., Bekaii-Saab, T., Chen, A., & Timmers, C. (2016). Veliparib alone or in combination with mitomycin C in patients with solid tumors with functional deficiency in homologous recombination repair. Journal of the National Cancer Institute, 108(7), [djv437]. https://doi.org/10.1093/jnci/djv437