Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.

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 DNA-breaking 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 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) 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.

• Authors: 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
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 108 Issue 7 (Jul 2016) ISSN: 1460-2105 [Electronic] United States
• PMID: 26848151 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• veliparib
• Mitomycin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzimidazoles (administration & dosage, adverse effects, therapeutic use)
• Diarrhea (chemically induced)
• Drug Administration Schedule
• Fanconi Anemia (genetics)
• Fatigue (chemically induced)
• Feasibility Studies
• Female
• Genes, BRCA1
• Genes, BRCA2
• Germ-Line Mutation
• Humans
• Male
• Middle Aged
• Mitomycin (administration & dosage)
• Neoplasms (drug therapy)
• Pedigree
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Recombinational DNA Repair (drug effects, genetics)
• Thrombocytopenia (chemically induced)