A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies

Antoinette R. Tan, Nancy Chan, Brian F. Kiesel, Mark N. Stein, Rebecca A. Moss, Jyoti Malhotra, Joseph Aisner, Mansi Shah, Murugesan Gounder, Hongxia Lin, Michael P. Kane, Yong Lin, Jiuping Ji, Alice Chen, Jan H. Beumer, Janice M. Mehnert

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. Methods: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1–4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1–4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1–7, and in Group 4, AC Day 1 plus V Days 1–14 was given in 21-day cycles to evaluate effects on γH2AX foci. Results: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1–4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. Conclusion: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)49-58
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume89
Issue number1
DOIs
StatePublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Keywords

  • PARP inhibitors
  • Pharmacokinetics
  • Phase I study
  • Veliparib

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