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

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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.

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Acknowledgements

We acknowledge Dr. Ulf Niemeyer, of Niomech -IIT GmbH, Bielefeld, Germany for the generous gift of PBOX-d4 (internal standard) for analysis of 4-OH-CPA.

Funding

Supported by Rutgers Cancer Institute of New Jersey Cancer Center Support Grant/Core Grant and NCI grants (U01-CA-132194-01, UM1-CA-186716, UM1-CA-186690, U01-CA099168, and R50 CA211241). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility and was supported in part by award P30-CA47904.

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Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan, Nancy Chan, Mark N. Stein, Rebecca A. Moss, Jyoti Malhotra, Joseph Aisner, Mansi Shah, Murugesan Gounder, Hongxia Lin, Michael P. Kane, Yong Lin & Janice M. Mehnert

  2. Atrium Health, Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC, 28204, USA

    Antoinette R. Tan

  3. University of Pittsburgh, Pittsburgh, PA, USA

    Brian F. Kiesel & Jan H. Beumer

  4. Columbia University Medical Center, New York, NY, USA

    Mark N. Stein

  5. Bristol-Myers Squibb, Lawrenceville, NJ, USA

    Rebecca A. Moss

  6. Frederick National Lab for Cancer Research, Bethesda, MD, USA

    Jiuping Ji

  7. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Alice Chen

  8. New York University Langone Health’s Perlmutter Cancer Center, New York, NY, USA

    Janice M. Mehnert

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  1. Antoinette R. Tan
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Corresponding author

Correspondence to Antoinette R. Tan.

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Conflict of interest

A. Tan has received research grants from Arvinas, Deciphera, Daiichi-Sankyo, Genentech, Merck, and Pfizer; advisory board member/paid consultant for Athenex, AstraZeneca, Eisai, G1 Therapeutics, Novartis, and Immunomedics. M. Stein has received research grants from Merck, Exelixis, Oncoceutics, Janssen, Medivation/Astellas, Advaxis, Suzhou Kintor, Harpoon, Bristol-Meyers Squibb, Genocea, Eli Lilly, Seattle Genetics and Xencor. R. Moss is an employee for Bristol-Myers Squibb. J. Malhotra has received commercial research grants from AstraZeneca, Beyond Spring, Bristol-Myers Squibb, Biohaven and Pfizer. J. Aisner is on the DMC for EMD Serono. J. Mehnert has received research grants from Merck, EMD Serono, Pfizer, Genentech, Amgen, Boehringer Ingelheim, Array BioPharma, Immunocore, AstraZeneca, Incyte, Macrogenics, Bristol-Myers Squibb, Novartis, and Polynoma. No potential conflicts of interest were disclosed by the other authors.

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Tan, A.R., Chan, N., Kiesel, B.F. et al. A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies. Cancer Chemother Pharmacol 89, 49–58 (2022). https://doi.org/10.1007/s00280-021-04350-x

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