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Phase I and pharmacokinetic study of veliparib, a PARP inhibitor, and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

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Abstract

Objective

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.

Methods

Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.

Results

44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.

Conclusions

The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.

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Authors and Affiliations

  1. NYU Langone Health, Division of Gynecologic Oncology, New York University School of Medicine, 240 East 38th street, 19th floor, New York, NY, USA

    Bhavana Pothuri, Allison L. Brodsky & Franco Muggia

  2. Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    Joseph A. Sparano & Mimi Kim

  3. Mt Sinai Medical Center, New York, NY, USA

    Stephanie V. Blank & Amy Tiersten

  4. Columbia Presbyterian, New York, NY, USA

    Dawn L. Hershman

  5. University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Brian F. Kiesel & Jan H. Beumer

  6. University of New England, Portland, ME, USA

    Leonard Liebes

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  1. Bhavana Pothuri
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  2. Allison L. Brodsky
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  4. Stephanie V. Blank
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  11. Franco Muggia
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Contributions

Dr. BP, Dr. JAS, Dr. SVB, Dr. LV, Dr. DLH, Dr. AT, and Dr. FM are oncologists who participated in this clinical trial by enrolling patients. Dr. AB analyzed the data sets for this trial and assisted Dr. BP in writing the manuscript. Dr. MK analyzed and calculated the statistics for this manuscript. BFK and JHB completed the veliparib pharmacokinetics portions of this trial and assisted in writing these sections of the manuscript.

Corresponding author

Correspondence to Bhavana Pothuri.

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Conflicts of interest

Dr. Pothuri reports grants from NIH/NCI CRADL award (US Government), which were awarded to specifically fund this project. Dr. Pothuri reports consulting fees from Tesaro, Astra Zeneca and Eisai. Dr. Beumer reports research funding to his institute from AbbVie. He has also declared a conflict of interest with the National Cancer Institute (NCI), he has received grant funding, P30CA047904 and UM1CA186690. Dr. Tiersten reports consulting fees and non-financial support from Puma, Astra Zeneca, Novartis, Eisai, Genetech-roche, and Immunomedics, all outside the submitted work.

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Pothuri, B., Brodsky, A.L., Sparano, J.A. et al. Phase I and pharmacokinetic study of veliparib, a PARP inhibitor, and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up. Cancer Chemother Pharmacol 85, 741–751 (2020). https://doi.org/10.1007/s00280-020-04030-2

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  • DOI: https://doi.org/10.1007/s00280-020-04030-2

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