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Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies

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Abstract

Purpose

Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin.

Methods

Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1–7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard “3 + 3” design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC–MS/MS and AAS during cycles 1 and 2.

Results

Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1–16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition.

Conclusion

Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.

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Acknowledgements

The authors would like to express their sincere thanks to the patients and their family members who were enrolled in this study. The authors would also like to thank the clinical research staff who were actively involved in the conduct of this study.

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Authors and Affiliations

  1. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Leonard J. Appleman, Jan H. Beumer, Yan Lin, Fei Ding, Shannon Puhalla, Leigh Swartz, Ronald Stoller, Daniel P. Petro, Hussein A. Tawbi, Athanassios Argiris, Sandra Strychor, Marie Pouquet, Brian Kiesel & Edward Chu

  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Leonard J. Appleman, Jan H. Beumer, Yan Lin, Fei Ding, Shannon Puhalla, Ronald Stoller, Daniel P. Petro, Hussein A. Tawbi, Athanassios Argiris, Sandra Strychor, Marie Pouquet, Brian Kiesel & Edward Chu

  3. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Leonard J. Appleman, Jan H. Beumer, Shannon Puhalla, Brian Kiesel & Edward Chu

  4. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan H. Beumer

  5. Penn State Hershey Cancer Institute, Hershey, PA, USA

    Yixing Jiang & Chandra P. Belani

  6. UPMC Hillman Cancer Center Biostatistics Facility, Pittsburgh, PA, USA

    Yan Lin & Fei Ding

  7. Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

    Yan Lin

  8. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Taofeek K. Owonikoko, R. Donald Harvey & Suresh S. Ramalingam

  9. National Cancer Institute, Bethesda, MD, USA

    Alice P. Chen

  10. Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Davis, CA, USA

    David Gandara

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  1. Leonard J. Appleman
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Correspondence to Leonard J. Appleman.

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The authors declare that they have no competing interests.

Financial support

The study was supported in part by the following grants: NIH/NCI UM1-CA186690, NIH/NCI U01-CA099168. This project used the UPMC Hillman Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF), Biostatistics Facility (BF), and Clinical Research Services (CRS), and was supported in part by award NIH/NCI P30-CA47904.

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Appleman, L.J., Beumer, J.H., Jiang, Y. et al. Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies. Cancer Chemother Pharmacol 84, 1289–1301 (2019). https://doi.org/10.1007/s00280-019-03960-w

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