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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1289–1301 | Cite as

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

  • Leonard J. ApplemanEmail author
  • Jan H. Beumer
  • Yixing Jiang
  • Yan Lin
  • Fei Ding
  • Shannon Puhalla
  • Leigh Swartz
  • Taofeek K. Owonikoko
  • R. Donald Harvey
  • Ronald Stoller
  • Daniel P. Petro
  • Hussein A. Tawbi
  • Athanassios Argiris
  • Sandra Strychor
  • Marie Pouquet
  • Brian Kiesel
  • Alice P. Chen
  • David Gandara
  • Chandra P. Belani
  • Edward Chu
  • Suresh S. Ramalingam
Original Article
  • 146 Downloads

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.

Keywords

Veliparib Poly(ADP-ribose) polymerase Paclitaxel Carboplatin Phase 1 Clinical trial Advanced cancer 

Notes

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.

Compliance with ethical standards

Conflict of interest

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.

Supplementary material

280_2019_3960_MOESM1_ESM.pdf (568 kb)
Supplementary material 1 (PDF 568 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Leonard J. Appleman
    • 1
    • 2
    • 3
    Email author
  • Jan H. Beumer
    • 1
    • 2
    • 3
    • 4
  • Yixing Jiang
    • 5
  • Yan Lin
    • 1
    • 2
    • 6
    • 7
  • Fei Ding
    • 1
    • 2
    • 6
  • Shannon Puhalla
    • 1
    • 2
    • 3
  • Leigh Swartz
    • 1
  • Taofeek K. Owonikoko
    • 8
  • R. Donald Harvey
    • 8
  • Ronald Stoller
    • 1
    • 2
  • Daniel P. Petro
    • 1
    • 2
  • Hussein A. Tawbi
    • 1
    • 2
  • Athanassios Argiris
    • 1
    • 2
  • Sandra Strychor
    • 1
    • 2
  • Marie Pouquet
    • 1
    • 2
  • Brian Kiesel
    • 1
    • 2
    • 3
  • Alice P. Chen
    • 9
  • David Gandara
    • 10
  • Chandra P. Belani
    • 5
  • Edward Chu
    • 1
    • 2
    • 3
  • Suresh S. Ramalingam
    • 8
  1. 1.UPMC Hillman Cancer CenterUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Cancer Therapeutics ProgramUPMC Hillman Cancer CenterPittsburghUSA
  3. 3.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA
  5. 5.Penn State Hershey Cancer InstituteHersheyUSA
  6. 6.UPMC Hillman Cancer Center Biostatistics FacilityPittsburghUSA
  7. 7.Department of BiostatisticsUniversity of Pittsburgh Graduate School of Public HealthPittsburghUSA
  8. 8.Winship Cancer Institute, Emory UniversityAtlantaUSA
  9. 9.National Cancer InstituteBethesdaUSA
  10. 10.Division of Hematology and OncologyUC Davis Comprehensive Cancer CenterDavisUSA

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