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01-12-2019 | Pharmacokinetics | Original Article

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

Authors: Leonard J. Appleman, 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2019

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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Title: Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies
Authors: Leonard J. Appleman
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
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pharmacokinetics
Neutropenia
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03960-w

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