A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620)

Monica K. Malhotra, Shalu Pahuja, Brian F. Kiesel, Leonard J. Appleman, Fei Ding, Yan Lin, Hussein A. Tawbi, Ronald G. Stoller, James J. Lee, Chandra P. Belani, Alice P. Chen, Vincent L. Giranda, Stacie Peacock Shepherd, Leisha A. Emens, S. Percy Ivy, Edward Chu, Jan H. Beumer, Shannon Puhalla

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). Methods: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. Results: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. Conclusion: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

Original languageEnglish (US)
Pages (from-to)487-498
Number of pages12
JournalBreast Cancer Research and Treatment
Volume198
Issue number3
DOIs
StatePublished - Apr 2023

Keywords

  • DNA damage
  • PARP
  • Pharmacokinetics
  • Phase 1 study
  • Solid tumors
  • Triple negative breast cancer
  • Veliparib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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