A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer

ETCTN-8282 study team

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. Patients and methods: Patients (n = 98) were dosed with veliparib 50–500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. Results: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13–35%) in BRCAmut overall, and 37% (95% CI 21–55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1–26%), and clinical benefit rate was 16% (95% CI 4–36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. Conclusions: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

Original languageEnglish (US)
Pages (from-to)721-735
Number of pages15
JournalCancer Chemotherapy and Pharmacology
Volume89
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

Keywords

  • BRCA1
  • BRCA2
  • DNA damage
  • Ovarian cancer
  • PARP inhibitor
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase I
  • Solid tumors
  • Triple-negative breast cancer
  • Veliparib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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