Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study

Minesh P. Mehta, Ding Wang, Fen Wang, Lawrence Kleinberg, Anthony Brade, H. Ian Robins, Aruna Turaka, Terri Leahy, Diane Medina, Hao Xiong, Nael M. Mostafa, Martin Dunbar, Ming Zhu, Jane Qian, Kyle Holen, Vincent Giranda, Walter J. Curran

Research output: Contribution to journalArticlepeer-review

Abstract

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood–brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10–300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9–13.5) and for the breast cancer subgroup was 7.7 mo (2.8–15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3–3.8) and 4.9 mo (4.2–5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalJournal of neuro-oncology
Volume122
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

  • Brain metastases
  • PARP inhibitor
  • Phase 1 clinical trial
  • Veliparib
  • Whole brain radiation therapy

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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