Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study
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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.
KeywordsPhase 1 clinical trial Veliparib PARP inhibitor Whole brain radiation therapy Brain metastases
Medical writing support was provided by Jacqueline Nielsen and Jaimee Glasgow, employees of AbbVie.
Conflict of interest
MMehta has served as a consultant for AbbVie, Elekta, Merck, BMS, Novelos, Novocure, and Roche. He serves on the Board of Directors for Pharmacyclics; owns stocks with Pharmacyclics, and Accuray. W Curran is a consultant for BMS and receives research funding from AbbVie. L Kleinberg receives research funding from AbbVie. HI Robins has been a consultant for AbbVie. A Turaka, D Wang, F Wang and A Brade have no conflicts of interest to declare. J Qian, M Zhu, TL Leahy, D Median, H Xiong, N Mostafa, M Dunbar, K Holen, and VL Giranda are AbbVie employees and may own stock; V. L. Giranda has a pending patent application related to the subject matter in the manuscript.
AbbVie provided financial support for this study and participated in the design, study conduct, analysis and interpretation of the data as well as the writing, review, and approval of this manuscript.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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