title: Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study.
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.
authors: Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene Street, GGK19, Baltimore, MD, 21201, USA, mmehta@umm.edu.
authors: Minesh P
authors: MP
authors: Mehta
authors: Ding
authors: D
authors: Wang
authors: Fen
authors: F
authors: Wang
authors: Lawrence
authors: L
authors: Kleinberg
authors: Anthony
authors: A
authors: Brade
authors: H Ian
authors: HI
authors: Robins
authors: Aruna
authors: A
authors: Turaka
authors: Terri
authors: T
authors: Leahy
authors: Diane
authors: D
authors: Medina
authors: Hao
authors: H
authors: Xiong
authors: Nael M
authors: NM
authors: Mostafa
authors: Martin
authors: M
authors: Dunbar
authors: Ming
authors: M
authors: Zhu
authors: Jane
authors: J
authors: Qian
authors: Kyle
authors: K
authors: Holen
authors: Vincent
authors: V
authors: Giranda
authors: Walter J
authors: WJ
authors: Curran
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib