title: A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers.
abstract: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV).
  
  
  
  Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed.
  
  
  
  32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed.
  
  
  
  ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Medical Oncology, United States.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Reiss
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Radiation Oncology, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Medical Oncology, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Armstrong
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Statistics, United States.
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Radiation Oncology, University of Toronto, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Radiation Oncology, University of Toronto, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brade
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Radiation Oncology, University of Toronto, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Radiation Oncology, University of Toronto, Canada.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Dawson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Medical Oncology, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Scardina
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Medical Oncology, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fischer
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Radiation Oncology, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Hacker-Prietz
authors.affiliation: National Cancer Institute, Office of the Director, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: National Cancer Institute, Office of the Director, United States.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Cancer Institute, Cancer Therapy Evaluation Program, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: The University of Maryland School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Temkin
authors.affiliation: The University of Maryland School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, United States.
authors.forename: Naomi
authors.initials: N
authors.lastname: Horiba
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Medical Oncology and Hematology, University of Toronto, Canada.
authors.forename: Lee-Anne
authors.initials: LA
authors.lastname: Stayner
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Department of Medical Oncology and Hematology, University of Toronto, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Department of Medical Oncology, United States. Electronic address: nazad2@jhmi.edu.
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D059248:Chemoradiotherapy; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib
keywords: BRCA; Ovarian cancer; PARP inhibition; Peritoneal carcinomatosis; Radiation; Veliparib