title: A Phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis.
abstract: OBJECTIVE
  The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies.
  
  
  METHODS
  Patients were treated with veliparib (80-320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire.
  
  
  RESULTS
  Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX-positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline).
  
  
  CONCLUSIONS
  Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation.
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Reiss
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.affiliation: Department of Statistics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.affiliation: Department of Radiation Oncology, Princess Margaret Cancer Centre/University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brade
authors.affiliation: Department of Radiation Oncology, Princess Margaret Cancer Centre/University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Dawson
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Angela
authors.initials: A
authors.lastname: Scardina
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Joffe
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Emily
authors.initials: E
authors.lastname: Petito
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Amy
authors.initials: A
authors.lastname: Hacker-Prietz
authors.affiliation: Office of the Director, National Cancer Institute, Bethesda, Maryland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: Office of the Director, National Cancer Institute, Bethesda, Maryland.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Temkin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Maryland School of Medicine, Baltimore, Maryland.
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, Ontario, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland. nazad2@jhmi.edu.
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy
chemical_list: D001562:Benzimidazoles; C521013:veliparib