title: Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma.
abstract: OBJECTIVE
  To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC).
  
  
  METHODS
  This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1-7 and 150 mg/m(2) TMZ PO daily on days 1-5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03.
  
  
  RESULTS
  We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months.
  
  
  CONCLUSIONS
  The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. CLINICALTRIALS.
  NCT01205828.
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gabrielson
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Anteneh A
authors.initials: AA
authors.lastname: Tesfaye
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Smaglo
authors.affiliation: Department of Radiology, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Jha
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Dorsch-Vogel
authors.affiliation: Department of Biostatistics and Bioinformatics, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA. aiwu.r.he@gunet.georgetown.edu.
authors.forename: Aiwu Ruth
authors.initials: AR
authors.lastname: He
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D016879:Salvage Therapy; D000077157:Sorafenib; D000077204:Temozolomide; D017211:Treatment Failure
chemical_list: D001562:Benzimidazoles; D004273:DNA, Neoplasm; D010671:Phenylurea Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D000077204:Temozolomide
keywords: Hepatocellular carcinoma; Refractory; Temozolomide; Veliparib