Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma

• Published in: Cancer chemotherapy and pharmacology Vol. 76; no. 5; pp. 1073 - 1079
• Main Authors: Gabrielson, Andrew, Tesfaye, Anteneh A., Marshall, John L., Pishvaian, Michael J., Smaglo, Brandon, Jha, Reena, Dorsch-Vogel, Karen, Wang, Hongkun, He, Aiwu Ruth
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2015; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Disease-Free Survival; DNA Methylation - drug effects; DNA Repair - drug effects; DNA Repair - genetics; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Drug Resistance, Neoplasm; Fatigue - chemically induced; Female; Genes, BRCA1; Genes, BRCA2; Humans; Kaplan-Meier Estimate; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Male; Medicine; Medicine & Public Health; Middle Aged; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Oncology; Original; Original Article; Pharmacology/Toxicology; Phenylurea Compounds - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Salvage Therapy; Sorafenib; Temozolomide; Treatment Failure; Refractory; Hepatocellular carcinoma; Temozolomide; Veliparib
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-015-2852-2

Purpose 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. Conclusion The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit. ClinicalTrials.gov Identifier NCT01205828.