Phase 2 trial of linifanib (ABT‐869) in patients with unresectable or metastatic hepatocellular carcinoma

• Published in: Cancer 2013-01, Vol.119 (2), p.380-387
• Main Authors: Toh, Han Chong, Chen, Pei‐Jer, Carr, Brian I., Knox, Jennifer J., Gill, Sharlene, Ansell, Peter, McKeegan, Evelyn M., Dowell, Barry, Pedersen, Michelle, Qin, Qin, Qian, Jiang, Scappaticci, Frank A., Ricker, Justin L., Carlson, Dawn M., Yong, Wei Peng
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; angiogenesis; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - blood; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - secondary; Diarrhea - chemically induced; Disease-Free Survival; Fatigue - chemically induced; Female; Gastroenterology. Liver. Pancreas. Abdomen; hepatocellular carcinoma (HCC); Humans; Indazoles - adverse effects; Indazoles - pharmacology; Indazoles - therapeutic use; Kaplan-Meier Estimate; linifanib; Liver Neoplasms - blood; Liver Neoplasms - drug therapy; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Lung Neoplasms - secondary; Lymphatic Metastasis; Male; Medical sciences; Middle Aged; Phenylurea Compounds - adverse effects; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; platelet‐derived growth factor receptor (PDGFR); sorafenib; Treatment Outcome; Tumor Burden - drug effects; Tumors; vascular endothelial growth factor receptor (VEGFR); Young Adult
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.27758

BACKGROUND: The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial. METHODS: Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression‐free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed. RESULTS: Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child‐Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression‐free rate at 16 weeks was 31.8% (34.2% for patients with Child‐Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child‐Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child‐Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child‐Pugh class A hepatic function). The most common linifanib‐related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib‐related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome. CONCLUSIONS: Single‐agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society. In this multicenter international phase 2 trial, the compelling clinical activity of linifanib was demonstrated in patients with advanced hepatocellular carcinoma (HCC). Further evaluation in patients with advanced HCC is ongoing.