title: Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma.
abstract: PURPOSE Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. PATIENTS AND METHODS Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. CONCLUSION In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.
authors.affiliation: University of North Carolina, 170 Manning Drive, Chapel Hill, NC 27599-730, USA. Bert_oneil@med.unc.edu
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.forename: John Sae Wook
authors.initials: JS
authors.lastname: Kauh
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Strosberg
authors.forename: Tanios S
authors.initials: TS
authors.lastname: Bekaii-Saab
authors.forename: Ruey-Min
authors.initials: RM
authors.lastname: Lee
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.forename: Maria
authors.initials: M
authors.lastname: Learoyd
authors.forename: Richard M
authors.initials: RM
authors.lastname: Lush
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2