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

Aslamuzzaman Kazi

Bert H. O'Neil

Daniel M. Sullivan

Davies BR

Dominic T. Moore

John Sae Wook Kauh

Jonathan R. Strosberg

Laura W. Goff

Maria Learoyd

Richard M. Lush

Ruey-min Lee

Said M. Sebti

Tanios S. Bekaii-Saab

PubMed

O'Neil, Bert H.

Goff, Laura W.

Kauh, John Sae Wook

Strosberg, Jonathan R.

Bekaii-Saab, Tanios S.

Lee, Ruey-min

Kazi, Aslamuzzaman

Moore, Dominic T.

Learoyd, Maria

Lush, Richard M.

Sebti, Said M.

Sullivan, Daniel M.

Carolina Digital Repository

Phase II Study of the Mitogen-Activated Protein Kinase 1/2 Inhibitor Selumetinib in Patients With Advanced Hepatocellular Carcinoma

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. </jats:sec

Crossref

Journal of Clinical Oncology

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3107750

Phase II Study of the Mitogen-Activated Protein Kinase 1/2 Inhibitor Selumetinib in Patients With Advanced Hepatocellular Carcinoma

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