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Ref Type Journal Article
PMID (26644411)
Authors Adjei AA, Richards DA, El-Khoueiry A, Braiteh F, Becerra CH, Stephenson JJ, Hezel AF, Sherman M, Garbo L, Leffingwell DP, Iverson C, Miner JN, Shen Z, Yeh LT, Gunawan S, Wilson DM, Manhard KJ, Rajagopalan P, Krissel H, Clendeninn NJ
Title A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 10
Date 2016 May 15
Abstract Text To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies.This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation.Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year.In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable Refametinib + Sorafenib Phase I Actionable In a Phase I trial, a patient with colorectal cancer demonstrated a durable partial response for 358 days when treated with the combination of Refametinib (BAY86-9766) and Nexavar (sorafenib) (PMID: 26644411). 26644411
Unknown unknown Advanced Solid Tumor not applicable Refametinib + Sorafenib Phase I Actionable In a Phase I trial, the combination treatment of Refametinib (BAY86-9766) and Nexavar (sorafenib) in patients with advanced solid tumors resulted in a disease control rate of 65.8% (25/38), specifically, 2.6% (1/38) experienced a partial response and 63.2% (24/38) demonstrated stable disease (PMID: 26644411). 26644411
Unknown unknown hepatocellular carcinoma not applicable Refametinib + Sorafenib Phase I Actionable In a Phase I trial, 43.8% (7/16) of hepatocellular carcinoma patients treated with a combination of Refametinib (BAY86-9766) and Nexavar (sorafenib) demonstrated stable disease (PMID: 26644411). 26644411