A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

作者:Adjei Alex A*; Richards Donald A; El Khoueiry Anthony; Braiteh Fadi; Becerra Carlos H R; Stephenson Joe J Jr; Hezel Aram F; Sherman Morris; Garbo Lawrence; Leffingwell Diane P; Iverson Cory; Miner Jeffrey N; Shen Zancong; Yeh Li Tain; Gunawan Sonny; Wilson David M; Manhard Kimberly J; Rajagopalan Prabhu; Krissel Heiko; Clendeninn Neil J
来源:Clinical Cancer Research, 2016, 22(10): 2368-2376.
DOI:10.1158/1078-0432.CCR-15-1681

摘要

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: 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. Results: 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 similar to 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. Conclusions: 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.

  • 出版日期2016-5-15