A phase I study of the safety, Pharmacokinetics, and Pharmacodynamics of combination therapy with refametinib plus sorafenib in patients with advanced cancer

Alex A. Adjei, Donald A. Richards, Anthony El-Khoueiry, Fadi Braiteh, Carlos H.R. Becerra, Joe J.Stephenson Jr, Aram F. Hezel, Morris Sherman, Lawrence Garbo, Diane P. Leffingwell, Cory Iverson, Jeffrey N. Miner, Zancong Shen, Li Tain Yeh, Sonny Gunawan, David M. Wilson, Kimberly J. Manhard, Prabhu Rajagopalan, Heiko Krissel, Neil J. Clendeninn

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Purpose: To assess the safety and tolerability of the smallmolecule 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 treatmentrelated 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. 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

Original languageEnglish (US)
Pages (from-to)2368-2376
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number10
DOIs
StatePublished - May 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Adjei, A. A., Richards, D. A., El-Khoueiry, A., Braiteh, F., Becerra, C. H. R., Jr, J. J. S., Hezel, A. F., Sherman, M., Garbo, L., Leffingwell, D. P., Iverson, C., Miner, J. N., Shen, Z., Yeh, L. T., Gunawan, S., Wilson, D. M., Manhard, K. J., Rajagopalan, P., Krissel, H., & Clendeninn, N. J. (2016). A phase I study of the safety, Pharmacokinetics, and Pharmacodynamics of combination therapy with refametinib plus sorafenib in patients with advanced cancer. Clinical Cancer Research, 22(10), 2368-2376. https://doi.org/10.1158/1078-0432.CCR-15-1681