title: A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.
abstract: 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.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York. alex.adjei@roswellpark.org.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Texas Oncology-Tyler, Houston, Texas.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Baylor Sammons Cancer Center, Houston, Texas.
authors.forename: Carlos H R
authors.initials: CH
authors.lastname: Becerra
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Institute of Translational Oncology Research, Houston, Texas.
authors.forename: Joe J
authors.initials: JJ
authors.lastname: Stephenson
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.affiliation: University of Toronto and University Health Network, Toronto, Canada.
authors.forename: Morris
authors.initials: M
authors.lastname: Sherman
authors.affiliation: The US Oncology Network, The Woodlands, Texas. New York Oncology Hematology, Albany, New York.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Garbo
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Leffingwell
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Cory
authors.initials: C
authors.lastname: Iverson
authors.affiliation: The US Oncology Network, The Woodlands, Texas. Ardea Biosciences, Inc., San Diego, California.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Zancong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Sonny
authors.initials: S
authors.lastname: Gunawan
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Manhard
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Rajagopalan
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Krissel
authors.affiliation: Ardea Biosciences, Inc., San Diego, California.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Clendeninn
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods; D004159:Diphenylamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D009536:Niacinamide; D004159:Diphenylamine; D000077157:Sorafenib