Abstract A88: Safety, pharmacokinetic, and pharmacodynamic results of BAY 86–9766, an oral MEK inhibitor, in combination with sorafenib, an oral multikinase inhibitor, in advanced cancer patients.
Authors: Adjei Alex A. , Richards Donald A. , El-Khoueiry Anthony , Becerra Carlos H.R. , Stephenson Joe J. , Leffingwell Diane P. , Iverson Cory , Miner Jeffrey N. , Shen Zancong , Gunawan Sonny , Wilson David , Manhard Kimberly J. , Dubowy Ron L. , Jeffers Michael , Rajagopalan Prabhu , Franklin Wilbur A. , Haney Jerry , Lenhart Patricia , Clendeninn Neil J. 
Published: June 2012

Abstract
Background: Preclinical data revealed a synergistic interaction between sorafenib (Nexavar®) and BAY 86-9766 (RDEA119). Sorafenib is an oral, small molecule, multikinase inhibitor that is approved for the treatment of unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma. BAY 86-9766 is an investigational, oral, potent, non-ATP competitive, highly selective inhibitor of MEK1/2. In a Phase 1 single-agent trial of BAY 86-9766 in advanced cancer patients, the maximum tolerated dose (MTD) was 100 mg daily, given as 50 mg twice daily (bid) or 100 mg once daily, with rash being the most common treatment-related adverse event (AE) and significant inhibition of tumor phosphorylated ERK (pERK) observed. This Phase 1 trial was conducted to determine the MTD, safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BAY 86-9766 in combination with sorafenib. Data from the dose escalation cohorts and MTD expansion cohort are reported here. An additional cohort of patients with advanced HCC is ongoing in the MTD expansion phase and is not described here.
Materials and Methods: Key eligibility criteria included advanced metastatic or locally recurrent solid tumors, ECOG performance status of 0–1, acceptable organ function, and life expectancy of at least 3 months. Patients initially received BAY 86-9766 alone for up to 3 days to determine PK and then began a 28-day course of combination treatment with BAY 86-9766 and sorafenib. Dose escalation proceeded with increasing doses of BAY 86-9766 from 5 mg to 50 mg bid and either 200 mg or 400 mg bid of sorafenib. At least 3 patients were treated at each of 6 dose escalation levels. Safety was assessed by AEs, clinical laboratory tests, vital signs, ECGs, ECHO/MUGA scans, and physical exams. If benefiting from treatment, patients continued with subsequent 28-day courses and response was assessed every 2 courses. Tumor mutational status and PD effect on pERK in tumor biopsies were evaluated.
Results: Forty-three patients have been enrolled (32 in dose escalation and 11 in MTD expansion). Tumor types included 23 colorectal, 6 melanoma, 4 pancreatic, 3 head & neck, 2 esophageal, 2 ovarian, and 1 each of NSCLC, prostate, and small bowel adenocarcinoma. The MTD was determined to be the full doses of both drugs, 50 mg bid for BAY 86-9766 and 400 mg bid for sorafenib. The most common AEs were diarrhea (81%), rash (63%), fatigue (61%), nausea (49%), and vomiting (37%). Following single and multiple doses, mean Cmax and AUC0–12 of BAY 86-9766 increased nearly proportionally with dose, ranging between 5 mg bid and 50 mg bid. Plasma exposures of sorafenib at 200 mg bid and 400 mg bid were generally within the range reported from other studies. There was 1 confirmed partial response in a patient with colorectal cancer and 24 patients achieved a best overall response of stable disease. Tumor mutational analysis as well as PD data on tumor pERK suppression will be presented.
Conclusions: BAY 86-9766 in combination with sorafenib was well tolerated with diarrhea and rash being the most common AEs. Based on the results of this study, a Phase 2 study with BAY 86-9766 in combination with sorafenib is underway in HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A88.