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

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.A88-A88
• Main 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.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-A88

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 a