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Grade 3 or 4 adverse events possibly related to refametinib or sorafenib, occurring in {greater than or equal to}2 patients in either cohort

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal–regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ∼12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate–stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232–43. ©2012 AACR.

Overview of dose-limiting toxicities and adverse events leading to discontinuation and relationship to study treatment

Refametinib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort

CTC enumeration and pERK analysis in course 1

Table S1: Dose-limiting toxicities; Table S2:Multiple-dose pharmacokinetic parameters (geometric mean (%CV) of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for once-daily dosing cohorts; Table S3: Multiple-dose pharmacokinetic parameters of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for twice-daily dosing cohorts

pERK levels in hair follicles by dose level and course

Legend for supplementary figure

Refametinib geometric mean (% coefficient of variation) single-dose pharmacokinetic data on day 1 of course 1

Treatment schema

Sorafenib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

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 ∼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. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal–regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ∼12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate–stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232–43. ©2012 AACR.

At the completion of a clinical trial it is often desirable to compare the treatments within subgroups of patients. The results of the subgroup analysis are usually reported for the subgroups within which sizable treatment differences are found. This practice can lead to an overestimate of the difference between treatments within the subgroups reported. One way of adjusting for this bias is to use empirical Bayes methods which shrink the extreme estimates toward the overall measure of treatment difference. Both point and interval estimates can be obtained. The computations are illustrated with an example using subgroup data from the Lipid Research Clinics Coronary Primary Prevention Trial.

3007 Background: BAY 86-9766 is a highly selective, allosteric inhibitor of MEK1/2. A phase I dose-escalation trial was conducted to determine the maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) in patients with advanced metastatic or locally recurrent solid tumors. Methods: Sixty-nine patients received doses from 2-160 mg once daily (QD) or 50-80 mg twice daily (BID). Tumor types included 22 colorectal (CRC), 8 melanoma, 5 prostate, 5 NSCLC, 5 pancreatic, 3 adrenal, 3 cholangiocarcinoma, 2 breast and 16 other. Patients were given a single oral dose on Day 1, were off drug for 7 days, and then began a 28-day course of daily continuous dosing. If benefiting, dosing continued in 28-day courses with tumor response and PD assessed every 2 courses. Safety was assessed by adverse events (AEs), clinical laboratory tests, vital signs, ECGs, ECHO/MUGA scans and physical exams. PK was collected each course. PD assessments included circulating tumor cells, leukocyte phosphorylated ERK (...