Safety, pharmacokinetics, and pharmacodynamics results from a phase I trial of BAY 86-9766 (RDEA119), a MEK inhibitor, in patients with advanced cancer.

Abstract

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 (pERK) and leukocyte released tumor necrosis factor alpha (TNFα). Biopsies from 12 of 20 MTD patients were genotyped, of which 8 were assessed for changes in Ki67, pERK, and phosphorylated AKT. Results: The MTD was 100 mg/day. At this dose, the most common treatment-related AEs were rash, diarrhea, nausea, vomiting, fatigue, and peripheral edema. Central nervous system AEs occurred predominantly at doses of 100-160 mg/day. Group mean Cmax and AUC0-24 values increased linearly with dose. At doses of 60 mg QD, 100 mg QD and 50 mg BID, a significant suppression of leukocyte pERK and TNFα was seen through 24 hours post dose. Tumor pERK showed significant reduction from baseline in 75% of the samples. Initial mutational analysis revealed 0% NRAS, 0% PTEN, 8% PIK3CA, 17% KRAS, 17% BRAF, and 17% KRAS/PIK3CA. Stable disease (≥ 4 courses) was achieved in 10 patients and 1 patient with CRC who was KRAS-wild type had a confirmed partial response. Conclusions: BAY 86-9766 was generally well tolerated at doses ≤ 100 mg daily with rash being the most common treatment-related AE. At the MTD, significant inhibition of tumor pERK was observed in a variety of disease types and genetic backgrounds.