Phase I dose-escalation study of E6201, a MEK-1 inhibitor, in advanced solid tumors.

Abstract

2505 Background: E6201 is a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)-1 and MEK kinase-1, with anticancer activity in preclinical models. Methods: This phase I, open-label study evaluated E6201 MTD in advanced solid tumors. Inclusion criteria were ECOG PS ≤1 and adequate bone marrow, renal, and liver function. Sequential cohorts of 3-6 subjects were given E6201 30-min IV infusion on Days 1, 8, and 15 of a 28-day cycle starting at 20 mg/m2 and increasing in 100% increments up to 320 mg/m2 until 2 Grade 2 toxicities or 1 DLT was observed. Doses were then increased by ≤50% up to 720 mg/m2 or until the MTD was determined. Blood samples were collected on days 1 and 15 for PK analysis. PD assessment included evaluation of CTC, serum IL-6 and IL-8 levels, and effects on proliferation and signal transduction pathway in skin and tumor biopsies. Results: 25 subjects (median age 66.6 [range 44-87] yr) received E6201 doses from 20 to 40, 80, 160, 320, and 480 mg/m2. At 480 mg/m2, 2 subjects had DLTs (QTc prolongation [Grade 3] and confusional state [Grade 4]). E6201 was reduced to 400 mg/m2, at which 1 subject had CNS toxicity (dizziness). Therefore, the 320 mg/m2 cohort was expanded to 3 additional subjects (total 6); 1 subject had 1 DLT (Grade 2 QTc prolongation) and Grade 2 CNS toxicities (dizziness, dysarthria, ataxia), confirming 320 mg/m2 as the MTD. Most-frequent AEs across doses were nausea (16%), constipation, dizziness, peripheral edema, and vomiting (all 12%, all Grade 1/2). E6201 was rapidly eliminated (mean t3/4=2.47- 5.60 hr). Exposure to E6201 was dose related and comparable on days 1 and 15. A trend for decreasing IL-6 and IL-8 levels was observed without clear dose dependency or duration of effect. Surrogate tissue (skin) biopsies were not informative. One subject with metastatic ocular melanoma had stable disease (>10 months) (B-Raf wild-type) and another, with B-Raf mutant papillary thyroid cancer, a partial remission. Conclusions: The E6201 MTD of 320 mg/m2 IV once weekly for 3 out of a 4-week cycle was well tolerated in patients with advanced solid tumors. An expansion phase at MTD will continue to assess efficacy and determine the optimal schedule using biomarker-driven endpoints and tumor response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai