Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

Abstract

Purpose: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors.Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule.Results: Forty-nine patients were enrolled. DLTs were blurred vision (n ¼ 1) and elevated creatine phosphokinase (n ¼ 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC 50 ). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15.Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors.

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

“…Common treatment-emergent AEs included gastrointestinal toxicity, fatigue, dermatologic toxicities, and anorexia, as reported in the phase I study and in a study of patients with unresectable HCC (14,24). Dermatologic toxicities were expected based on previous trials of other MEK inhibitors (25)(26)(27)(28). Most AEs were managed by temporary dose interruptions or modifications, concomitant treatments, and supportive care.…”

Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

“…Other small-molecule inhibitors of MEK are currently under clinical investigation (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). RO4987655 is a potent, highly selective adenosine triphosphate noncompetitive oral MEK inhibitor with manageable toxicity profile, favorable pharmacokinetics/pharmacodynamics characteristics, and preliminary antitumor activity in a phase I dose escalation (part 1) study in advanced solid cancers (21). Doselimiting toxicities (DLT) were blurred vision (n ¼ 1) and elevated creatine phosphokinase (CPK; n ¼ 3), all of which were reversible without treatment.…”

“…Therefore, a dose regime of 8.5 mg twice daily was recommended for the phase I expansion (part 2) study. The significant incidence of RAS and/or RAF mutations in colorectal cancer, in NSCLC, and in melanoma (3)(4)(5) associated with favorable preclinical data (12,14,18,20,21) was the rationale to choose these specific tumor types for the expansion study. The relatively low response rate expected in each tumor type based on previous study data (18,22) was the rationale for the chosen number of patients treated in each cohort.…”

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

“…The toxicity profile of WX-554 had similarities to that of other MEK inhibitors, with fatigue, diarrhoea, and dermatological reactions being the most frequent adverse reactions [13][14][15][16][17][18].…”