Phase I Dose-escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumours
Menée sur 49 patients atteints d'une tumeur solide de stade avancé, cette étude évalue l'acitivté antitumorale et la toxicité d'un inhibiteur de MEK, RO4987655
Purpose: This Phase I study of the MEK inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK)/pharmacodynamics (PD) profile and anti-tumour activity in patients with advanced solid tumours. Patients and Methods: An initial dose-escalation was performed using a once-daily (QD) dosing schedule, with oral RO4987655 administered at doses of 1.0-2.5 mg QD over 28 consecutive days in 4-week cycles. Doses were then escalated to 3.0-21.0 mg (total daily dose [TDD]) using a twice-daily (BID) dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n=1) and elevated creatine phosphokinase (n=3). The MTD was 8.5 mg BID (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 demonstrated dose-linearity and a half-life of ~4 hours. At the MTD, target inhibition, assessed by suppression of ERK phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). 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 demonstrated a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and Day 15. Conclusion: In this population of heavily pre-treated patients, oral RO4987655 demonstrated manageable toxicity, a favourable PK/PD profile and promising preliminary anti-tumour activity, which has been further investigated in specific population of patients with RAS and/or RAF mutation driven tumours.