Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors
Jean-Pierre Delord1, Antoine Italiano2,3, Ahmad Awada4
1Clinical Research Unit, Institut Universitaire du Cancer, Oncopole, Toulouse, France. delord.jean-pierre@iuct-oncopole.fr.
Background:
The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor.
Objective:
Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints.
Patients And Methods:
Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity.
Results:
Overall, 180 patients received pimasertib (dose range 1-255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing.
Conclusions:
Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid.
Trial Registration:
ClinicalTrials.gov, NCT00982865.
Insights
Pimasertib, a MEK1/2 inhibitor, was evaluated in a Phase I trial for advanced cancers. A continuous twice-daily regimen of 60 mg was identified as the recommended Phase II dose, showing manageable safety and efficacy signals.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- The Ras/Raf/MEK/ERK pathway is often overactive in human cancers.
- Pimasertib is a potent, selective inhibitor targeting MEK1/2.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of pimasertib.
- To assess the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of pimasertib in patients with advanced solid tumors.
Main Methods:
- A Phase I, first-in-human, dose-escalation trial evaluated four pimasertib dosing schedules in 180 patients.
- Dose-limiting toxicities (DLTs) were assessed during cycle 1 to establish the MTD and RP2D.
Main Results:
- DLTs, including rash and ocular events, occurred at doses ≥120 mg/day.
- Common adverse events included diarrhea, skin disorders, and fatigue.
- Pimasertib effectively inhibited ERK phosphorylation, with sustained effects at higher doses and with twice-daily (bid) dosing.
Conclusions:
- A continuous bid dosing schedule was preferred due to safety and efficacy signals.
- The recommended Phase II dose (RP2D) was established at 60 mg bid.
