Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors
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ORIGINAL RESEARCH ARTICLE
Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors Jean‑Pierre Delord1 · Antoine Italiano2,3 · Ahmad Awada4 · Philippe Aftimos4 · Nadine Houédé5 · Céleste Lebbé6 · Celine Pages6 · Thierry Lesimple7 · Monica Dinulescu8 · Jan H. M. Schellens9,10 · Suzanne Leijen9 · Sylvie Rottey11 · Vibeke Kruse11 · Richard Kefford12 · Sandrine Faivre13 · Carlos Gomez‑Roca1 · Armin Scheuler14 · Giorgio Massimini15 · Eric Raymond16
© Springer Nature Switzerland AG 2020
Abstract 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.
Key Points The overall safety profile observed with pimasertib treatment was consistent with other mitogen-activated protein kinase kinase (MEK)-1/2 inhibitors. Electronic supplementary material The online version of this article (doi:https://doi.org/10.1007/s11523-020-00768-0) contains supplementary material, which is available to authorized users.
Dose-limiting toxicities mainly occurred with pimasertib doses ≥ 120 mg/day. Therefore, continuous twice-daily dosing was the optimal pimasertib dose schedule, and the recommended phase
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