TY - JOUR
T1 - Selective oral MEK1/2 inhibitor pimasertib
T2 - a phase I trial in patients with advanced solid tumors
AU - Delord, Jean Pierre
AU - Italiano, Antoine
AU - Awada, Ahmad
AU - Aftimos, Philippe
AU - Houédé, Nadine
AU - Lebbé, Céleste
AU - Pages, Celine
AU - Lesimple, Thierry
AU - Dinulescu, Monica
AU - Schellens, Jan H. M.
AU - Leijen, Suzanne
AU - Rottey, Sylvie
AU - Kruse, Vibeke
AU - Kefford, Richard
AU - Faivre, Sandrine
AU - Gomez-Roca, Carlos
AU - Scheuler, Armin
AU - Massimini, Giorgio
AU - Raymond, Eric
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095724227&partnerID=8YFLogxK
U2 - 10.1007/s11523-020-00768-0
DO - 10.1007/s11523-020-00768-0
M3 - Article
C2 - 33170484
AN - SCOPUS:85095724227
SN - 1776-2596
VL - 16
SP - 37
EP - 46
JO - Targeted Oncology
JF - Targeted Oncology
IS - 1
ER -