Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors

Abstract

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

Keywords: MAPK; MEK; Pimasertib; Safety; Solid tumors; Temsirolimus.

Conflict of interest statement

Conflict of Interest: M Mita has no conflicts of interest to declare.

S Fu has no conflicts of interest to declare.

SA Piha-Paul has no conflicts of interest to declare.

F Janku has no conflicts of interest to declare.

A Mita has no conflicts of interest to declare.

R Natale has no conflicts of interest to declare

W Guo was an employee of EMD Serono Inc, Billerica, USA who sponsored this trial.

C Zhao is an employee of EMD Serono Inc., Billerica, USA who sponsored this trial.

R Kurzrock has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant/advisory board fees from Sequenom, Actuate Therapeutics, and Xbiotech, and an ownership interest in Novena, Inc. and Curematch, Inc.

A Naing has no conflicts of interest to declare.

Figures

Fig 1. Trial design

*End of treatment visit: For subject not eligible for treatment. Visit scheduled for within 7 days of last treatment †Follow up visit performed within 30±7 days of last treatment

Fig 2. Plasma or blood concentration vs time plots for pimasertib

(A) alone (Day 1) and (B) in the presence of temsirolimus (Day 9), and for temsirolimus (C) in the presence of pimasertib (Day 9) and (D) alone (Day 16), in the DDI (Drug-Drug Interaction) cohorts who received pimasertib (45 mg) and either temsirolimus 12.5 mg (Group 1) or 25 mg (Group 2)

Fig 3. Tumor response over time and best response in patients receiving PIM plus TEM from treatment initiation