A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers.

Gallagher, Peter, Rolfo, Christian, Elez, Elena, Taieb, Julien, Houlden, Jennifer, Collins, Linda, Roberts, Corran, André, Thierry, Lawler, Mark, Di Nicolantonio, Federica, Grayson, Margaret, Boyd, Ruth, Popovici, Vlad, Bardelli, Alberto, Carson, Robbie, Khawaja, Hajrah, Laurent-Puig, Pierre, Salto-Tellez, Manuel, Hennessy, Bryan T, Maughan, Tim S, Tabernero, Josep, Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Peeters, Marc, Middleton, Mark R, Wilson, Richard H and Van Schaeybroeck, Sandra 2025. A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers. BJC Reports 3 (1) , 17. 10.1038/s44276-025-00133-6

PDF - Published Version Download (619kB)

Abstract

BackgroundSingle-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials.MethodsIn this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected.ResultsTwenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%).ConclusionsPD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients.Eudract-number2014-000463-40.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR)
Additional Information:	License information from Publisher: LICENSE 1: Title: cc by, Type: cc by
Publisher:	Springer Nature
Date of First Compliant Deposit:	4 April 2025
Date of Acceptance:	8 March 2025
Last Modified:	04 Apr 2025 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/177412

Actions (repository staff only)

Edit Item