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

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

Přehled o publikaci

J 2025

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; Christian ROLFO; Elena ELEZ; Julien TAIEB; Jennifer HOULDEN et. al.

Základní údaje

Originální název

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

Autoři

Vydání

BJC REPORTS, LONDON, SPRINGERNATURE, 2025, 2731-9377

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Organizace

Přírodovědecká fakulta – Masarykova univerzita – Repozitář

DOI

https://doi.org/10.1038/s44276-025-00133-6

UT WoS

001578324800001

Klíčová slova anglicky

PLUS IRINOTECAN; RAS MUTATIONS; KINASE; KRAS; RESISTANCE; FLUOROURACIL; LEUCOVORIN

Návaznosti

EH22_008/0004644, projekt VaV. LM2023069, projekt VaV. 602901, interní kód Repo.

Změněno: 20. 11. 2025 00:51, RNDr. Daniel Jakubík

Anotace

V originále

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

Přiložené soubory

https://is.muni.cz/publication/2533958/2533958.pdf

Citovat

GALLAGHER, Peter; Christian ROLFO; Elena ELEZ; Julien TAIEB; Jennifer HOULDEN; Linda COLLINS; Corran ROBERTS; Thierry ANDRE; Mark LAWLER; Federica DI NICOLANTONIO; Margaret GRAYSON; Ruth BOYD; Vlad POPOVICI; Alberto BARDELLI; Robbie CARSON; Hajrah KHAWAJA; Pierre LAURENT-PUIG; Manuel SALTO-TELLEZ; Bryan T. HENNESSY; Tim S. MAUGHAN; Josep TABERNERO; Richard ADAMS; Robert JONES; Marc PEETERS; Mark R. MIDDLETON; Richard H. WILSON; Sandra VAN SCHAEYBROECK a MErCuRIC Trial CONSORTIUM. 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. LONDON: SPRINGERNATURE, 2025, roč. 3, č. 1, s. 1-9. ISSN 2731-9377. Dostupné z: https://doi.org/10.1038/s44276-025-00133-6.

@article{89994,
   author = {Gallagher, Peter and Rolfo, Christian and Elez, Elena and Taieb, Julien and Houlden, Jennifer and Collins, Linda and Roberts, Corran and Andre, Thierry and Lawler, Mark and Di Nicolantonio, Federica and Grayson, Margaret and Boyd, Ruth and Popovici, Vlad and Bardelli, Alberto and Carson, Robbie and Khawaja, Hajrah and LaurentandPuig, Pierre and SaltoandTellez, Manuel and Hennessy, Bryan T. and Maughan, Tim S. and Tabernero, Josep and Adams, Richard and Jones, Robert and Peeters, Marc and Middleton, Mark R. and Wilson, Richard H. and Van Schaeybroeck, Sandra and Consortium, MErCuRIC Trial},
   article_location = {LONDON},
   article_number = {1},
   doi = {https://doi.org/10.1038/s44276-025-00133-6},
   keywords = {PLUS IRINOTECAN; RAS MUTATIONS; KINASE; KRAS; RESISTANCE; FLUOROURACIL; LEUCOVORIN},
   language = {eng},
   issn = {2731-9377},
   journal = {BJC REPORTS},
   title = {A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers},
   url = {https://www.nature.com/articles/s44276-025-00133-6},
   volume = {3},
   year = {2025}
}

TY  - JOUR
ID  - 89994
AU  - Gallagher, Peter - Rolfo, Christian - Elez, Elena - Taieb, Julien - Houlden, Jennifer - Collins, Linda - Roberts, Corran - Andre, 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 - Jones, Robert - Peeters, Marc - Middleton, Mark R. - Wilson, Richard H. - Van Schaeybroeck, Sandra - Consortium, MErCuRIC Trial
PY  - 2025
TI  - A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers
JF  - BJC REPORTS
VL  - 3
IS  - 1
SP  - 1-9
EP  - 1-9
PB  - SPRINGERNATURE
SN  - 2731-9377
KW  - PLUS IRINOTECAN
KW  - RAS MUTATIONS
KW  - KINASE
KW  - KRAS
KW  - RESISTANCE
KW  - FLUOROURACIL
KW  - LEUCOVORIN
UR  - https://www.nature.com/articles/s44276-025-00133-6
N2  - 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
ER  -

GALLAGHER, Peter; Christian ROLFO; Elena ELEZ; Julien TAIEB; Jennifer HOULDEN; Linda COLLINS; Corran ROBERTS; Thierry ANDRE; Mark LAWLER; Federica DI NICOLANTONIO; Margaret GRAYSON; Ruth BOYD; Vlad POPOVICI; Alberto BARDELLI; Robbie CARSON; Hajrah KHAWAJA; Pierre LAURENT-PUIG; Manuel SALTO-TELLEZ; Bryan T. HENNESSY; Tim S. MAUGHAN; Josep TABERNERO; Richard ADAMS; Robert JONES; Marc PEETERS; Mark R. MIDDLETON; Richard H. WILSON; Sandra VAN SCHAEYBROECK a MErCuRIC Trial CONSORTIUM. A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers. \textit{BJC REPORTS}. LONDON: SPRINGERNATURE, 2025, roč.~3, č.~1, s.~1-9. ISSN~2731-9377. Dostupné z: https://doi.org/10.1038/s44276-025-00133-6.