BACKGROUND: Single-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. METHODS: In 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. RESULTS: Twenty-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%). CONCLUSIONS: PD-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-NUMBER: 2014-000463-40.

Cardiff University and Velindre University NHS Trust Cardiff UK

Centre de recherche des cordeliers INSERM Sorbonne Université Université Paris Cité Paris France

Department of GI Oncology Hôpital Européen Georges Pompidou Institut du cancer Paris Carpem AP HP Université Paris Cité Paris France

Department of Medical Oncology Sorbonne Université Hôpital Saint Antoine Paris France

Department of Medical Oncology University of Antwerp Antwerp University Hospital Wilrijk Belgium

Department of Molecular and Clinical Cancer Medicine University of Liverpool Ashton St Liverpool UK

Department of Oncology and Candiolo Cancer Institute University of Torino Candiolo TO Italy

Department of Oncology Molecular Biotechnology Center University of Torino Torino Italy

Department of Oncology Old Road Campus Research Building Roosevelt Drive University of Oxford Oxford UK

Department of Oncology Oncology Clinical Trials Office University of Oxford Oxford UK

IFOM ETS The AIRC Institute of Molecular Oncology Milano Italy

Northern Ireland Cancer Centre Belfast Health and Social Care Trust Belfast UK

Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences Centre for Statistics in Medicine University of Oxford Oxford UK

Patrick G Johnston Centre for Cancer Research School of Medicine Dentistry and Biomedical Science Queen's University Belfast Belfast UK

RECETOX Faculty of Science Masaryk University Brno Czech Republic

Royal College of Surgeons in Ireland University of Medicine and Health Sciences Dublin Ireland

Vall d'Hebron University Hospital and Institute of Oncology Barcelona Spain

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A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC)