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Background <p>Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting <i>RAS</i> mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated <i>RAS</i>MT 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.</p> Methods <p>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.</p> Results <p>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%).</p> Conclusions <p>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 <i>RAS</i>MT CRC patients.</p> EudraCT-Number <p>2014-000463-40</p>

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

  • 期刊论文

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  • 发表日期：

    2025年3月26日

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  • Peter Gallagher,
  • Christian Rolfo,
  • Elena Elez,
  • Julien Taieb,
  • Jennifer Houlden,
  • Linda Collins,
  • Corran Roberts,
  • Thierry André,
  • 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,
  • Federica Di Nicolantonio,
  • Vicky Coyle,
  • Francesca Aroldi,
  • Geraldine Perkins,
  • Hans Prenen,
  • Karolien Bettens,
  • Jurgen Delfavero,
  • Sandra Van Schaeybroeck

摘要

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