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

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• Single-agent MEK1/2 inhibitors have shown limited success in RAS-mutant cancers due to resistance mechanisms.
• Previous research indicated that combined c-MET/MEK1/2 inhibition could reduce tumor growth in RAS-mutant colorectal cancer models.

Purpose of the Study:

• To assess the safety and tolerability of combining MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib.
• To determine the optimal biological doses for future clinical trials involving this combination therapy.

Main Methods:

• A dose-escalation Phase I clinical trial was conducted using a rolling-6 design.
• Patients with advanced solid tumors received escalating doses of PD-0325901 and crizotinib.
• Pharmacokinetic and safety data, including dose-limiting toxicities, were collected.

Main Results:

• Twenty-five patients were enrolled across four cohorts, with the maximum tolerated dose (MTD) established at crizotinib 200 mg B.D. continuously and PD-0325901 8 mg B.D. on days 1-21 every 28 days.
• One in six patients experienced dose-limiting toxicity at the MTD.
• The best overall response observed was stable disease in 29% of patients.

Conclusions:

• The combination of PD-0325901 and crizotinib can be safely administered at pharmacologically active doses.
• The MTD was determined for future clinical investigations.
• The combination warrants further exploration, particularly in RAS-mutant colorectal cancer patients, potentially with alternative MEK1/2 inhibitors.