A Phase I/II Study of Foretinib in Patients With Previously Treated Non-Small Cell Lung Cancer Receiving Standard Erlotinib Therapy

OBJECTIVES:

• To determine the recommended phase II dose of MET/VEGFR2 inhibitor Foretinibin combination with standard erlotinib hydrochloride therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen, and whose EGFR-expression status is positive or unknown.
• To determine the safety, tolerability, toxicity profile, dose-limiting toxicities, and pharmacokinetic profile of MET/VEGFR2 inhibitor Foretinib and erlotinib hydrochloride in this schedule.
• To determine the correlation, if any, between the toxicity profile and pharmacokinetics.
• To assess the anti-tumor activity of MET/VEGFR2 inhibitor Foretinib in combination with erlotinib hydrochloride as evidenced by response rates, clinical benefit (complete or partial response or stable disease ≥ 8 weeks duration), and an exploratory endpoint of early assessment of tumor size as a continuous variable (when compared to erlotinib hydrochloride alone).
• To assess one-year survival rate in these patients.
• To investigate the correlation, if any, between response and biomarkers, including EGFR gene mutation, EGFR gene amplification, EGFR gene polymorphisms, c-Met gene mutation, amplification and expression, phospho-c-Met expression, K-Ras gene mutation, and baseline serum HGF levels.

OUTLINE: This is a multicenter, dose-escalation phase I study of MET/VEGFR2 inhibitor Foretinib followed by a randomized, open-label phase II study.

• Phase I (dose-escalation) : Patients receive oral erlotinib hydrochloride once daily on days 1-28. Patients receive oral MET/VEGFR2 inhibitor GSK1363089 once daily on days 15-28 during course 1 and on days 1-28 during all other courses. Courses repeat every 28 days until the maximum-tolerated dose of MET/VEGFR2 inhibitor Foretinib is determined.

Blood samples are collected on days 14 and 28 of course 1 for pharmacokinetics and day 1 of courses 1 and 2 and post treatment for pharmacodynamic studies.