A Phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR in advanced hepatocellular carcinoma (HCC)

Abstract

BACKGROUND AND AIMS: Foretinib is an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR. HGF/MET signaling plays a pivotal role in tumour cell proliferation, migration and invasion, and circulating levels of HGF correlate with poor prognosis in HCC. This phase I/II trial (MET111645) is evaluating oral foretinib as first line therapy in advanced Asian HCC patients. METHODS: Patients with measurable unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0–1, adequate organ function and Child–Pugh grade A are eligible for enrolment. Phase I is a standard 3+3 design using increasing doses of oral foretinib to evaluate safety and determine the maximum tolerated dose (MTD). Secondary objectives include antitumour activity and pharmacokinetics. RESULTS: As of November 16, 2010, 13 patients have been enrolled: median age 57 years (range 31–78 years), M/F = 9/4. BCLC stage 0/A/B/C at screening: 0/0/3/10. Prior lines of therapy including local treatment: unknown/1/2/3/4: 1/3/5/2/1. Drug-related adverse events (AE) were reported in 10 patients (77%). The most common AEs were hypertension (54%), diarrhoea (31%), thrombocytopenia (23%), and peripheral oedema (23%). Serious treatment-emergent toxicities were reported in 54% of patients. Two dose-limiting toxicities (renal failure, proteinuria) were observed in 2/6 patients at 45mg OD but no DLTs were observed in 6 patients at 30mg OD. Nine patients were evaluable for response according to RECIST 1.0; 2 patients had a best response of partial response (PR); objective response rate (ORR) 22%. When tumour response was assessed according to modified RECIST criteria for HCC, 1 patient showed a complete response and 3 patients had a PR; ORR 44%. Exposure of 30- and 45-mg OD foretinib was overlapping and similar to higher doses in other tumour types. CONCLUSION: The foretinib MTD was determined to be 30mg OD. The early promising signal of activity observed in this phase I trial needs to be confirmed in phase II.