A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases.

PURPOSE: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. PATIENTS AND METHODS: Patients with p-Met (phosphorylated c-Met)-positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. RESULTS: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (-53%), p-ERK (-43%), p-Akt (-2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4-10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year. CONCLUSIONS: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle.