Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer

摘要

Background KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparinbinding epidermal growth factor-like growth factor (HBEGF). Objective To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first- in- human, phase 1 study. Materials and Methods Using a standard 3+ 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment. Results The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose- limiting at 3 mg/kg in the original dose- escalation cohorts (n= 2), at 1 mg/kg in the MTD dose expansion cohort (n= 1), and at 0.1 mg/kg (n= 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HBEGF levels, generally below the lower limit of quantification. Conclusions The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov#NCT0179291]