Abstract
PurposeTo evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)—a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein—in Japanese patients, we conducted a phase 1, dose escalation study.MethodsEligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.ResultsFrom June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).ConclusionTrebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.
Highlights
Angiogenesis is an essential process for tumor growth and metastasis [1, 2]
Anti-trebananib binding antibodies were detected in 2 patients at 3 mg/kg and one at 10 mg/kg
Concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) transiently increased after the infusion according to the dose administered
Summary
Angiogenesis is an essential process for tumor growth and metastasis [1, 2]. Unless angiogenesis occurs, tumor growth is limited because it is dependent on the continued supply of oxygen [3]. On the basis of these findings, several antiangiogenic agents have been developed and have already been approved for anticancer treatment. These agents include the inhibitors targeting vascular endothelial growth factor receptor (VEGFR) pathway [5, 6], such as monoclonal antibodies and tyrosine kinase inhibitors [7]. Much attention has been focused on the clinical toxicity profile of these agents [8] They may increase the risk for several adverse events such as hypertension, proteinuria, coagulation disorders, and gastro-intestinal toxicity [8, 9].
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