A Phase I and Pharmacokinetic Study of Squalamine, an Aminosterol Angiogenesis Inhibitor

Purpose: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m 2 /day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. Results: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m 2 /day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m 2 /day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m 2 /day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m 2 /day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m 2 (85%), 9.46 h (81%), and 36.84 liters/m 2 (124%), respectively, and steady-state concentrations [20.08 μg/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. Conclusions: At the recommended Phase II dose of 500 mg/m 2 /day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.