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A Phase I and Pharmacokinetic Study of Squalamine, an Aminosterol Angiogenesis Inhibitor¹

Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio, San Antonio, Texas [D. H., L. A. H., S. G. E., A. P., C. H. T., A. D. G., A. W. T., H. A. M., E. K. R.]; Brooke Army Medical Center, San Antonio, Texas [G. H. S.]; and Genaera Corp., Plymouth Meeting, Pennsylvania [K. M., J. I. W., K. J. H.]

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/m²/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/m²/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m²/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m²/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/m²/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m² (85%), 9.46 h (81%), and 36.84 liters/m² (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/m²/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.

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