A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.

Abstract

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 micro g/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.

• Authors: Desirée Hao, Lisa A Hammond, S Gail Eckhardt, Amita Patnaik, Chris H Takimoto, Garry H Schwartz, Andrew D Goetz, Anthony W Tolcher, Heather A McCreery, Khalid Mamun, Jon I Williams, Kenneth J Holroyd, Eric K Rowinsky
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 7 Pg. 2465-71 (Jul 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12855619 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Cholestanols
• Sterols
• squalamine

Topics

• Adolescent
• Adult
• Angiogenesis Inhibitors (pharmacokinetics, therapeutic use)
• Area Under Curve
• Cholestanols (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Liver (drug effects)
• Male
• Middle Aged
• Models, Chemical
• Neoplasms (drug therapy)
• Sterols (chemistry)
• Time Factors