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University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792 [J. B., K. D. T., R. Z. A., D. A., K. B., C. F., A. D., R. M., G. W.], and Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. P.]
Purpose: This Phase I study was conducted to evaluate the toxicity profile and determine the maximum tolerated dose (MTD) of an oral micronized formulation of the signal transduction inhibitor carboxyamidotriazole (CAI). Bioavailability of the micronized formulation relative to a gelatin capsule (gelcap) formulation was assessed. The effects of food intake and timing on CAI steady-state plasma concentrations (Css) were also investigated.
Experimental Design: Patients received continuous daily CAI (28-day cycles). Starting dose was 150 mg/m2 daily and escalations were by 50 mg/m2 increments. The first three patients enrolled were given test doses of the original gelcap formulation and two different micronized formulations to determine relative bioavailability. Toxicity and pharmacokinetic assessments were performed weekly. Additional cohorts were added after MTD determination to assess the effect of food intake and duration of fast on CAI Css.
Results: The micronized formulation was absorbed more slowly than the gelcap formulation. Twenty-nine patients were enrolled in the dose-escalation portion of the study. After dose escalation to 300 mg/m2, dose-limiting neurotoxicities occurred including reversible vision loss in two patients. Other toxicities were mild. The final MTD was 150 mg/m2. Pharmacokinetics appeared linear with significant inter- and intrapatient variability. Patients with Css of 
4.0 mg/liter were more likely to have neurotoxicity. Nine patients with renal cell cancer and one with hepatocellular cancer had prolonged stable disease. CAI plasma concentrations were higher when taken with food.
Conclusions: Micronized CAI was well tolerated at the MTD of 150 mg/m2. Higher doses were limited by significant neurotoxicity. The variability in CAI pharmacokinetics may be partially attributable to concomitant food intake and timing of the dose.
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