Journal of Clinical Oncology, Vol 15, 1985-1993, Copyright © 1997 by American Society of Clinical Oncology
Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations
EC Kohn, WD Figg, GA Sarosy, KS Bauer, PA Davis, MJ Soltis, A Thompkins, LA Liotta and E Reed
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. eckohn@helix.nih.gov
PURPOSE: Cytostatic agents targeted against angiogenesis and tumor cell
invasive potential form a new class of investigational drugs. Orally
administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic
and antimetastatic. An encapsulated micronized powder formulation has been
developed to optimize CAI administration. A phase I dose escalation trial
with pharmacokinetic analysis has been performed. PATIENTS AND METHODS:
Twenty-one patients with refractory solid tumors and good end organ
function and performance status were enrolled onto the study. Patients
received a test dose followed 1 week later by daily administration of CAI
in the encapsulated micronized formulation at doses of 100 to 350 mg/m2.
Patients remained on CAI until disease progression or dose-limiting
toxicity. Plasma samples were taken to characterize the pharmacokinetic
parameters of this formulation of CAI. RESULTS: All patients were
assessable for toxicity and 18 were assessable for pharmacokinetics and
response analysis. Grade 1 and 2 gastrointestinal side effects were
observed in up to 50% of patients. Dose-limiting toxicity was observed in
both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3
cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR)
was observed in a patient with renal cell carcinoma and another nine
patients had disease stabilization (MR + SD = 47%). Pharmacokinetic
analysis demonstrated reduced bioavailability (58% reduction) compared with
the PEG-400 liquid formulation previously reported. CONCLUSION: The better
toxicity profile of encapsulated micronized CAI with similar frequency of
disease stabilization and ease of administration compared with the liquid
or gelatin capsule, suggests that the micronized formulation is a
preferable formulation for subsequent studies. A dose of 300 mg/m2/d is
proposed for phase II investigations.
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