title: Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. eckohn@helix.nih.gov
authors.forename: E C
authors.initials: EC
authors.lastname: Kohn
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: G A
authors.initials: GA
authors.lastname: Sarosy
authors.forename: K S
authors.initials: KS
authors.lastname: Bauer
authors.forename: P A
authors.initials: PA
authors.lastname: Davis
authors.forename: M J
authors.initials: MJ
authors.lastname: Soltis
authors.forename: A
authors.initials: A
authors.lastname: Thompkins
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
authors.forename: E
authors.initials: E
authors.lastname: Reed
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D014230:Triazoles; C062058:carboxyamido-triazole