title: Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.
abstract: Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. Inhibition of calcium influx and calcium-dependent events is a potential common mechanism underlying these effects of CAI. The cytostatic and antiangiogenic properties of CAI led to its development for clinical investigation. In a Phase I clinical trial open to patients with refractory solid tumors, 49 patients received p.o. administered CAI daily or every other day. Two oral formulations, PEG-400 CAI solution and a gelatin capsule containing CAI in PEG-400, were tested. All administered dosages of CAI yielded plasma concentration at or above the range demonstrated to be effective in inhibiting signaling and cancer progression in vitro and in preclinical models (1 microgram/ml, 2.3 microM). Toxicity of p.o. administered CAI most commonly consisted of dose-related grade 1-2 nausea, vomiting, and occasional anorexia. CAI administration at bedtime ameliorated gastrointestinal complaints in many patients; others required addition of simple antiemetic regimens, usually consisting of metoclopropamide or prochlorperazine. Gastrointestinal complaints were the cause for compliance-limiting toxicity at 175 mg/m2/day of the liquid formulation and 125 mg/m2/day of the gelatin capsule formation. Reversible and rare sensory axonal neuropathy (grade 3, 1 patient) and neutropenia (grade 4, 1 patient) were dose-limiting toxicities observed at the 330 mg/m2 every-other-day liquid CAI dose level. No evidence of cumulative end organ damage or central nervous system injury was observed. Disease stabilization and improvement in performance status was observed. Disease stabilization and improvement in performance status was observed in 49% of evaluable patients who had disease progression before CAI. Disease stabilization and associated improvement in performance status was seen in patients with renal cell carcinoma (7 months), pancreaticobiliary carcinomas (3, 5, and 5 months), melanoma (7 months), ovarian cancer (7 months), and non-small cell lung cancer (3 months). The recommended Phase II doses from this trial are 150 mg/m2/day in the liquid formation and 100 mg/m2/day in the gelatin capsule formation.
authors.affiliation: Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Kohn
authors.forename: E
authors.initials: E
authors.lastname: Reed
authors.forename: G
authors.initials: G
authors.lastname: Sarosy
authors.forename: M
authors.initials: M
authors.lastname: Christian
authors.forename: C J
authors.initials: CJ
authors.lastname: Link
authors.forename: K
authors.initials: K
authors.lastname: Cole
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: P A
authors.initials: PA
authors.lastname: Davis
authors.forename: J
authors.initials: J
authors.lastname: Jacob
authors.forename: B
authors.initials: B
authors.lastname: Goldspiel
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D014230:Triazoles; C062058:carboxyamido-triazole