title: Phase II clinical and pharmacologic study of radiation therapy and carboxyamido-triazole (CAI) in adults with newly diagnosed glioblastoma multiforme.
abstract: BACKGROUND
  Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-voltage-gated calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. This study examined the efficacy, safety and pharmacokinetics of oral CAI in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) in an open-label, single arm non-randomized phase 2 trial.
  
  
  METHODS
  Eligible patients with histologically confirmed GBM started CAI therapy (250 mg daily) on the first day of radiation (6000 cGy in 30 fractions) and continued until progression, unless side effects became intolerable. The primary outcome was survival compared to historical controls within the NABTT CNS Consortium database. Secondary outcomes included toxicity and pharmacokinetic parameters.
  
  
  RESULTS
  Fifty-five patients were enrolled with a median Karnofsky performance status of 90 and age of 56 years. Forty-six (84%) of these patients had debulking surgeries and 52 have died. The median survival was 10.3 months (95% confidence interval (CI), 8.5-12.8) compared to 12.1 months (95% CI, 10.3-13.3) in the NABTT reference group (p = 0.97). Significant toxicities included 2 incidents of reversible vision loss. The mean CAI plasma concentration for patients taking enzyme inducing antiepileptic drugs (EIAED) was 1.35 +/-1.22 compared to 4.06 +/- 1.50 (p < 0.001) for subjects not taking these agents. Overall survival and grade > or = 3 toxicities were comparable by EIAED status.
  
  
  CONCLUSIONS
  This study demonstrated that (1) CAI can be administered safely with concomitant cranial irradiation, (2) the pharmacokinetics of CAI are significantly affected by co-administration of EIAED, and (3) the survival of patients with newly diagnosed GBM was not improved with this novel agent, despite achieving adequate drug levels.
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan 48202, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.forename: Jane B
authors.initials: JB
authors.lastname: Alavi
authors.forename: Steve
authors.initials: S
authors.lastname: Rosenfeld
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D004347:Drug Interactions; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018714:Radiotherapy, Adjuvant; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014481:United States / Q000453:epidemiology
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D014230:Triazoles; C062058:carboxyamido-triazole