Phase II clinical and pharmacologic study of radiation therapy and carboxyamido-triazole (CAI) in adults with newly diagnosed glioblastoma multiforme

Tom Mikkelsen, Richard Lush, Stuart A Grossman, Kathryn Anne Carson, Joy D. Fisher, Jane B. Alavi, Steve Rosenfeld

Research output: Contribution to journalArticle

Abstract

Introduction: 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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)259-263
Number of pages5
JournalInvestigational New Drugs
Volume25
Issue number3
DOIs
StatePublished - Jun 2007

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carboxyamido-triazole
Glioblastoma
Radiotherapy
Anticonvulsants
Survival
Pharmacokinetics
Enzymes
Confidence Intervals
Cranial Irradiation
Karnofsky Performance Status
Calcium Channels
Clinical Studies
Cell Proliferation
Databases
Radiation
Safety

Keywords

  • Angiogenesis
  • CAI
  • GBM
  • Phase II

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Phase II clinical and pharmacologic study of radiation therapy and carboxyamido-triazole (CAI) in adults with newly diagnosed glioblastoma multiforme. / Mikkelsen, Tom; Lush, Richard; Grossman, Stuart A; Carson, Kathryn Anne; Fisher, Joy D.; Alavi, Jane B.; Rosenfeld, Steve.

In: Investigational New Drugs, Vol. 25, No. 3, 06.2007, p. 259-263.

Research output: Contribution to journalArticle

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abstract = "Introduction: 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 ≥ 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.",
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AU - Carson, Kathryn Anne

AU - Fisher, Joy D.

AU - Alavi, Jane B.

AU - Rosenfeld, Steve

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