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Investigational New Drugs

, Volume 25, Issue 3, pp 259–263 | Cite as

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 A. Carson
  • Joy D. FisherEmail author
  • Jane B. Alavi
  • Steve Rosenfeld
Phase II Studies

Summary

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.

Keywords

CAI Phase II Angiogenesis GBM 

Abbreviations

CAI

Carboxyamido-triazole

CI

Confidence interval

EIAED

enzyme inducing anticonvulsants

GBM

glioblastoma multiforme

KPS

Karnofsky performance status

NABTT

New Approaches to Brain Tumor Therapy

RT

radiation therapy

Notes

Acknowledgment

Supported by NIH grant #CA062475.

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Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Tom Mikkelsen
    • 1
  • Richard Lush
    • 2
  • Stuart A. Grossman
    • 3
  • Kathryn A. Carson
    • 4
  • Joy D. Fisher
    • 3
    • 5
    Email author
  • Jane B. Alavi
    • 6
  • Steve Rosenfeld
    • 7
  1. 1.Departments of Neurology and NeurosurgeryHenry Ford Health SystemDetroitUSA
  2. 2.Department of Neuro-OncologyH. Lee Moffitt Cancer CenterTampaUSA
  3. 3.Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  4. 4.Department of EpidemiologyBloomberg School of Public Health, Johns HopkinsBaltimoreUSA
  5. 5.The New Approaches to Brain Tumor Therapy CNS ConsortiumCancer Research Building IIBaltimoreUSA
  6. 6.Department of Hematology/OncologyHospital of the University of PennsylvaniaPhiladelphiaUSA
  7. 7.Department of Neuro-OncologyColumbia UniversityNew YorkUSA

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