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


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.


CAI Phase II Angiogenesis GBM 





Confidence interval


enzyme inducing anticonvulsants


glioblastoma multiforme


Karnofsky performance status


New Approaches to Brain Tumor Therapy


radiation therapy



Supported by NIH grant #CA062475.


  1. 1.
    Kohn EC, Liotta LA (1990) L651582: A novel antiproliferative and antimetastasis agent. J Natl Cancer Inst 82:54–60PubMedCrossRefGoogle Scholar
  2. 2.
    Felder CC, Ma AL, Liotta LA, Kohn EC (1991) The antiproliferative and antimetastatic compound L651582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release. J Pharmacol Exp Ther 257:967–971PubMedGoogle Scholar
  3. 3.
    Kohn EC, Sandeen MA, Liotta LA (1992) In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phophates. Cancer Res 52:3208–3212PubMedGoogle Scholar
  4. 4.
    Jacobs W, Mikkelsen T, Smith R, Nelson K, Rosenblum ML, Kohn EC (1997) Inhibitory effects of CAI in glioblastoma growth and invasion. J Neurooncol 32:93–101PubMedCrossRefGoogle Scholar
  5. 5.
    Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW, Weichselbaum RR (1998) Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394:287–291PubMedCrossRefGoogle Scholar
  6. 6.
    Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff, GA, Kufe DW, Weichselbaum RR (1998) Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 58:5686–5689PubMedGoogle Scholar
  7. 7.
    Bauer KS, Figg WD, Hamilton JM, Jones EC, Premkumar A, Steinberg SM, Dyer V, Linehan WM, Pluda JM, Reed E (1999) A pharmacokinetically guided Phase II study of carboxyamido-triazole in androgen-independent prostate cancer. Clin Cancer Res 5:2324–2329PubMedGoogle Scholar
  8. 8.
    Kohn, EC, Figg WD, Sarosy GA, Bauer KS, Davis PA, Soltis MJ, Thompkins A, Liotta LA, Reed E (1997) Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations. J Clin Oncol 15:1985–1993PubMedGoogle Scholar
  9. 9.
    Simmons BR, Bauer KS, McCall NA, Kohn E, William D (1997) An optimized method for the quantitation of carboxyamido-triazole (CAI) in human plasma with solid phase extraction and reverse phase HPLC. Anal Lett 30:2009–2021Google Scholar
  10. 10.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  11. 11.
    Kalbfleisch JD, Prentice RL (1980) Estimation of the survivor function. In: The statistical analysis of failure time data. John Wiley and Sons, New York, pp 16–19Google Scholar
  12. 12.
    Cox DR (1972) Regression models and life tables (with discussion). JR Stat Soc B 34:187–220Google Scholar
  13. 13.
    Brem S, Grossman SA, Carson K, New P, Phuphanich S, Alavi JB, Mikkelsen T, Fisher JD (2005) The new approaches to brain tumor therapy CNS consortium. Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. Neuro-Oncol 7:246–253PubMedCrossRefGoogle Scholar
  14. 14.
    Kleinberg L, Grossman SA, Piantadosi S, Pearlman J, Engelhard H, Lesser G, Ruffer J, Gerber M (1999) For the new approaches to brain tumor therapy central nervous system consortium. Phase I trial to determine the safety, pharmacodynamics and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme. J Clin Oncol 17:2593–2603PubMedGoogle Scholar
  15. 15.
    Kleinberg L, Grossman SA, Carson K, Lesser G, O’Neill A, Pearlman J, Phillips P, Herman T, Gerber M (2002) Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy cns consortium safety and efficacy study. J Clin Oncol 20:3149–3155PubMedCrossRefGoogle Scholar
  16. 16.
    Laterra JJ, Grossman SA, Carson KA, Lesser GJ, Hochberg FH, Gilbert M (2004) Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study. Neuro-Oncol 6:15–20PubMedCrossRefGoogle Scholar
  17. 17.
    Grossman SA, Hochberg F, Fisher J, Chen TL, Kim L, Gregory R, Grochow LB, Piantadosi S (1998) Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS consortium. The new approaches to brain tumor therapy. Cancer Chemother Pharmacol 42:118–126PubMedCrossRefGoogle Scholar
  18. 18.
    Phuphanich S, Baker SD, Grossman SA, Carson KA, Gilbert MR, Fisher JD, Carducci MA (2005) Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study. Neuro-Oncol 7:177–182PubMedCrossRefGoogle Scholar
  19. 19.
    McKillop D, McCormick AD, Millar A, Miles GS, Phillips PJ, Hutchison M (2005) Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 35:39–50PubMedCrossRefGoogle Scholar

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

Personalised recommendations