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Phase I trial of carmustine plus O-6-benzylguanine for patients with recurrent or progressive malignant glioma

  1. Author:
    Friedman, H. S.
    Pluda, J.
    Quinn, J. A.
    Ewesuedo, R. B.
    Long, L.
    Friedman, A. H.
    Cokgor, I.
    Colvin, O. M.
    Haglund, M. M.
    Ashley, D. M.
    Rich, J. N.
    Sampson, J.
    Pegg, A. E.
    Moschel, R. C.
    McLendon, R. E.
    Provenzale, J. M.
    Stewart, E. S.
    Tourt-Uhlig, S.
    Garcia-Turner, A. M.
    Herndon, J. E.
    Bigner, D. D.
    Dolan, M. E.

  2. Author Address

    Duke Univ, Med Ctr, Dept Surg, DUMC-3624, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. Penn State Univ, Milton S Hershey Med Ctr, Sch Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Sch Med, Dept Pharmacol, Hershey, PA 17033 USA. NCI, Frederick Canc Res & Dev Ctr, Adv Biosci Labs, Chem Carcinogenesis Lab, Frederick, MD USA. NCI, Investigat Drug Branch, NIH, Bethesda, MD 20892 USA. Royal Childrens Hosp, Melbourne, Vic, Australia.
    1. Year: 2000
  2. Journal: Journal of Clinical Oncology
    1. 18
    2. 20
    3. Pages: 3522-3528
  4. Type of Article: Article
  1. Abstract:

    Purpose: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O-6 position of guanine. O-6- benlylguanine (O-6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O-6-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O-6-BG with recurrent or progressive malignant glioma. Patients and Methods: Patients were treated with O-6-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O-6-BG, 8-oxa-O- 6-BG, and 8-oxoguanine concentration. Results: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O-6-BG rapidly disappeared from plasma (elimination half-life = 0.54 +/- 0.14 hours) and was converted to ct longer-lived metabolite, 8-oxo-O-6-BG (elimination half- life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O-6-BG 5 hours after the start of the O-6-BG infusion; however, 8-oxo-O-6-BG and 8-oxoguanine concentrations were detected 25 hours after O-6-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O-6-BG was 17.5 times greater than the mean AUC for O-6-BG. Conclusion: These results indicate that the MTD of BCNU when given in combination with O-6-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O-6-BG plus BCNU in nitrosourea-resistant malignant glioma. (C) 2000 by American Society of Clinical Oncology.

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