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

  1. Author:
    Quinn, J. A.
    Desjardins, A.
    Weingart, J.
    Brem, H.
    Dolan, M. E.
    Delaney, S. M.
    Vredenburgh, J.
    Rich, J.
    Friedman, A. H.
    Reardon, D. A.
    Sampson, J. H.
    Pegg, A. E.
    Moschel, R. C.
    Birch, R.
    McLendon, R. E.
    Provenzale, J. M.
    Gururangan, S.
    Dancey, J. E.
    Maxwell, J.
    Tourt-Uhlig, S.
    Herndon, J. E.
    Bigner, D. D.
    Friedman, H. S.

  2. Author Address

    Duke Univ, Med Ctr, Dept Surg, 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 Biostat & Bioinformat, Durham, NC 27710 USA. Johns Hopkins Univ Hosp, Dept Neurosurg, Baltimore, MD 21287 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. NCI, Invest Drug Branch, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Comm Canc Biol, Chicago, IL 60637 USA. Univ Chicago, Canc Res Inst, Chicago, IL 60637 USA. Milton S Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA USA. AOI Pharmaceut, Lab Comparat Carcinogenesis, Memphis, TN USA Quinn, JA, Duke Univ, Brain Tumor Ctr, S Hosp, Room 047 Baker House,Trent Dr, Durham, NC 27710 USA
    1. Year: 2005
    2. Date: OCT 1
  2. Journal: Journal of Clinical Oncology
    1. 23
    2. 28
    3. Pages: 7178-7187
  4. Type of Article: Article
  1. Abstract:

    Purpose We conducted a two-phase clinical trial in patients with progressive malignant glionna (MG). The first phase of this trial was designed to determine the dose of O-6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O-6-BG. In addition, plasma concentrations of O-6-BG and O-6-benzyl-8-oxoguanine were evaluated after O-6-BG.Patients and Methods For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O-6-BG infusion at 120 mg/m(2) followed by a continuous infusion at an initial dose of 30 mg/m(2)/d for 48 hours. The dose of the continuous infusion of O-6-BG escalated until tumor AGT was depleted. Once the O-6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O-6-BG infusion, was escalated until the MTD was determined.Results The O-6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m(2) over 1 hour followed by a continuous infusion of 30 mg/m(2)/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m(2) with dose-limiting toxicities limited to myelosuppression.Conclusion This study provides the foundation for a phase II trial of O-6-BG plus temozolomide in temozolomide-resistant MG

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  1. View record in Web of Science®
  2. WOS: 000232232000046

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