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Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas

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Journal of Neuro-Oncology Aims and scope Submit manuscript

Supported by National Institutes of Health grant nos. 1-P50-CA108786-01, NS20023 and CA11898 and by grant no. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

Abstract

Purpose

Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG).

Patients and method

Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate.

Results

Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1–7) and the median number of prior treatment regimens was 3 (range, 1–8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses.

Conclusion

Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

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Abbreviations

AA:

anaplastic astrocytoma

AO:

anaplastic oligodendroglioma

AOA:

anaplastic oligoastrocytoma

CBC:

complete blood count

CI:

confidence interval

CNS:

central nervous system

CR:

complete response

DLT:

dose-limiting toxicity

EIAED:

enzyme inducing anti-epileptic drugs

18FDG PET [18F]:

fluorodeoxyglucose positron emission tomography

FDA:

Food and Drug Administration

GBM:

glioblastoma multiforme

G-CSF:

granulocyte colony stimulating factor

GS:

gliosarcoma

IRB:

institutional review board

ITT:

intent-to treat

KM:

Kaplan-Meier

KPS:

Karnofsky performance status

MG:

malignant glioma

MRI:

magnetic resonance imaging

MTD:

maximum-tolerated dose

OS:

overall survival

PD:

progressive disease

PFS:

progression-free survival

PR:

partial response

SD:

stable disease

TTP:

time to progression

XRT:

external beam radiotherapy

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Authors and Affiliations

  1. Department of Medicine, Division of Neurology, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Box 3624, Durham, NC, 27710, USA

    Annick Desjardins, Jennifer A. Quinn, James J. Vredenburgh, Sith Sathornsumetee & Jeremy N. Rich

  2. Department of Surgery, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA

    Allan H. Friedman, John H. Sampson, Henry S. Friedman & David A. Reardon

  3. Department of Radiology, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA

    James M. Provenzale

  4. Cancer Center Biostatistics, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA

    James E. Herndon & Jeannette M. Dowell

  5. Department of Pathology, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA

    Roger E. McLendon

  6. Department of Pediatrics, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, 27710, USA

    Sridharan Gururangan, Henry S. Friedman & David A. Reardon

  7. Novartis Pharmaceuticals, East Hanover, NJ, USA

    August Salvado

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  1. Annick Desjardins
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  2. Jennifer A. Quinn
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  3. James J. Vredenburgh
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Correspondence to Annick Desjardins.

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Desjardins, A., Quinn, J.A., Vredenburgh, J.J. et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol 83, 53–60 (2007). https://doi.org/10.1007/s11060-006-9302-2

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  • DOI: https://doi.org/10.1007/s11060-006-9302-2

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