Journal of Neuro-Oncology

, Volume 83, Issue 1, pp 53–60

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

  • Annick Desjardins
  • Jennifer A. Quinn
  • James J. Vredenburgh
  • Sith Sathornsumetee
  • Allan H. Friedman
  • James E. Herndon
  • Roger E. McLendon
  • James M. Provenzale
  • Jeremy N. Rich
  • John H. Sampson
  • Sridharan Gururangan
  • Jeannette M. Dowell
  • August Salvado
  • Henry S. Friedman
  • David A. Reardon
Original Paper

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.

Keywords

Anaplastic astrocytoma Anaplastic oligodendroglioma Growth factor Imatinib mesylate Malignant glioma Phase II trial Platelet-derived 

Abbreviations List

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

References

  1. 1.
    See SJ, Gilbert MR (2004) Anaplastic astrocytoma: diagnosis, prognosis, and management. Semin Oncol 31:618–634PubMedCrossRefGoogle Scholar
  2. 2.
    Engelhard HH, Stelea A, Mundt A (2003) Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment, and prognosis. Surg Neurol 60:443–456PubMedCrossRefGoogle Scholar
  3. 3.
    Lonardi S, Tosoni A, Brandes AA (2005) Adjuvant chemotherapy in the treatment of high-grade gliomas. Cancer Treat Rev 31:79–89PubMedCrossRefGoogle Scholar
  4. 4.
    Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP (1993) Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71:2585–2597PubMedCrossRefGoogle Scholar
  5. 5.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018PubMedCrossRefGoogle Scholar
  6. 6.
    Levin VA, Wilson CB, Davis R, Wara WM, Pischer TL, Irwin L (1979) A phase III comparison of BCNU, hydroxyurea, and radiation therapy to BCNU and radiation therapy for treatment of primary malignant gliomas. J Neurosurg 51:526–532PubMedGoogle Scholar
  7. 7.
    Buckner JC, Schomberg PJ, McGinnis WL, Cascino TL, Scheithauer BW, O’Fallon JR, Morton RF, Kuross SA, Mailliard JA, Hatfield AK, Cole JT, Steen PD, Bernath AM (2001) A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer 92:420–433PubMedCrossRefGoogle Scholar
  8. 8.
    Prados MD, Larson DA, Lamborn K, McDermott MW, Sneed PK, Wara WM, Chang SM, Mack EE, Krouwer HG, Chandler KL, Warnick RE, Davis RL, Rabbitt JE, Malec M, Levin VA, Gutin PH, Phillips TL, Wilson CB (1998) Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors. Int J Radiat Oncol Biol Phys 40:57–63PubMedCrossRefGoogle Scholar
  9. 9.
    Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, Kimmel D, Yates A, Burger PC, Scheithauer BW, Jenkins RB (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645PubMedGoogle Scholar
  10. 10.
    Ino Y, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Jhung S, Ramsay DA, von Deimling A, Louis DN, Cairncross JG (2000) Long survival and therapeutic responses in patients with histologically disparate high-grade gliomas demonstrating chromosome 1p loss. J Neurosurg 92:983–990PubMedCrossRefGoogle Scholar
  11. 11.
    Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Ramsay DA, Cairncross JG, Louis DN (2001) Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res 7:839–845PubMedGoogle Scholar
  12. 12.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479PubMedCrossRefGoogle Scholar
  13. 13.
    Behin A, Hoang-Xuan K, Carpentier AF, Delattre JY (2003) Primary brain tumours in adults. Lancet 361:323–331PubMedCrossRefGoogle Scholar
  14. 14.
    DeAngelis LM (2001) Brain tumors. N Engl J Med 344:114–123PubMedCrossRefGoogle Scholar
  15. 15.
    Kleihues P, Cavenee WK (2000) Pathology and Genetics of Tumours of the Nervous System. International Agency for Research on Cancer (IARC), Lyon, FranceGoogle Scholar
  16. 16.
    Reardon DA, Egorin MJ, Quinn JA, Rich JN Sr, Gururangan I, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE, 2nd. Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368PubMedCrossRefGoogle Scholar
  17. 17.
    Wen PY, Yung WK, Lamborn K, Peng B, Dahia P, Abrey L, Raiser J, Cloughesy T, Fink K, Gilbert M, Chang SM, Junck L, Schiff D, Lieberman F, Fine H, Mehta M, Robins HI, DeAngelis LM, Hess K, Groves M, Puduvalli VK, Levin VA, Conrad C, Kuhn J, Maher E, Hayes M, Silberman S, Letvak L, Capdeville R, Kaplan R, Murgo A, Stiles CD, Prados MD: Phase I/II study of imatinib mesylate (ST1571) for patients with recurrent malignant gliomas (NABTC 99–08). In: Bigner DD (ed) Society for Neuro-oncology Ninth Annual Meeting, Toronto, CanadaGoogle Scholar
  18. 18.
    Van Den Bent MJ, Brandes AA, van Oosterom A, Dittrich C, Fumoleau P, Coudert B, Twelves C, de Balincourt C, Lacombe D, Raymond E: Multicentre phase II study of imatinib mesylate (Gleevec) in patients with recurrent glioblastoma: an EORTC NDDG/BTG intergroup study. In: Bigner DD (ed) Society for Neuro-Oncology Ninth Annual Meeting, Toronto, Canada, p 383Google Scholar
  19. 19.
    Geyer JR, Zeltzer PM, Boyett JM, Rorke LB, Stanley P, Albright AL, Wisoff JH, Milstein JM, Allen JC, Finlay JL, et al. (1994) Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group. J Clin Oncol 12:1607–1615PubMedGoogle Scholar
  20. 20.
    Levin VA (1992) The place of hydroxyurea in the treatment of primary brain tumors. Semin Oncol 19:34–39PubMedGoogle Scholar
  21. 21.
    Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics 38:29–41CrossRefGoogle Scholar
  22. 22.
    Cox DR (1972) Regression models and life-tables (with discussion). J Roy Stat Soc B 34:187–220Google Scholar
  23. 23.
    Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O’Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal brain tumour group. J Clin Oncol 17:2762–2771PubMedGoogle Scholar
  24. 24.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  25. 25.
    Dresemann G (2005) Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 16:1702–1708PubMedCrossRefGoogle Scholar
  26. 26.
    Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Annick Desjardins
    • 1
  • Jennifer A. Quinn
    • 1
  • James J. Vredenburgh
    • 1
  • Sith Sathornsumetee
    • 1
  • Allan H. Friedman
    • 2
  • James E. Herndon
    • 4
  • Roger E. McLendon
    • 5
  • James M. Provenzale
    • 3
  • Jeremy N. Rich
    • 1
  • John H. Sampson
    • 2
  • Sridharan Gururangan
    • 6
  • Jeannette M. Dowell
    • 4
  • August Salvado
    • 7
  • Henry S. Friedman
    • 2
    • 6
  • David A. Reardon
    • 2
    • 6
  1. 1.Department of Medicine, Division of NeurologyThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  2. 2.Department of SurgeryThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  3. 3.Department of RadiologyThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  4. 4.Cancer Center BiostatisticsThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  5. 5.Department of PathologyThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  6. 6.Department of PediatricsThe Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical CenterDurhamUSA
  7. 7.Novartis PharmaceuticalsEast HanoverUSA

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