Skip to main content

Advertisement

Springer Nature Link
Log in

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

  • Original Paper
  • Published:
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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

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

References

  1. See SJ, Gilbert MR (2004) Anaplastic astrocytoma: diagnosis, prognosis, and management. Semin Oncol 31:618–634

    Article  PubMed  Google Scholar 

  2. Engelhard HH, Stelea A, Mundt A (2003) Oligodendroglioma and anaplastic oligodendroglioma: clinical features, treatment, and prognosis. Surg Neurol 60:443–456

    Article  PubMed  Google Scholar 

  3. Lonardi S, Tosoni A, Brandes AA (2005) Adjuvant chemotherapy in the treatment of high-grade gliomas. Cancer Treat Rev 31:79–89

    Article  PubMed  CAS  Google Scholar 

  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 71:2585–2597

    Article  PubMed  CAS  Google Scholar 

  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 359:1011–1018

    Article  PubMed  CAS  Google Scholar 

  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 51:526–532

    PubMed  CAS  Google Scholar 

  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 92:420–433

    Article  PubMed  CAS  Google Scholar 

  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 40:57–63

    Article  PubMed  CAS  Google Scholar 

  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 18:636–645

    PubMed  CAS  Google Scholar 

  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 92:983–990

    Article  PubMed  CAS  Google Scholar 

  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 7:839–845

    PubMed  CAS  Google Scholar 

  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 90:1473–1479

    Article  PubMed  CAS  Google Scholar 

  13. Behin A, Hoang-Xuan K, Carpentier AF, Delattre JY (2003) Primary brain tumours in adults. Lancet 361:323–331

    Article  PubMed  Google Scholar 

  14. DeAngelis LM (2001) Brain tumors. N Engl J Med 344:114–123

    Article  PubMed  CAS  Google Scholar 

  15. Kleihues P, Cavenee WK (2000) Pathology and Genetics of Tumours of the Nervous System. International Agency for Research on Cancer (IARC), Lyon, France

    Google Scholar 

  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 23:9359–9368

    Article  PubMed  CAS  Google Scholar 

  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, Canada

  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 383

  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 12:1607–1615

    PubMed  CAS  Google Scholar 

  20. Levin VA (1992) The place of hydroxyurea in the treatment of primary brain tumors. Semin Oncol 19:34–39

    PubMed  CAS  Google Scholar 

  21. Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics 38:29–41

    Article  Google Scholar 

  22. Cox DR (1972) Regression models and life-tables (with discussion). J Roy Stat Soc B 34:187–220

    Google Scholar 

  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 17:2762–2771

    PubMed  CAS  Google Scholar 

  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 17:2572–2578

    PubMed  CAS  Google Scholar 

  25. Dresemann G (2005) Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 16:1702–1708

    Article  PubMed  CAS  Google Scholar 

  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 12:908–916

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

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

Authors
  1. Annick Desjardins
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jennifer A. Quinn
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. James J. Vredenburgh
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Sith Sathornsumetee
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Allan H. Friedman
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. James E. Herndon
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Roger E. McLendon
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. James M. Provenzale
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Jeremy N. Rich
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. John H. Sampson
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Sridharan Gururangan
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Jeannette M. Dowell
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. August Salvado
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Henry S. Friedman
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. David A. Reardon
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Annick Desjardins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Profiles

  1. Sith Sathornsumetee View author profile