Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas
- First Online:
- 170 Downloads
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.
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.
Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.
KeywordsAnaplastic astrocytoma Anaplastic oligodendroglioma Growth factor Imatinib mesylate Malignant glioma Phase II trial Platelet-derived
complete blood count
central nervous system
enzyme inducing anti-epileptic drugs
- 18FDG PET [18F]
fluorodeoxyglucose positron emission tomography
Food and Drug Administration
granulocyte colony stimulating factor
institutional review board
Karnofsky performance status
magnetic resonance imaging
time to progression
external beam radiotherapy
- 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.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.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.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
- 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
- 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.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.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.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.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
- 22.Cox DR (1972) Regression models and life-tables (with discussion). J Roy Stat Soc B 34:187–220Google 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 17:2762–2771PubMedGoogle Scholar