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


METHODS
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.


CONCLUSIONS
Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.
Desjardins
Annick
A
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. desja002@mc.duke.edu
Quinn
Jennifer A
JA
Vredenburgh
James J
JJ
Sathornsumetee
Sith
S
Friedman
Allan H
AH
Herndon
James E
JE
McLendon
Roger E
RE
Provenzale
James M
JM
Rich
Jeremy N
JN
Sampson
John H
JH
Gururangan
Sridharan
S
Dowell
Jeannette M
JM
Salvado
August
A
Friedman
Henry S
HS
Reardon
David A
DA
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy*; D001549:Benzamides; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009837:Oligodendroglioma / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006918:Hydroxyurea