Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.
OBJECTIVE
We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM).


METHODS
Patients with GBM 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 antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).


RESULTS
Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.


CONCLUSIONS
Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.
Reardon
David A
DA
Department of Medicine, Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. reard003@mc.duke.edu
Egorin
Merrill J
MJ
Quinn
Jennifer A
JA
Rich
Jeremy N
JN
Rich
Jeremy N
JN
Gururangan
Sridharan
S
Gururangan
Idharan
I
Vredenburgh
James J
JJ
Desjardins
Annick
A
Sathornsumetee
Sith
S
Provenzale
James M
JM
Herndon
James E
JE
Dowell
Jeannette M
JM
Badruddoja
Michael A
MA
McLendon
Roger E
RE
Lagattuta
Theodore F
TF
Kicielinski
Kimberly P
KP
Dresemann
Gregor
G
Sampson
John H
JH
Friedman
Allan H
AH
Salvado
August J
AJ
Friedman
Henry S
HS
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006918:Hydroxyurea