Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08.
OBJECTIVE
Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib.


METHODS
Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response.


RESULTS
Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages.


CONCLUSIONS
Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.
Wen
Patrick Y
PY
Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA. pwen@partners.org
Yung
W K Alfred
WK
Lamborn
Kathleen R
KR
Dahia
Patricia L
PL
Wang
Yanfeng
Y
Peng
Bin
B
Abrey
Lauren E
LE
Raizer
Jeffrey
J
Cloughesy
Timothy F
TF
Fink
Karen
K
Gilbert
Mark
M
Chang
Susan
S
Junck
Larry
L
Schiff
David
D
Lieberman
Frank
F
Fine
Howard A
HA
Mehta
Minesh
M
Robins
H Ian
HI
DeAngelis
Lisa M
LM
Groves
Morris D
MD
Puduvalli
Vinay K
VK
Levin
Victor
V
Conrad
Charles
C
Maher
Elizabeth A
EA
Aldape
Kenneth
K
Hayes
Michael
M
Letvak
Laurie
L
Egorin
Merrill J
MJ
Capdeville
Renaud
R
Kaplan
Richard
R
Murgo
Anthony J
AJ
Stiles
Charles
C
Prados
Michael D
MD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate