Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08).
Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.
Wen
Patrick Y
PY
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, SW430D, 44 Binney St., Boston, MA 02115, USA. pwen@partners.org
Yung
W K Alfred
WK
Lamborn
Kathleen R
KR
Norden
Andrew D
AD
Cloughesy
Timothy F
TF
Abrey
Lauren E
LE
Fine
Howard A
HA
Chang
Susan M
SM
Robins
H Ian
HI
Fink
Karen
K
Deangelis
Lisa M
LM
Mehta
Minesh
M
Di Tomaso
Emmanuelle
E
Drappatz
Jan
J
Kesari
Santosh
S
Ligon
Keith L
KL
Aldape
Ken
K
Jain
Rakesh K
RK
Stiles
Charles D
CD
Egorin
Merrill J
MJ
Prados
Michael D
MD
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy*; D009367:Neoplasm Staging; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta