Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma.
BACKGROUND
The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG).


METHODS
Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum.


RESULTS
CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks.


CONCLUSIONS
The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.
Reardon
David A
DA
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. reard003@mc.duke.edu
Quinn
Jennifer A
JA
Rich
Jeremy N
JN
Desjardins
Annick
A
Vredenburgh
James
J
Gururangan
Sridharan
S
Sathornsumetee
Sith
S
Badruddoja
Michael
M
McLendon
Roger
R
Provenzale
James
J
Herndon
James E
JE
Dowell
Jeannette M
JM
Burkart
Jill L
JL
Newton
Herbert B
HB
Friedman
Allan H
AH
Friedman
Henry S
HS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D000077146:Irinotecan; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D016879:Salvage Therapy; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide