Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.
OBJECTIVE
To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma.


METHODS
Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed.


RESULTS
Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease.


CONCLUSIONS
We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.
Reardon
David A
DA
AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA. reard003@mc.duke.edu
Quinn
Jennifer A
JA
Vredenburgh
James J
JJ
Gururangan
Sridharan
S
Friedman
Allan H
AH
Desjardins
Annick
A
Sathornsumetee
Sith
S
Herndon
James E
JE
Dowell
Jeannette M
JM
McLendon
Roger E
RE
Provenzale
James M
JM
Sampson
John H
JH
Smith
Robert P
RP
Swaisland
Alan J
AJ
Ochs
Judith S
JS
Lyons
Peggy
P
Tourt-Uhlig
Sandy
S
Bigner
Darell D
DD
Friedman
Henry S
HS
Rich
Jeremy N
JN
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000077156:Gefitinib; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage*; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077156:Gefitinib; D020123:Sirolimus