Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report.
OBJECTIVE
To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O(6)-benzylguanine in patients < or =21 years with recurrent brain tumors.


METHODS
Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.v. administration of O(6)-benzylguanine at 120 mg/m(2) was followed by 48-h continuous infusion at 30 mg/m(2)/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628, and 835 mg/m(2)) was given at least 6 h after completion of O(6)-benzylguanine bolus. Treatment was repeated after recovery from toxicities at least 4 weeks apart for a maximum of 12 courses. Dose escalation followed the modified continual reassessment method. Pharmacokinetic analyses of temozolomide and 5-triazeno imidazole carboxamide (MTIC) were done in 28 patients.


RESULTS
A total of 44 and 26 eligible patients were enrolled on Str1 and Str2, respectively. Median age at study entry in each stratum was 8.6 and 11.3 years, respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and Str2 were 562 and 407 mg/m(2), respectively, the doses recommended for phase II investigations are 472 and 355 mg/m(2), respectively. DLTs were predominantly neutropenia and thrombocytopenia. Three patients with gliomas experienced centrally confirmed partial responses to therapy. Four patients completed all planned therapy. Temozolomide and MTIC exposures were statistically associated with temozolomide dosage.


CONCLUSIONS
The current schedule of temozolomide and O(6)-benzylguanine is safe and showed modest activity against recurrent brain tumors in children.
Broniscer
Alberto
A
Department of Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. alberto.broniscer@stjude.org
Gururangan
Sridharan
S
MacDonald
Tobey J
TJ
Goldman
Stewart
S
Packer
Roger J
RJ
Stewart
Clinton F
CF
Wallace
Dana
D
Danks
Mary K
MK
Friedman
Henry S
HS
Poussaint
Tina Y
TY
Kun
Larry E
LE
Boyett
James M
JM
Gajjar
Amar
A
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007223:Infant; D008297:Male; D000077204:Temozolomide; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide