Treatment > Temozolomide Clinical Trials

Meeting Abstract

Pilot study of oral continuous administration of low dose temozolomide in pediatric brain tumors

Darren Hargrave, Diana Stempak, Max Coppes, Albert Moghrabi, Janet Gammon, Angela Rodgers, Eric Bouffet, Gideon Koren, Jean Marie Leclerc, Sylvain Baruchel

Hospital for Sick Children, Toronto, ON, Canada; Alberta Children's Hospital, Calgary, AB, Canada; Sainte-Justine Hospital, Montreal, QC, Canada; Schering-Plough Canada, Montreal, QC, Canada

Temozolomide is an imidazotetrazine, in vivo it is spontaneously cleaved to MTIC. 
It is licensed in adults (PO qd x 5 days, every 4 weeks) for the treatment of anaplastic astrocytoma. 
This 5 day regimen has been unsuccessful in pediatric CNS tumors. 
Extended dosing (75 mg/m²/day PO qd for 6 weeks) has been studied in adults. 

Objectives. To determine the pediatric maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of temozolomide administered continuously as a 42 day cycle in children with recurrent CNS tumors. 

Design. Patients were stratified into heavily pre-treated or less heavily pre-treated groups and the starting doses for these groups were 50 mg/m² and 75 mg/m² daily x 42 days. 
Between cycles there was a 3 week rest. 

Results. 20 patients entered, 14 were evaluable (6 failed to complete cycle 1). 
Median age, 11.6 (range 5-18) years; 9 males, 11 females; total number of cycles received, 42 (range 1-9). 
Diagnosis: 4 brain stem glioma; 3 ependymoma; 4 PNET/medulloblastoma; 7 high grade glioma; 1 meningioma and 1 low grade glioma . 
Responses were documented in 3 patients: 1 CR (recurrent medulloblastoma post ABMT) NED, 15 months and 2 PRs (gliomatosis cerebri and gliosarcoma), 9 & 6 months. 
Stable disease was seen in 1 ependymoma, 21 months; 1 meningioma, 5 months and 1 high grade glioma, 5 months. 
Patient accrual is ongoing with additional patients receiving 65 mg/m² to confirm the MTD in the heavily pre-treated group. PK data (see Table 1). 
Results are comparable to adult PK data with a similar protocol. 
Additional PK data of patients heavily pre-treated treated with 65 mg/m² will be presented. 

Conclusion. These data confirm the possibility of administering continuous low doses of temozolomide. 
The DLT is thrombocytopenia at 100 mg/m² and the MTD in non heavily pre-treated patients is 75 mg/m². 
The response rate is extremely encouraging and warrants the development of this schedule into phase II.

Table 1: Results of Pharmacokinetic Data

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