Treatment > Temozolomide Clinical Trials

Meeting Abstract

Phase I study of temozolomide in pediatric patients with advanced cancer

S Ablett, V Batra, M Dugan, EJ Estlin, R Gowing, J Kohler, L Lashford, I Lewis, H MacDowell, B Moreland, AD Pearson, CR Pinkerton, L Price, P Reidenberg, P Statkevich, D Walker

The alkylating agent temozolomide (T) is an imidazotetrazine derivative undergoing chemical conversion to the active
methylating MTIC.
Aim of this multicenter Phase I trial was to determine MTD, DLT and pharmacokinetics (PK) of T, when given po, once a day (d) for 5 d, to pediatric patients (pts) with advanced cancer.
Pts were stratified according to whether (Arm A) or not (Arm B) they had prior nitrosoureas or spinal irradiation.
PK was done on d 5 of C 1.
Cycles were repeated every 28 d for up to 13 courses.
Starting dose of T was 500 mg/m2 escalated to 600, 800, 1000 and 1200 mg/m2 (tot dose over 5 d) until DLT.
To date, 26 pts have been enrolled (20 evaluable) and received 59 courses: 6 evaluable pts in Arm A (3M/3F; median age 8 yr); Tumors: primitive neoectodermal tumor (5) ependymoma (1); 14 evaluable pts in Arm B (5M/9F; median age 9 yr); Tumors:brain stem glioma (8), high grade astrocytoma (HGA) (3), hemangiopericytoma (1), osteogenic sarcoma (1) and pancreatic neuro endocrine (1).
Dose escalation of T is up to 600 mg/m2 for Arm A (no DLT) and up to 1200 mg/m2 in Arm B: CTC Gr4 thrombocytopenia was DLT in 1 pt at 1000 and 1 pt at 1200 mg/m2.
In Arm B: 5/14 pts have responded (PR/SD) after 2 courses (persisted for 3-16 mo) CR was observed in 1 pt (HGA) after 10 courses.
4/14 pts (2 brain stem glioma and 2 HGA) have completed 26 cycles of T.
Pts in Arm A have all progressed.
PK results have been analyzed for 12 pts at 500 (5 pts), 800 (3 pts) and 1000 (4 pts) mg/m2 of T and indicates that T is rapidly absorbed (Tmax approx 0.33-3 hr) and eliminated (t1/2 approx 1.7 hr).
AUC increased proportionately with dose with no evidence of accumulation.
In summary, T, a new agent with dose-limiting thrombocytopenia, has shown activity especially in childhood HGA.
Further evaluation of T in the pediatric pts is warranted.

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