Phase II study of the combination of cisplatin + temozolomide in malignant glial tumours in children and adolescents at diagnosis or in relapse (cistem2/nct00147160)

Abstract

9543 Background: Temozolomide has been shown moderately effective in pediatric high-grade glioma (HGG). By decreasing the activity of MGMT, principal mechanism of resistance to temozolomide, cisplatin may increase the activity of this alkylating agent. Methods: Patients aged 4 to 21y with HGG outside the brainstem were treated at diagnosis or at relapse every 28 days with a combination of cisplatin 80 mg/m2 intravenously on day-1 and temozolomide 200 mg/m2 orally on days 2–6, according to the pediatric phase I recommendations. Patients treated at diagnosis had to proceed to involved field radiotherapy after the chemotherapy window. According to initial response, patients were offered additional courses, up to seven. We considered that this combination would be of interest if the response rate was superior or equal to 20%, using a two-stage Simon design in 3 cohorts: evaluable non measurable (infiltrative) at diagnosis (cohort A1); measurable disease (nodular) at diagnosis (A2); recurrent disease (B). The primary endpoint was complete or partial response after two courses, confirmed by central review. Up to 29 evaluable pts were to be entered in each cohort. If fewer than 4/29 responses were observed, it would be concluded that the combination is ineffective. Results: 56 pts were entered from 10/2003 through 07/2006 in 25 centers. One was excluded after central pathology review and 3 due to insufficient radiology work-out. 42 had grade III and 13 grade IV gliomas, including 21 tumors with oligodendroglial features. No response was observed in the first 11 pts in cohort A1 and in the first 12 pts in cohort B. Two partial and 4 minor responses were confirmed in 29 pts of cohort A2 leading to a 7% response rate (95% CI, 1–23%). Median time to progression was 1.7, 7.1 and 6.9 months in cohorts A1, A2 and B, respectively. Toxicity was manageable except in pts with large infiltrative lesions who did not tolerate hydration. Conclusion: CISTEM combination has insufficient efficacy in pediatric compared to adult HGG despite efficient down-regulation of MGMT activity. To overcome resistance to temozolomide in children and adolescents, one may need to target other known resistance mechanisms such as mismatch-repair deficiency. [Table: see text]