Phase II single-arm study of irinotecan in combination with temozolomide in children with recurrent or refractory medulloblastoma

Abstract

10018 Background: Irinotecan and temozolomide have demonstrated moderate single agent activity in childhood medulloblastoma (MB). Using the recommended dose established from a prior pediatric phase I study, the combination of irinotecan and temozolomide was investigated in relapsed MB. Methods: Patients aged 6 months to 18 years with radiological measurable relapsed/refractory MB were treated with temozolomide 100–125 mg/m2/day on days 1–5 orally and irinotecan 10 mg/m2/day on days 1–5 and days 8–12 intravenously. After cycle 5, patients who did not progress could receive irinotecan 125 mg/m2 once weekly on days 1 and 8 of the 3-week cycle. The primary objective was confirmed tumor response (partial or complete) after 4 cycles of treatment. According to a two-stage Optimum Simon design, at least 6 of the first 15 evaluable subjects were to have a confirmed objective response, to proceed to stage 2; a total of 19 responses in 46 subjects are required for success. A central radiological review determined tumor response in all patients. Results: Preliminary results are reported on 33 patients entered from May 2007 through to November 2008 in 19 treatment centers. The median age was 9 years (range 2 to 17 years); 23 male and 10 female. The number of relapsed patients with M3:M2:M1:M0 (Chang M stage) were 10:15:2:6, and 17 had more than 1 prior therapy. Previous treatment included chemotherapy, 7 with high-dose regimens, and craniospinal (CSI) (n=30) or posterior fossa irradiation (n=2). Central radiological review is ongoing: 16/26 reviewed patients were evaluable for response. Six patients had confirmed PR, 3 had SD, and 7 had PD. To date, 10 patients have been excluded after central review (8, poor imaging; 2, no measurable disease). Toxicity has been manageable with dose reduction required in 11/33 MB patients, all of these had received prior CSI. The study is ongoing in stage 2 and centrally verified results will be reported at the Meeting. Conclusions: This multi-centre international study is the largest phase II trial of the irinotecan and temozolomide combination in pediatric central nervous system tumors. The activity of the combination in heavily pre-treated recurrent MB patients is promising. [Table: see text]