The RIST design: A molecularly targeted multimodal approach for the treatment of patients with relapsed and refractory neuroblastoma.

Abstract

10017 Background: The prognosis for children with recurrent or refractory neuroblastoma (rNB) remains dismal. Novel therapeutic approaches are urgently needed. Methods: Based on promising in vitro data unselected patients with rNB were treated as compassionate use according to a multimodal approach (RIST design). The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). Twenty-one patients (median age: 38 months) with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1 st and 8 with 2 nd and 3 rd relapses were included. Seven patients presented within 18 months after diagnosis (median age: 28 months). 18 patients were MIBG positive, 4 MYCN amplified. Dissemination was present in the bone in 15, bone marrow in 11 and lymph nodes in 6 patients, respectively. Results: The patients received a median of 16 courses of R/S (4 to 72) and 7 courses of I/T (4 to 65). 19 patients (90%) showed an initial response according to imaging criteria after a median of 7 R/S and 4 I/T courses (median treatment duration 12 weeks): CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS after a median of 148 weeks was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities (CTC 3.0) were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively. Conclusions: This RIST treatment design applied as a multimodal approach in a compassionate use setting exhibited very promising results considering the adequately long follow-up period of 3 years. This molecular targeted therapy design for rNB warrants confirmation in a prospective clinical trial.