Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.

PURPOSE: To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma. PATIENTS AND METHODS: This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently. RESULTS: Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia. CONCLUSION: Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.

Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study.

AIM: To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours. METHODS: This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra-cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m(2) over 100 min followed by oxaliplatin at 100mg/m(2) over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria. RESULTS: Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non-CNS solid tumours. Median age was 11.7 years (range, 1.3-20.8 years). Tumour control (CR+PR+SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9-42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1-24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia). CONCLUDING STATEMENT: The gemcitabine-oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours.