9517 Background: Temozolomide and topotecan have shown activity in several pediatric cancers, including neuroblastoma. Resistance to alkylating agents due to MGMT expression, MMR deficiency or microsatellite instability may be overcome through the combination with topoisomerase I inhibitors. The combination of temozolomide and topotecan (TOTEM) was well tolerated and showed preliminary activity in children with neuroblastoma and glioma (Rubie et al, 2010). Methods: This multicenter, non-randomized, multi-cohort Phase II study included children with neuroblastoma according to a 2-stage Simon design, and patients with central nervous system (CNS) and extra-cranial solid tumors in a descriptive design. Temozolomide was administered orally at 150 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously for 5 consecutive days every 28 days. The main endpoint was objective response (OR), i.e., Complete or Partial Response (CR+PR), evaluated after 2 cycles according to WHO criteria, or INRC criteria for neuroblastoma patients with mIBG-positive lesions, by an independent radiological review. Independent review of mIBG imaging is pending. Results: 103 patients, median age 9.4 years (range 1-21), were treated between June 2009 and May 2011 in 18 centers: 38 neuroblastoma, 33 CNS tumors and 32 other solid tumors. Overall 420 cycles were administered (median 3 per patient; range 1-12). Grade 3 or 4 neutropenia was frequent (55% courses), though only 6% of patients developed febrile neutropenia. In the neuroblastoma cohort, 1 CR and 7 PR were observed, leading to an estimated OR rate of 21% (95%CI, 10-37%). Additionally 22 patients had disease stabilization (SD), leading to an overall tumor control (CR+PR+SD) of 79% (63-90%), and a 12-month progression-free survival rate of 47% (31-64%). Overall, 17/102 evaluable patients achieved an OR (17%, 10-25%), with 1 CR and 3 PR in 9 medulloblastoma (44%, 14-79%), 2 PR in 4 PNET, 1 PR in 12 malignant glioma, and 2 PR in 9 RMS. Conclusions: Temozolomide-topotecan combination results in significant tumor control in children with neuroblastoma and medulloblastoma/PNET with favorable toxicity profile.
