Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study. Pediatric blood & cancer

Gwénaël Le Teuff, Alicia Castaneda-Heredia, Christelle Dufour, Timothy Jaspan, Raphael Calmon, Annick Devos, Kieran McHugh, Pierre Leblond, Didier Frappaz, Isabelle Aerts, Christian M. Zwaan, Stéphane Ducassou, Pascal Chastagner, Arnauld Verschuur, Nadège Corradini, Michela Casanova, Hervé Rubie, Riccardo Riccardi, Marie-Cecile Le Deley, Gilles VassalBirgit Geoerger

Research output: Contribution to journalArticlepeer-review

Abstract

AIM: To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET). PROCEDURE: Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one-stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m(2) /day followed by topotecan at 0.75 mg/m(2) /day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently. RESULTS: Thirty-two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9-20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7-47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3-44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment-related toxicities of the combination therapy were hematologic. CONCLUSIONS: Temozolomide-topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.
Original languageEnglish
Pages (from-to)e28032
JournalPediatric Blood and Cancer
Volume67
Issue number1
DOIs
Publication statusPublished - 2020

Keywords

  • Adult
  • Female
  • Humans
  • Male
  • Child
  • Child, Preschool
  • Follow-Up Studies
  • Infant
  • Survival Rate
  • Adolescent
  • Prognosis
  • Young Adult
  • Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
  • *Salvage Therapy
  • Drug Resistance, Neoplasm/*drug effects
  • Neoplasm Recurrence, Local/*drug therapy/pathology
  • Bayes Theorem
  • *Bayesian analysis
  • *medulloblastoma
  • *pediatric solid tumors
  • *temozolomide
  • *topotecan
  • Central Nervous System Neoplasms/*drug therapy/pathology
  • Cerebellar Neoplasms/drug therapy/pathology
  • Medulloblastoma/*drug therapy/pathology
  • Neuroectodermal Tumors, Primitive/*drug therapy/pathology
  • Temozolomide/administration & dosage
  • Topotecan/administration & dosage

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