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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
Author(s) -
Le Teuff Gwénaël,
CastanedaHeredia Alicia,
Dufour Christelle,
Jaspan Timothy,
Calmon Raphael,
Devos Annick,
McHugh Kieran,
Leblond Pierre,
Frappaz Didier,
Aerts Isabelle,
Zwaan Christian M.,
Ducassou Stéphane,
Chastagner Pascal,
Verschuur Arnauld,
Corradini Nadège,
Casanova Michela,
Rubie Hervé,
Riccardi Riccardo,
Le Deley MarieCecile,
Vassal Gilles,
Geoerger Birgit
Publication year - 2020
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.28032
Subject(s) - medicine , medulloblastoma , topotecan , temozolomide , post hoc analysis , oncology , cohort , refractory (planetary science) , glioma , pathology , radiation therapy , chemotherapy , cancer research , physics , astrobiology
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.