IMPORTANCE: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. OBJECTIVE: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. INTERVENTIONS: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. MAIN OUTCOMES AND MEASURES: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. RESULTS: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. CONCLUSIONS AND RELEVANCE: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01356290.

Aix Marseille University Cancer Research Center of Marseille Marseille France

Centre Léon Bérard Institut d'Hématologie et d'Oncologie Pediatrique Lyon France

Childhood Cancer Centre Queen Silvia Children's Hospital Sahlgrenska University Hospital Gothenburg Sweden

Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Division of Neuroradiology and Musculoskeletal Radiology Medical University of Vienna Vienna Austria

Department of Neurology Medical University of Vienna Vienna Austria

Department of Paediatric and Adolescent Medicine Haukeland University Hospital Bergen Norway

Department of Paediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Paediatrics Linköping University Hospital Linköping Sweden

Department of Pediatric Hematology and Oncology Karolinska University Hospital Stockholm Sweden

Department of Pediatric Neuro Oncology Dana Farber Cancer Institute Boston Massachusetts

Department of Pediatric Neuro Oncology Hospital Infantil Universitario Niño Jesús Madrid Spain

Départment of Pediatric Oncology Assistance Publique Hopitaux de Marseille Marseille France

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Department of Pediatrics Uppsala University Uppsala Sweden

Department of Radio Oncology Medical University of Vienna Vienna Austria

Division of Pediatric Hemato Oncology Department of Pediatrics and Adolescent Medicine Medical University of Graz Graz Austria

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Kinderonkologie Salzburger Universitätsklinikum Salzburg Austria

Pediatric Cancer Center Skane University Hospital Lund Sweden

Pediatric Oncology Department University Hospital Brno Brno Czech Republic

Pediatric Oncology Unit Oscar Lambret Comprehensive Cancer Center Lille France

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

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Individualized therapeutic approaches for relapsed and refractory pediatric ependymomas: a single institution experience

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ClinicalTrials.gov
NCT01356290