Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma
NCT ID: NCT04402073
Last Updated: 2025-10-23
Study Results
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Basic Information
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TERMINATED
PHASE2
20 participants
INTERVENTIONAL
2022-11-11
2025-09-10
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
HEALTH_SERVICES_RESEARCH
NONE
Study Groups
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standard arms
Criteria: Adult SHH (p53wt) M0-1, adult WNT M0-1, adult Group 4 M0-1.
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
Criteria: Post pubertal \< 18 y SHH (p53wt) M0.
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.
Cisplatin
Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.
Lomustine
Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.
Vincristine
Vincristine sulfate (VCR) is an inhibitor of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Vincristine sulfate is indicated in acute leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. The application route is through the vein.
radiotherapy
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
experimental arms
Radiotherapy Criteria: Adult and post-pubertal SHH (p53wt) M0; adult WNT M0, adult Group 4 M0.
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.
SMO-inhibitor Criteria: Adult and post-pubertal SHH (p53wt) M0.
Sonidegib 200 mg/day (daily) from first day of radio-chemotherapy until end of maintenance chemotherapy, including 6w chemotherapy break.
Sonidegib
Sonidegib is a selective smoothened inhibitor that inhibits the sonic hedgehog-signaling pathway. It is used in patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
Cisplatin
Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.
Lomustine
Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.
Vincristine
Vincristine sulfate (VCR) is an inhibitor of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Vincristine sulfate is indicated in acute leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. The application route is through the vein.
radiotherapy
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
Interventions
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Sonidegib
Sonidegib is a selective smoothened inhibitor that inhibits the sonic hedgehog-signaling pathway. It is used in patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
Cisplatin
Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.
Lomustine
Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.
Vincristine
Vincristine sulfate (VCR) is an inhibitor of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Vincristine sulfate is indicated in acute leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. The application route is through the vein.
radiotherapy
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
Eligibility Criteria
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Inclusion Criteria
* Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1
* Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA)
* Adult (18 years and above): in WNT-activated and Group 4 medulloblastoma
* Post-pubertal, defined as females with a bone age of at least 15 years and males with a bone age of at least 17 years, or adult (greater than 18 y of age) (see appendix N) in SHH-activated and TP53-wildtype medulloblastoma
* Availability of prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
* Availability of paraffin embedded tumour tissue (FFPE) (1 block or 30 unstained slides) and whole blood sample (10 ml) for central review
* For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH, SUFU, BRCA2 and PALB2 if known before randomization
* Clinical status within 2 weeks of randomization: Karnofsky 50-100. NANO-score 0 to 9 (allowing full-blown cerebellar symptoms)
* Clinically standard-risk (centrally assessed MRI review) defined as: total or near total surgical resection with less than or equal to 1.5 cm2 (measured in axial plane) of residual tumour on early post-operative MRI, without and with contrast; no CNS metastasis on MRI (cranial and spinal); Chang stage M0-1 with no clinical evidence of extra-CNS metastasis
* Full recovery from surgery or any post-surgical complication (e.g. Bleeding, infections etc)
* Pre-surgery and/or post-surgery MRI available.
* Baseline brain MRI and spinal MRI available within 2 weeks of randomization.
* Normal liver, renal and haematological function within 2 weeks of randomization.
* WBC greater than or equal to 3×10\^9/L
* ANC greater than or equal to 1.5×10\^9/L
* Platelet count of greater than or equal to 100×10\^9/L independent of transfusion
* Hemoglobin greater than or equal to 10 g/dl
* Total Bilirubin less than or equal to 1.5 ULN
* ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) less than or equal to 2.5 × ULN
* Serum creatinine less than 1.5 x ULN or creatinine clearance (CrCl) greater than 30 mL/min (using the Cockcroft-Gault formula)
* Negative serum or urine pregnancy test within 7 days of randomization for WOCBP.
* Patients of childbearing / reproductive potential (WOCBP) must use two methods of adequate birth control, including a highly effective method and a barrier method during the study treatment period and for at least 20 months after the last study treatment is mandatory for the patients that received sonidegib, for all other patients this period is at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Male patients even those who have had a vasectomy must always use a condom during treatment and for 6 months after last treatment. Men should not donate semen during treatment and for at least 6 months after ending treatment (donation of semen for the semen analyses of the fertility project 1 b is allowed). Appendix H.
* Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 20 months after the last study treatment.
* Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. For patients less than 18 years of age, consent has to be obtained from the parent(s) or legal representative.
Exclusion Criteria
* Unavailability of central review pathology results.
* Inability to start radiotherapy within 43 days of surgery
* Significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing impairment greater than or equal to 20 dB at 1-3 kHz
* Any medical contraindication to radiotherapy or chemotherapy.
* Hypersensitivity to contrast medium for MRI.
* Hypersensitivity towards the active substance of any of study drugs or their excipients
* Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or statins
* Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
* Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score less than or equal to 6 and PSA less than 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance as per ESMO guidelines. Other cancers for which the subject has completed potentially curative treatment more than 5 years prior to diagnosis of medulloblastoma study entry are allowed
* Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV RNA \[qualitative\] is detected)
* Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive HIV-1/2 antibodies)
* Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
15 Years
ALL
No
Sponsors
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European Organisation for Research and Treatment of Cancer - EORTC
NETWORK
Responsible Party
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Principal Investigators
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Peter Hau
Role: PRINCIPAL_INVESTIGATOR
EORTC study coordinator
Locations
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Royal Adelaide Hospital
Adelaide, , Australia
Princess Alexandra Hospital - University Of Queensland
Brisbane, , Australia
Austin Health - Austin hospital
Melbourne, , Australia
Peter Maccallum Cancer Institute
Melbourne, , Australia
Sir Charles Gairdner Hospital
Nedlands, , Australia
John Hunter Children's Hospital
New Lambton Heights, , Australia
Prince Of Wales Hospital
Sydney, , Australia
Royal North Shore Hospital
Sydney, , Australia
Sydney Children's Hospital
Sydney, , Australia
Westmead Hospital - Crown Princess Mary Cancer Center
Westmead, , Australia
A.O Landeskrankenhaus - Innsbruck Universitaetsklinik
Innsbruck, , Austria
AKH unikliniken
Vienna, , Austria
CHRU de Lille
Lille, , France
Centre Leon Berard
Lyon, , France
Hopital de La Timone (APHM)
Marseille, , France
CHU de Nice - Hopital Pasteur
Nice, , France
Hopital la Pitie-Salpetriere
Paris, , France
Institut de Cancerologie de l'Ouest (ICO) - Saint Herblain
Saint-Herblain, , France
CHU de Toulouse - Institut Claudius Regaud - IUCT oncopole
Toulouse, , France
Knappschaft Krankenhaus Langendreer
Bochum, , Germany
Universitaetsklinikum Bonn
Bonn, , Germany
Universitaetsklinikum Carl Gustav Carus
Dresden, , Germany
HELIOS Kliniken - HELIOS Klinikum Erfurt GmbH
Erfurt, , Germany
Universitaetsklinikum - Essen
Essen, , Germany
University Frankfurt - Goethe Univ. - University Hospital Frankfurt -Senckenberg Institute of Neurooncology
Frankfurt, , Germany
Universitaetsklinikum Freiburg - Klinik fuer Neurochirurgie
Freiburg im Breisgau, , Germany
Universitaetsmedizin Goettingen - Georg-August Universitaet
Goettigen, , Germany
Universitaets Krankenhaus Eppendorf - Universitaetsklinikum Hamburg-Eppendorf KE - University Cancer Center
Hamburg, , Germany
Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital
Heidelberg, , Germany
Universitaetsklinikum Leipzig-Klinik fuer Strahlentherapie und Radioonkologie
Leipzig, , Germany
Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center
Mainz, , Germany
UniversitaetsMedizin Mannheim
Mannheim, , Germany
Klinikum Rechts der isar Der Technische Universitaet Muenchen
Munich, , Germany
Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern
Munich, , Germany
Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg
Regensburg, , Germany
Universitaetsklinikum Tuebingen- Crona Kliniken
Tübingen, , Germany
AUSL Bologna - Ospedale Bellaria
Bologna, , Italy
Univ. of Florence -Azienda Ospedaliero-Universitaria Careggi
Florence, , Italy
IRCCS - Istituto Neurologico Carlo Besta
Milan, , Italy
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
Torino, , Italy
ULSS2 - Marca Trevigniana
Treviso, , Italy
Universitair Medisch Centrum Groningen
Groningen, , Netherlands
Erasmus MC
Rotterdam, , Netherlands
Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol
Badalona, , Spain
Hospital Clinic de Barcelona
Barcelona, , Spain
Hospital Universitari Vall d'Hebron
Barcelona, , Spain
Hospital Universitario 12 De Octubre
Madrid, , Spain
Hospital Universitario Ramon y Cajal
Madrid, , Spain
Centre Hospitalier Universitaire Vaudois - Lausanne
Lausanne, , Switzerland
University Hospital zurich
Zurich, , Switzerland
Countries
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Other Identifiers
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1634
Identifier Type: -
Identifier Source: org_study_id
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