Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma

NCT04402073 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: 1634
• Study Type: interventional
• Target: 20
• Locations: 7 countries
• Sites: 40

Brief Summary

Medulloblastoma is a rare brain malignancy, mainly affecting children. Treatment of this rapidly growing tumor begins with maximal surgical removal plus radiation and chemotherapy. Treatment toxicity is high. Post-pubertal and pediatric medulloblastomas are biologically and prognostically different, which mandates age-adapted treatment strategies. Patients after puberty bear an intermediate to high prognostic risk. This means that a large number of these patients, are faced with death and/or disability (mainly neurocognitive). Therefore, the scientific and medical need is high. One of the genetic subgroups of medulloblastoma, the SHH-subgroup (Sonic HedgeHog- subgroup), is highly overrepresented in medulloblastoma patients after puberty. This subgroup can be treated with a targeted therapy. The investigators will therefore randomize patients and treat SHH-subgroup patients with sonidegib and a reduction of radiotherapy dose in the experimental arm of the trial. The hypothesis that this personalized risk-adapted therapy will improve outcomes in view of increased efficacy and decreased toxicity.

Conditions

Medulloblastoma

Keywords

brain; medullobalstoma; MRI; radiotherapy; biomarkers

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival

  compare progression-free survival (PFS) by central review of a personalized intensity-modulated therapy (experimental arm; sonidegib) vs. standard therapy in the SHH-activated subgroup in post-pubertal patients with newly diagnosed standard risk medulloblastoma.

  91 months after the date of recruitment of the first patient

Secondary Outcomes (5)

• Progression Free Survival (PFS)

  when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.

• overall survival (OV)

  when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.

• safety and tolerability profile: CTCAE

  when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.

• health-related quality of life (HRQoL)

  when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.

• overall survival

  when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.

Study Arms (2)

standard arms

OTHER

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.

Drug: Cisplatin; Drug: Lomustine; Drug: Vincristine; Radiation: radiotherapy

experimental arms

EXPERIMENTAL

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.

Drug: Sonidegib; Drug: Cisplatin; Drug: Lomustine; Drug: Vincristine; Radiation: radiotherapy

Interventions

Sonidegib DRUG

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.

experimental arms

Cisplatin DRUG

Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.

experimental arms; standard arms

Lomustine DRUG

Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.

experimental arms; standard arms

Vincristine DRUG

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.

experimental arms; standard arms

radiotherapy RADIATION

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; standard arms

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma (WNT M0-1, SHH M0-1 (p53wt), Group 4 M0-1)
• 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
• 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

You may not qualify if:

• Prior treatment for medulloblastoma
• 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.

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (50)

Royal Adelaide Hospital

Adelaide, Australia

Location

Princess Alexandra Hospital - University Of Queensland

Brisbane, Australia

Location

Austin Health - Austin hospital

Melbourne, Australia

Location

Peter Maccallum Cancer Institute

Melbourne, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Australia

Location

John Hunter Children's Hospital

New Lambton Heights, Australia

Location

Prince Of Wales Hospital

Sydney, Australia

Location

Royal North Shore Hospital

Sydney, Australia

Location

Sydney Children's Hospital

Sydney, Australia

Location

Westmead Hospital - Crown Princess Mary Cancer Center

Westmead, Australia

Location

A.O Landeskrankenhaus - Innsbruck Universitaetsklinik

Innsbruck, Austria

Location

AKH unikliniken

Vienna, Austria

Location

CHRU de Lille

Lille, France

Location

Centre Leon Berard

Lyon, France

Location

Hopital de La Timone (APHM)

Marseille, France

Location

CHU de Nice - Hopital Pasteur

Nice, France

Location

Hopital la Pitie-Salpetriere

Paris, France

Location

Institut de Cancerologie de l'Ouest (ICO) - Saint Herblain

Saint-Herblain, France

Location

CHU de Toulouse - Institut Claudius Regaud - IUCT oncopole

Toulouse, France

Location

Knappschaft Krankenhaus Langendreer

Bochum, Germany

Location

Universitaetsklinikum Bonn

Bonn, Germany

Location

Universitaetsklinikum Carl Gustav Carus

Dresden, Germany

Location

HELIOS Kliniken - HELIOS Klinikum Erfurt GmbH

Erfurt, Germany

Location

Universitaetsklinikum - Essen

Essen, 45147, Germany

Location

University Frankfurt - Goethe Univ. - University Hospital Frankfurt -Senckenberg Institute of Neurooncology

Frankfurt, Germany

Location

Universitaetsklinikum Freiburg - Klinik fuer Neurochirurgie

Freiburg im Breisgau, Germany

Location

Universitaetsmedizin Goettingen - Georg-August Universitaet

Goettigen, Germany

Location

Universitaets Krankenhaus Eppendorf - Universitaetsklinikum Hamburg-Eppendorf KE - University Cancer Center

Hamburg, Germany

Location

Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital

Heidelberg, Germany

Location

Universitaetsklinikum Leipzig-Klinik fuer Strahlentherapie und Radioonkologie

Leipzig, Germany

Location

Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center

Mainz, 55131, Germany

Location

UniversitaetsMedizin Mannheim

Mannheim, Germany

Location

Klinikum Rechts der isar Der Technische Universitaet Muenchen

Munich, Germany

Location

Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern

Munich, Germany

Location

Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg

Regensburg, 93053, Germany

Location

Universitaetsklinikum Tuebingen- Crona Kliniken

Tübingen, Germany

Location

AUSL Bologna - Ospedale Bellaria

Bologna, Italy

Location

Univ. of Florence -Azienda Ospedaliero-Universitaria Careggi

Florence, Italy

Location

IRCCS - Istituto Neurologico Carlo Besta

Milan, Italy

Location

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

Torino, Italy

Location

ULSS2 - Marca Trevigniana

Treviso, Italy

Location

Universitair Medisch Centrum Groningen

Groningen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol

Badalona, Spain

Location

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital Universitario 12 De Octubre

Madrid, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Spain

Location

Centre Hospitalier Universitaire Vaudois - Lausanne

Lausanne, Switzerland

Location

University Hospital zurich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Medulloblastoma

Interventions

sonidegib; Cisplatin; Lomustine; Vincristine; Radiotherapy

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Therapeutics

Study Officials

• Peter Hau

  EORTC study coordinator

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Phase II, comparative, randomized (experimental : standard arm 1:1, no blinding, no active or placebo control, parallel group, therapeutic

Study Record Dates

• First Submitted: April 1, 2020
• First Posted: May 26, 2020
• Study Start: November 11, 2022
• Primary Completion: June 16, 2025
• Study Completion: September 10, 2025
• Last Updated: October 23, 2025

Record last verified: 2025-10

Locations

IT (5); NL (2); AU (2); FR (7); ES (5); CH (2); DE (17)