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International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

Primary Purpose

Brain Tumors

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Radiotherapy without Carboplatin
Reduced-intensity maintenance chemotherapy
Radiotherapy with Carboplatin
Maintenance chemotherapy
WNT-HR < 16 years
WNT-HR >= 16 years
Induction Chemotherapy
SHH-TP53 M0
SHH-TP53 M+ (germline)
SHH-TP53 (somatic)
Vinblastin Maintenance
Sponsored by
Universitätsklinikum Hamburg-Eppendorf
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain Tumors focused on measuring pediatric brain tumor, medulloblastoma, event-free survival (EFS), progression-free survival (PFS), overall survival (OS), PNET, posterior fossa, chemotherapy, radiotherapy, biological profile, ß-catenin

Eligibility Criteria

3 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years (LR-arm: less than 16 years). The date of diagnosis is the date on which surgery is undertaken.
  2. Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007): classic medulloblastoma, desmoplastic/nodular medulloblastoma. Pre-treatment central pathology review is considered mandatory.
  3. Standard-risk medulloblastoma, defined as;

    • total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumour on early post-operative MRI, without and with contrast, on central review;
    • no central nervous system (CNS) metastasis on MRI (cranial and spinal) on central review;
    • no tumour cells on the cytospin of lumbar CSF
    • no clinical evidence of extra-CNS metastasis; Patients with a reduction of postoperative residual tumor through second surgery to less than or equal to 1.5 cm2 are eligible, if if timeline for start of radiotherapy can be kept.
  4. Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of myelocytomatosis oncogene (MYC) copy number status) in national biological reference centers. Submission of blood is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended.
  5. No amplification of MYC or MYCN (determined by FISH).
  6. For LR-arm: Low-risk biological profile, defined as WNT subgroup positivity. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).

    For SR-arm: average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC (mandatory) and mutation analysis (optional).

  7. No prior therapy for medulloblastoma other than surgery.
  8. Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study.
  9. Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy.
  10. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function
  11. no significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing no impairment ≥ 20 decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit.
  12. No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome or other reasons as defined by patient's clinician.
  13. No identified Turcot and Li Fraumeni syndrome.
  14. Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation.
  15. National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).

Exclusion Criteria:

  1. One of the inclusion criteria is lacking.
  2. Brainstem or supratentorial primitive neuro-ectodermal tumour.
  3. Atypical teratoid rhabdoid tumour.
  4. Medulloepithelioma; Ependymoblastoma
  5. Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), centrally confirmed.
  6. Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or MYC or MYCN or WNT subgroup status not determinable.
  7. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF).
  8. Patient previously treated for a brain tumour or any type of malignant disease.
  9. DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin,Turcot, or Li Fraumeni syndrome.
  10. Patients who are pregnant.
  11. Female patients who are sexually active and not taking reliable contraception.
  12. Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons.
  13. Patients in whom non-compliance with toxicity management guidelines can be expected.

Sites / Locations

  • Medical University of Graz
  • University Hospital Gasthuisberg
  • University Hospital Brno
  • Rigshospitalet
  • CHU de Grenoble
  • Institute Curie
  • CHU-TOURS - Hôpital Clocheville
  • Hôpital NANCY-BRABOIS
  • University Hospital Aachen
  • Klinikum Augsburg
  • Helios Klinikum Berlin-Buch
  • Charite Campus, University of Berlin
  • Evangelisches Krankenhaus Bielefeld
  • University Hospital Bonn
  • Klinikum Braunschweig
  • Klinikum Bremen-Mitte
  • Klinikum Chemnitz
  • University Hospital Cologne
  • Carl-Thiem-Klinikum Cottbus
  • Vestische Kinder- und Jugendklinik, University Witten/Herdecke
  • Klinikum Dortmund
  • University Hospital Dresden
  • Klinikum Duisburg
  • University Hospital Düsseldorf
  • HELIOS Klinikum-Erfurt
  • University Hospital Erlangen
  • University Hospital Essen
  • University Hospital Frankfurt/Main
  • University Hospital Freiburg
  • University Hospital Gießen and Marburg
  • University Hospital Greifswald
  • University Hospital Göttingen
  • University Hospital Halle/Saale
  • University Medical Center Hamburg-Eppendorf
  • Medizinische Hochschule Hannover
  • Angelika-Lautenschläger-Klinik
  • Gemeinschaftskrankenhaus Herdecke
  • University Hospital Homburg/Saar
  • University Hospital Jena
  • Städtisches Klinikum Karlsruhe
  • Klinikum Kassel
  • UK-SH Campus Kiel
  • Gemeinschaftsklinikum Koblenz-Mayen
  • HELIOS Klinikum Krefeld
  • Kliniken der Stadt Köln
  • University Hospital Leipzig
  • University Hospital Lübeck
  • University Hospital Magdeburg
  • University Hospital Mainz
  • University Hospital Mannheim
  • Johannes Wesling Klinikum Minden
  • University Hospital München, Dr. von Haunersches Kinderspital
  • Klinikum Schwabing, Pediatric Hospital of Technical University
  • University Hospital Münster
  • Cnopf'sche Kinderklinik
  • Klinikum Oldenburg
  • University Hospital Regensburg
  • University Hospital Rostock
  • Asklepios Klinik Sankt Augustin
  • HELIOS-Kliniken Schwerin
  • Klinikum Stuttgart
  • Mutterhaus der Borromäerinnen
  • University Hospital Tübingen
  • University Hospital Ulm
  • Dr. Horst Schmidt Kliniken
  • Klinikum der Stadt Wolfsburg
  • University Hospital Würzburg
  • Our Lady's Children's Hospital
  • Fondazione IRCCS Istituto Nazionale Tumori
  • Prinses Máxima Center for Pediatric Oncology
  • Rigshospitalet
  • The Children's Memorial Health Institute
  • University Hospital S.Joao
  • Oncology Hospital Cruces Bilbao
  • Barncancercentrum Drottning Silvias Barnochungdomssjukhus
  • University Children's Hospital
  • Great Ormond Street Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

PNET 5 MB-LR (low-risk)

PNET 5 MB-SR (standard-risk)

PNET 5 MB WNT-HR

PNET 5 MB SHH-TP53

Arm Description

Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.

Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks.

Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks.

Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to presence of metastasis germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year

Outcomes

Primary Outcome Measures

3-year Event-Free Survival (EFS)

Secondary Outcome Measures

Overall survival
Pattern of relapse
Defined in 5 categorical variables: no relapse, local relapse, distant relapse, local and distant relapse, death
Late effects of therapy on endocrine function
measured as subfertility (FSH > 15 IU/L) endocrine deficits (hormone supplementation necessary) growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 years
Late effects of therapy on audiology
measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)
Late effects of therapy on neurology
Measured as presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively) presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy) cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years) presence of symptoms for brain nerve dysfunction (2 and 5 years after diagnosis and age of 18 years)
Late effects of therapy on quality of survival
measured with standardized questionnaires/ scores: HUI3 (health status) BRIEF (executive functions) SDQ (behavioural outcome) PedsQL (quality of life) QLQ-C30 (quality of life) MEES (neurological function, educational provision) MFI (fatigue) 2 and 5 years after diagnosis and age of 18 years
Progression-free survival
Feasibility of carboplatin treatment
measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy
Residual tumor
measured by central MRI review postoperatively
Leukoencephalopathy grading
measured 2 years after diagnosis grades 0, 1, 2, 3, 4

Full Information

First Posted
February 7, 2014
Last Updated
April 11, 2022
Sponsor
Universitätsklinikum Hamburg-Eppendorf
Collaborators
Deutsche Kinderkrebsstiftung
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1. Study Identification

Unique Protocol Identification Number
NCT02066220
Brief Title
International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
Official Title
AN INTERNATIONAL PROSPECTIVE TRIAL ON MEDULLOBLASTOMA (MB) IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH WNT BIOLOGICAL PROFILE (PNET 5 MB - LR and PNET 5 MB - WNT-HR), AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR), OR TP53 MUTATION, AND REGISTRY FOR MB OCCURRING IN THE CONTEXT OF GENETIC PREDISPOSITION
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 2014 (undefined)
Primary Completion Date
December 2026 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitätsklinikum Hamburg-Eppendorf
Collaborators
Deutsche Kinderkrebsstiftung

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study PNET 5 MB has been designed for children with medulloblastoma of standard risk (according to the risk-group definitions which have been used so far; e.g. in PNET 4). With the advent of biological parameters for stratification into clinical medulloblastoma trials, the ß-catenin status will be the only criterion according to which study patients will be assigned to either treatment arm PNET 5 MB - LR or to PNET 5 MB - SR, respectively. The initial diagnostic assessments (imaging, staging, histology, and tumor biology) required for study entry are the same for both treatment arms. With the amendment for version 12 of the protocol, patients who have a WNT-activated medulloblastoma with clinically high-risk features can be included in the PNET 5 MB WNT-HR study, and patients with a high-risk SHH medulloblastoma with TP53 mutation (both somatic or germline including mosaicism) can be included in the PNET5 MB SHH-TP53 study. Data on patients with pathogenic germline alteration or cancer predisposition syndrome, who cannot be included in any prospective trial due to unavailability or due to physician or family decision, can be documented within the observational PNET 5 MB registry.
Detailed Description
The aim of the LR-study is to confirm the high rate of event-free survival in patients between the ages of 3 to 5 years and less than 22, with 'standard risk' medulloblastoma with a low-risk biological profile. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and low-risk biological profile, defined as ß-catenin nuclear immuno-positivity by immuno-histochemistry (IHC). Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 18.0 Gy to the craniospinal axis. Following radiotherapy, patients will receive a reduced-intensity chemotherapy with a total of 6 cycles of chemotherapy consisting of 3 courses of cisplatin, CCNU and vincristine alternating with 3 courses of cyclophosphamide and vincristine. The aim of the SR-study is to test whether concurrent carboplatin during radiotherapy followed by 8 cycles of maintenance chemotherapy in patients with 'standard risk' medulloblastoma with an average-risk biological profile may improve outcome. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC. Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 23.4 Gy to the craniospinal axis. Following radiotherapy, patients will receive a modified-intensity chemotherapy with a total of 8 cycles of chemotherapy consisting of 4 courses of cisplatin, CCNU and vincristine alternating with 4 courses of cyclophosphamide and vincristine. The primary aim of the WNT-HR study is to maintain a 3-year EFS over 80 %. The small number of patients does not allow neither conventional methods of test size and power, nor strict stopping rules. The 3-year EFS will be estimated by the Kaplan-Meier method at the end of the trial and its two-sided 95 % confidence interval will be calculated. The primary endpoint of the SHH-TP53 study is event-free survival (EFS). The aim of the study is the comparison of EFS between patients receiving a dose reduced induction chemotherapy, radiotherapy and maintenance chemotherapy and a historic population from unpublished data.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Tumors
Keywords
pediatric brain tumor, medulloblastoma, event-free survival (EFS), progression-free survival (PFS), overall survival (OS), PNET, posterior fossa, chemotherapy, radiotherapy, biological profile, ß-catenin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
360 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PNET 5 MB-LR (low-risk)
Arm Type
Experimental
Arm Description
Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.
Arm Title
PNET 5 MB-SR (standard-risk)
Arm Type
Experimental
Arm Description
Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks.
Arm Title
PNET 5 MB WNT-HR
Arm Type
Experimental
Arm Description
Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks.
Arm Title
PNET 5 MB SHH-TP53
Arm Type
Experimental
Arm Description
Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to presence of metastasis germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy without Carboplatin
Intervention Description
Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks LR Arm after Amendment (Protocol version 11- 17 Nov 2014): Brain - 18.0 Gy in 10 daily fractions of 1.80 Gy Spine - 18.0 Gy in 10 daily fractions of 1.80 Gy Primary tumour boost - 36.0 Gy in 20 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks
Intervention Type
Drug
Intervention Name(s)
Reduced-intensity maintenance chemotherapy
Other Intervention Name(s)
Cisplatin, Lomustin (CCNU), Vincristine, Cyclophosphamide
Intervention Description
Starts 6 weeks after radiotherapy. 6 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15, Regimen B: (cycles 2, 4, 6): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1. Interval after cycle A: 6 weeks, after cycle B: 3 weeks, for a total duration of 27 weeks. Cumulative doses of chemotherapy drugs: cisplatin 210 mg/m2, lomustine (CCNU) 225 mg/m2, vincristine 18 mg/m2, cyclophosphamide 6 g/m2.
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy with Carboplatin
Other Intervention Name(s)
Carboplatin
Intervention Description
Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 G Carboplatin 35 mg/m2 5 times/week.
Intervention Type
Drug
Intervention Name(s)
Maintenance chemotherapy
Other Intervention Name(s)
Cisplatin, Lomustine (CCNU), Vincristine, Cyclophosphamide
Intervention Description
Starts 6 weeks after radiotherapy. 8 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5, 7): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15 Regimen B: (cycles 2, 4, 6, 8): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1. Interval after cycle A: 6 weeks, after cycle B: 3 weeks. Duration 36 weeks. Cumulative doses of chemotherapy drugs: cisplatin 280 mg/m2, lomustine (CCNU) 300 mg/m2, vincristine 24 mg/m2, cyclophosphamide 8 g/m2, carboplatin 1050 mg/m2 (in randomized patients).
Intervention Type
Radiation
Intervention Name(s)
WNT-HR < 16 years
Intervention Description
Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Boost to macroscopic metastases - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy
Intervention Type
Radiation
Intervention Name(s)
WNT-HR >= 16 years
Intervention Description
Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 14.4 Gy in 8 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 50.4 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy
Intervention Type
Drug
Intervention Name(s)
Induction Chemotherapy
Intervention Description
Doxorubicin 37,5mg/m² in 24h-infusion, days 1 and 2 (If administration of doxorubicin is not deemed appropriate, doxorubicin can be substituted by carboplatin 200mg/m²) VCR 1,5mg/m² (max. dose 2mg) in short infusion, days 1, 15, 29, 43 HD-MTX 5g/m²in two doses (0.5g/m² in 0.5h and 4.5g/m² in 23.5h), days 15 and 29 (+ Leucovorin) Carboplatin 200mg/m² in 1h-infusion, days 43, 44, and 45 MTX 2mg intraventricularly, days 1-4, 15, 16, 29, 30, 43-46
Intervention Type
Radiation
Intervention Name(s)
SHH-TP53 M0
Intervention Description
with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks clinical target volume (CTV): safety margin along typical spread 10 mm: 23.4.Gy in 13 fractions to CTV. focal RT boost to tumour bed and residual tumour (GTV) (boost: 30.6 Gy in 17 daily fractions of 1.8 Gy)
Intervention Type
Radiation
Intervention Name(s)
SHH-TP53 M+ (germline)
Intervention Description
craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (cranial) - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (spinal) - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy
Intervention Type
Radiation
Intervention Name(s)
SHH-TP53 (somatic)
Intervention Description
craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45 Gy in 25 daily fractions of 1.80 Gy
Intervention Type
Drug
Intervention Name(s)
Vinblastin Maintenance
Intervention Description
Weekly VBL (5mg/m², max. 10mg/dose) for 24 weeks
Primary Outcome Measure Information:
Title
3-year Event-Free Survival (EFS)
Time Frame
LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)
Secondary Outcome Measure Information:
Title
Overall survival
Time Frame
10 years
Title
Pattern of relapse
Description
Defined in 5 categorical variables: no relapse, local relapse, distant relapse, local and distant relapse, death
Time Frame
10 years
Title
Late effects of therapy on endocrine function
Description
measured as subfertility (FSH > 15 IU/L) endocrine deficits (hormone supplementation necessary) growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 years
Time Frame
10 years
Title
Late effects of therapy on audiology
Description
measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)
Time Frame
8 years
Title
Late effects of therapy on neurology
Description
Measured as presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively) presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy) cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years) presence of symptoms for brain nerve dysfunction (2 and 5 years after diagnosis and age of 18 years)
Time Frame
10 years
Title
Late effects of therapy on quality of survival
Description
measured with standardized questionnaires/ scores: HUI3 (health status) BRIEF (executive functions) SDQ (behavioural outcome) PedsQL (quality of life) QLQ-C30 (quality of life) MEES (neurological function, educational provision) MFI (fatigue) 2 and 5 years after diagnosis and age of 18 years
Time Frame
10 years
Title
Progression-free survival
Time Frame
10 years
Title
Feasibility of carboplatin treatment
Description
measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy
Time Frame
approx. 7 years
Title
Residual tumor
Description
measured by central MRI review postoperatively
Time Frame
6 years
Title
Leukoencephalopathy grading
Description
measured 2 years after diagnosis grades 0, 1, 2, 3, 4
Time Frame
8 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years (LR-arm: less than 16 years). The date of diagnosis is the date on which surgery is undertaken. Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007): classic medulloblastoma, desmoplastic/nodular medulloblastoma. Pre-treatment central pathology review is considered mandatory. Standard-risk medulloblastoma, defined as; total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumour on early post-operative MRI, without and with contrast, on central review; no central nervous system (CNS) metastasis on MRI (cranial and spinal) on central review; no tumour cells on the cytospin of lumbar CSF no clinical evidence of extra-CNS metastasis; Patients with a reduction of postoperative residual tumor through second surgery to less than or equal to 1.5 cm2 are eligible, if if timeline for start of radiotherapy can be kept. Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of myelocytomatosis oncogene (MYC) copy number status) in national biological reference centers. Submission of blood is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended. No amplification of MYC or MYCN (determined by FISH). For LR-arm: Low-risk biological profile, defined as WNT subgroup positivity. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing). For SR-arm: average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC (mandatory) and mutation analysis (optional). No prior therapy for medulloblastoma other than surgery. Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study. Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function no significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing no impairment ≥ 20 decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit. No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome or other reasons as defined by patient's clinician. No identified Turcot and Li Fraumeni syndrome. Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation. National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies). Exclusion Criteria: One of the inclusion criteria is lacking. Brainstem or supratentorial primitive neuro-ectodermal tumour. Atypical teratoid rhabdoid tumour. Medulloepithelioma; Ependymoblastoma Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), centrally confirmed. Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or MYC or MYCN or WNT subgroup status not determinable. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF). Patient previously treated for a brain tumour or any type of malignant disease. DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin,Turcot, or Li Fraumeni syndrome. Patients who are pregnant. Female patients who are sexually active and not taking reliable contraception. Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons. Patients in whom non-compliance with toxicity management guidelines can be expected.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francois Doz, Prof. Dr.
Organizational Affiliation
Institut Curie Paris, France
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Till Milde, Dr. med.
Organizational Affiliation
Hopp Children´s Tumor Center at the NCT (KiTZ) and German Cancer Research Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Graz
City
Graz
ZIP/Postal Code
8010
Country
Austria
Facility Name
University Hospital Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
University Hospital Brno
City
Brno
ZIP/Postal Code
61300
Country
Czechia
Facility Name
Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
CHU de Grenoble
City
Grenoble
ZIP/Postal Code
38045
Country
France
Facility Name
Institute Curie
City
Paris Cedex 05
ZIP/Postal Code
75231
Country
France
Facility Name
CHU-TOURS - Hôpital Clocheville
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
Hôpital NANCY-BRABOIS
City
Vandoeuvre Les Nancy
ZIP/Postal Code
54500
Country
France
Facility Name
University Hospital Aachen
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Klinikum Augsburg
City
Augsburg
ZIP/Postal Code
86156
Country
Germany
Facility Name
Helios Klinikum Berlin-Buch
City
Berlin
ZIP/Postal Code
13125
Country
Germany
Facility Name
Charite Campus, University of Berlin
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Evangelisches Krankenhaus Bielefeld
City
Bielefeld
ZIP/Postal Code
33617
Country
Germany
Facility Name
University Hospital Bonn
City
Bonn
ZIP/Postal Code
53113
Country
Germany
Facility Name
Klinikum Braunschweig
City
Braunschweig
ZIP/Postal Code
38118
Country
Germany
Facility Name
Klinikum Bremen-Mitte
City
Bremen
ZIP/Postal Code
28177
Country
Germany
Facility Name
Klinikum Chemnitz
City
Chemnitz
ZIP/Postal Code
09116
Country
Germany
Facility Name
University Hospital Cologne
City
Cologne
ZIP/Postal Code
50924
Country
Germany
Facility Name
Carl-Thiem-Klinikum Cottbus
City
Cottbus
ZIP/Postal Code
03048
Country
Germany
Facility Name
Vestische Kinder- und Jugendklinik, University Witten/Herdecke
City
Datteln
ZIP/Postal Code
45711
Country
Germany
Facility Name
Klinikum Dortmund
City
Dortmund
ZIP/Postal Code
44137
Country
Germany
Facility Name
University Hospital Dresden
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Klinikum Duisburg
City
Duisburg
ZIP/Postal Code
47055
Country
Germany
Facility Name
University Hospital Düsseldorf
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
HELIOS Klinikum-Erfurt
City
Erfurt
ZIP/Postal Code
99089
Country
Germany
Facility Name
University Hospital Erlangen
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
University Hospital Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
University Hospital Frankfurt/Main
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
University Hospital Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
University Hospital Gießen and Marburg
City
Gießen
ZIP/Postal Code
35392
Country
Germany
Facility Name
University Hospital Greifswald
City
Greifswald
ZIP/Postal Code
17475
Country
Germany
Facility Name
University Hospital Göttingen
City
Göttingen
ZIP/Postal Code
37075
Country
Germany
Facility Name
University Hospital Halle/Saale
City
Halle
ZIP/Postal Code
06120
Country
Germany
Facility Name
University Medical Center Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Angelika-Lautenschläger-Klinik
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Gemeinschaftskrankenhaus Herdecke
City
Herdecke
ZIP/Postal Code
58313
Country
Germany
Facility Name
University Hospital Homburg/Saar
City
Homburg
ZIP/Postal Code
66421
Country
Germany
Facility Name
University Hospital Jena
City
Jena
ZIP/Postal Code
07740
Country
Germany
Facility Name
Städtisches Klinikum Karlsruhe
City
Karlsruhe
ZIP/Postal Code
76133
Country
Germany
Facility Name
Klinikum Kassel
City
Kassel
ZIP/Postal Code
34125
Country
Germany
Facility Name
UK-SH Campus Kiel
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Facility Name
Gemeinschaftsklinikum Koblenz-Mayen
City
Koblenz
ZIP/Postal Code
56073
Country
Germany
Facility Name
HELIOS Klinikum Krefeld
City
Krefeld
ZIP/Postal Code
47805
Country
Germany
Facility Name
Kliniken der Stadt Köln
City
Köln
ZIP/Postal Code
50735
Country
Germany
Facility Name
University Hospital Leipzig
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
University Hospital Lübeck
City
Lübeck
ZIP/Postal Code
23538
Country
Germany
Facility Name
University Hospital Magdeburg
City
Magdeburg
ZIP/Postal Code
39120
Country
Germany
Facility Name
University Hospital Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
University Hospital Mannheim
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
Facility Name
Johannes Wesling Klinikum Minden
City
Minden
ZIP/Postal Code
32429
Country
Germany
Facility Name
University Hospital München, Dr. von Haunersches Kinderspital
City
München
ZIP/Postal Code
80337
Country
Germany
Facility Name
Klinikum Schwabing, Pediatric Hospital of Technical University
City
München
ZIP/Postal Code
80804
Country
Germany
Facility Name
University Hospital Münster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Cnopf'sche Kinderklinik
City
Nürnberg
ZIP/Postal Code
90419
Country
Germany
Facility Name
Klinikum Oldenburg
City
Oldenburg
ZIP/Postal Code
26133
Country
Germany
Facility Name
University Hospital Regensburg
City
Regensburg
ZIP/Postal Code
93053
Country
Germany
Facility Name
University Hospital Rostock
City
Rostock
ZIP/Postal Code
18057
Country
Germany
Facility Name
Asklepios Klinik Sankt Augustin
City
Sankt Augustin
ZIP/Postal Code
53757
Country
Germany
Facility Name
HELIOS-Kliniken Schwerin
City
Schwerin
ZIP/Postal Code
19049
Country
Germany
Facility Name
Klinikum Stuttgart
City
Stuttgart
ZIP/Postal Code
70176
Country
Germany
Facility Name
Mutterhaus der Borromäerinnen
City
Trier
ZIP/Postal Code
54290
Country
Germany
Facility Name
University Hospital Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
University Hospital Ulm
City
Ulm
ZIP/Postal Code
89075
Country
Germany
Facility Name
Dr. Horst Schmidt Kliniken
City
Wiesbaden
ZIP/Postal Code
65199
Country
Germany
Facility Name
Klinikum der Stadt Wolfsburg
City
Wolfsburg
ZIP/Postal Code
38440
Country
Germany
Facility Name
University Hospital Würzburg
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Our Lady's Children's Hospital
City
Dublin
ZIP/Postal Code
12
Country
Ireland
Facility Name
Fondazione IRCCS Istituto Nazionale Tumori
City
Milano
ZIP/Postal Code
20133
Country
Italy
Facility Name
Prinses Máxima Center for Pediatric Oncology
City
Bilthoven
ZIP/Postal Code
3720
Country
Netherlands
Facility Name
Rigshospitalet
City
Oslo
ZIP/Postal Code
0424
Country
Norway
Facility Name
The Children's Memorial Health Institute
City
Warsaw
ZIP/Postal Code
04-730
Country
Poland
Facility Name
University Hospital S.Joao
City
Porto
ZIP/Postal Code
4200
Country
Portugal
Facility Name
Oncology Hospital Cruces Bilbao
City
Baracaldo
ZIP/Postal Code
48903
Country
Spain
Facility Name
Barncancercentrum Drottning Silvias Barnochungdomssjukhus
City
Göteburg
ZIP/Postal Code
41685
Country
Sweden
Facility Name
University Children's Hospital
City
Zürich
ZIP/Postal Code
8032
Country
Switzerland
Facility Name
Great Ormond Street Hospital
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

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