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ACTIVE NOT RECRUITING

NCT02066220

PHASE2/PHASE3

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

Sponsor: Universitätsklinikum Hamburg-Eppendorf

View on ClinicalTrials.gov

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.

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

Key Details

Gender

All

Age Range

3 Years - 21 Years

Study Type

INTERVENTIONAL

Enrollment

360

Start Date

2014-06

Completion Date

2026-12

Last Updated

2025-12-04

Healthy Volunteers

Conditions

Brain Tumors

Interventions

RADIATION

Radiotherapy without Carboplatin

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

DRUG

Reduced-intensity maintenance chemotherapy

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.

RADIATION

Radiotherapy with Carboplatin

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.

DRUG

Maintenance chemotherapy

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).

RADIATION

WNT-HR < 16 years

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

RADIATION

WNT-HR >= 16 years

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

DRUG

Induction Chemotherapy

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

RADIATION

SHH-TP53 M0

* 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)

RADIATION

SHH-TP53 M+ (germline)

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

RADIATION

SHH-TP53 (somatic)

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

DRUG

Vinblastin Maintenance

Weekly VBL (5mg/m², max. 10mg/dose) for 24 weeks

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.

Locations (77)

Medical University of Graz

Graz, Austria

University Hospital Gasthuisberg

Leuven, Belgium

University Hospital Brno

Brno, Czechia

Rigshospitalet

Copenhagen, Denmark

CHU de Grenoble

Grenoble, France

Institute Curie

Paris, France

CHU-TOURS - Hôpital Clocheville

Tours, France

Hôpital NANCY-BRABOIS

Vandœuvre-lès-Nancy, France

University Hospital Aachen

Aachen, Germany

Klinikum Augsburg

Augsburg, Germany

Helios Klinikum Berlin-Buch

Berlin, Germany

Charite Campus, University of Berlin

Berlin, Germany

Evangelisches Krankenhaus Bielefeld

Bielefeld, Germany

University Hospital Bonn

Bonn, Germany

Klinikum Braunschweig

Braunschweig, Germany

Klinikum Bremen-Mitte

Bremen, Germany

Klinikum Chemnitz

Chemnitz, Germany

Kliniken der Stadt Köln

Cologne, Germany

University Hospital Cologne

Cologne, Germany

Carl-Thiem-Klinikum Cottbus

Cottbus, Germany

Vestische Kinder- und Jugendklinik, University Witten/Herdecke

Datteln, Germany

Klinikum Dortmund

Dortmund, Germany

University Hospital Dresden

Dresden, Germany

Klinikum Duisburg

Duisburg, Germany

University Hospital Düsseldorf

Düsseldorf, Germany

HELIOS Klinikum-Erfurt

Erfurt, Germany

University Hospital Erlangen

Erlangen, Germany

University Hospital Essen

Essen, Germany

University Hospital Frankfurt/Main

Frankfurt, Germany

University Hospital Freiburg

Freiburg im Breisgau, Germany

University Hospital Gießen and Marburg

Giessen, Germany

University Hospital Göttingen

Göttingen, Germany

University Hospital Greifswald

Greifswald, Germany

University Hospital Halle/Saale

Halle, Germany

University Medical Center Hamburg-Eppendorf

Hamburg, Germany

Medizinische Hochschule Hannover

Hanover, Germany

Angelika-Lautenschläger-Klinik

Heidelberg, Germany

Gemeinschaftskrankenhaus Herdecke

Herdecke, Germany

University Hospital Homburg/Saar

Homburg, Germany

University Hospital Jena

Jena, Germany

Städtisches Klinikum Karlsruhe

Karlsruhe, Germany

Klinikum Kassel

Kassel, Germany

UK-SH Campus Kiel

Kiel, Germany

Gemeinschaftsklinikum Koblenz-Mayen

Koblenz, Germany

HELIOS Klinikum Krefeld

Krefeld, Germany

University Hospital Leipzig

Leipzig, Germany

University Hospital Lübeck

Lübeck, Germany

University Hospital Magdeburg

Magdeburg, Germany

University Hospital Mainz

Mainz, Germany

University Hospital Mannheim

Mannheim, Germany

Johannes Wesling Klinikum Minden

Minden, Germany

University Hospital München, Dr. von Haunersches Kinderspital

München, Germany

Klinikum Schwabing, Pediatric Hospital of Technical University

München, Germany

University Hospital Münster

Münster, Germany

Cnopf'sche Kinderklinik

Nuremberg, Germany

Klinikum Oldenburg

Oldenburg, Germany

University Hospital Regensburg

Regensburg, Germany

University Hospital Rostock

Rostock, Germany

Asklepios Klinik Sankt Augustin

Sankt Augustin, Germany

HELIOS-Kliniken Schwerin

Schwerin, Germany

Klinikum Stuttgart

Stuttgart, Germany

Mutterhaus der Borromäerinnen

Trier, Germany

University Hospital Tübingen

Tübingen, Germany

University Hospital Ulm

Ulm, Germany

Dr. Horst Schmidt Kliniken

Wiesbaden, Germany

Klinikum der Stadt Wolfsburg

Wolfsburg, Germany

University Hospital Würzburg

Würzburg, Germany

Our Lady's Children's Hospital

Dublin, Ireland

Fondazione IRCCS Istituto Nazionale Tumori

Milan, Italy

Prinses Máxima Center for Pediatric Oncology

Bilthoven, Netherlands

Rigshospitalet

Oslo, Norway

The Children's Memorial Health Institute

Warsaw, Poland

University Hospital S.Joao

Porto, Portugal

Oncology Hospital Cruces Bilbao

Barakaldo, Spain

Barncancercentrum Drottning Silvias Barnochungdomssjukhus

Göteburg, Sweden

University Children's Hospital

Zurich, Switzerland

Great Ormond Street Hospital

London, United Kingdom

Clinical Research Directory

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

Summary

Key Details

Conditions

Interventions

Eligibility Criteria

Locations (77)