International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
Conditions
Brain Tumors
Conditions: official terms
Brain Neoplasms - Medulloblastoma
Conditions: 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
Study Type
Interventional
Study Phase
Phase 2/Phase 3
Study Design
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Radiotherapy without Carboplatin Type: Radiation
Name: Reduced-intensity maintenance chemotherapy Type: Drug
Name: Radiotherapy with Carboplatin Type: Radiation
Name: Maintenance chemotherapy Type: Drug
Overall Status
Recruiting
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.
Detailed Description
The aim of the LR-treatment arm 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-arm 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: 21 Years
Minimum Age: 3 Years
Gender: Both
Criteria: 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
Medical University of Graz
Graz, Austria
Status: Not yet recruiting
Contact: Martin Benesch, Dr. - martin.benesch@klinikum-graz.at
University Hospital Gasthuisberg
Leuven, Belgium
Status: Not yet recruiting
Contact: Stefaan van Gool, Prof. - stefaan.vangool@uz.leuven.be
University Hospital Brno
Brno, Czech Republic
Status: Not yet recruiting
Contact: Jaroslav Sterba, Prof. - jsterb@fnbrno.cz
Rigshospitalet
Copenhagen, Denmark
Status: Not yet recruiting
Contact: Astrid Sehested, Dr.
CHU de Grenoble
Grenoble, France
Status: Recruiting
Institute Curie
Paris Cedex 05, France
Status: Recruiting
Contact: Francois Doz, Prof. Dr. - francois.doz@curie.net
CHU-TOURS - Hôpital Clocheville
Tours, France
Status: Recruiting
Hôpital NANCY-BRABOIS
Vandoeuvre Les Nancy, France
Status: Recruiting
University Hospital Aachen
Aachen, Germany
Status: Not yet recruiting
Klinikum Augsburg
Augsburg, Germany
Status: Recruiting
Charite Campus, University of Berlin
Berlin, Germany
Status: Recruiting
Helios Klinikum Berlin-Buch
Berlin, Germany
Status: Recruiting
Evangelisches Krankenhaus Bielefeld
Bielefeld, Germany
Status: Recruiting
University Hospital Bonn
Bonn, Germany
Status: Recruiting
Klinikum Braunschweig
Braunschweig, Germany
Status: Recruiting
Klinikum Bremen-Mitte
Bremen, Germany
Status: Recruiting
Klinikum Chemnitz
Chemnitz, Germany
Status: Recruiting
University Hospital Cologne
Cologne, Germany
Status: Recruiting
Carl-Thiem-Klinikum Cottbus
Cottbus, Germany
Status: Not yet recruiting
Vestische Kinder- und Jugendklinik, University Witten/Herdecke
Datteln, Germany
Status: Recruiting
Klinikum Dortmund
Dortmund, Germany
Status: Recruiting
University Hospital Dresden
Dresden, Germany
Status: Recruiting
Klinikum Duisburg
Duisburg, Germany
Status: Not yet recruiting
University Hospital Düsseldorf
Düsseldorf, Germany
Status: Recruiting
HELIOS Klinikum-Erfurt
Erfurt, Germany
Status: Recruiting
University Hospital Erlangen
Erlangen, Germany
Status: Recruiting
University Hospital Essen
Essen, Germany
Status: Recruiting
University Hospital Frankfurt/Main
Frankfurt, Germany
Status: Not yet recruiting
University Hospital Freiburg
Freiburg, Germany
Status: Recruiting
University Hospital Gießen and Marburg
Gießen, Germany
Status: Recruiting
University Hospital Greifswald
Greifswald, Germany
Status: Recruiting
University Hospital Göttingen
Göttingen, Germany
Status: Recruiting
University Hospital Halle/Saale
Halle, Germany
Status: Recruiting
University Medical Center Hamburg-Eppendorf
Hamburg, Germany
Status: Recruiting
Contact: Stefan Rutkowski, Prof. - +49-40-7410 - s.rutkowski@uke.de
Medizinische Hochschule Hannover
Hannover, Germany
Status: Recruiting
Angelika-Lautenschläger-Klinik
Heidelberg, Germany
Status: Recruiting
Gemeinschaftskrankenhaus Herdecke
Herdecke, Germany
Status: Recruiting
University Hospital Homburg/Saar
Homburg, Germany
Status: Recruiting
University Hopsital Jena
Jena, Germany
Status: Recruiting
Städtisches Klinikum Karlsruhe
Karlsruhe, Germany
Status: Recruiting
Klinikum Kassel
Kassel, Germany
Status: Recruiting
UK-SH Campus Kiel
Kiel, Germany
Status: Recruiting
Gemeinschaftsklinikum Koblenz-Mayen
Koblenz, Germany
Status: Recruiting
HELIOS Klinikum Krefeld
Krefeld, Germany
Status: Recruiting
Kliniken der Stadt Köln
Köln, Germany
Status: Not yet recruiting
University Hospital Leipzig
Leipzig, Germany
Status: Recruiting
University Hospital Lübeck
Lübeck, Germany
Status: Recruiting
University Hospital Magdeburg
Magdeburg, Germany
Status: Recruiting
University Hospital Mainz
Mainz, Germany
Status: Recruiting
University Hospital Mannheim
Mannheim, Germany
Status: Recruiting
Johannes Wesling Klinikum Minden
Minden, Germany
Status: Recruiting
Klinikum Schwabing, Pediatric Hospital of Technical University
München, Germany
Status: Recruiting
University Hospital München, Dr. von Haunersches Kinderspital
München, Germany
Status: Recruiting
University Hospital Münster
Münster, Germany
Status: Recruiting
Cnopf'sche Kinderklinik
Nürnberg, Germany
Status: Recruiting
Klinikum Oldenburg
Oldenburg, Germany
Status: Recruiting
University Hospital Regensburg
Regensburg, Germany
Status: Recruiting
University Hospital Rostock
Rostock, Germany
Status: Recruiting
Asklepios Klinik Sankt Augustin
Sankt Augustin, Germany
Status: Recruiting
Klinikum Stuttgart
Stuttgart, Germany
Status: Recruiting
Mutterhaus der Borromäerinnen
Trier, Germany
Status: Recruiting
University Hospital Tübingen
Tübingen, Germany
Status: Not yet recruiting
University Hospital Ulm
Ulm, Germany
Status: Not yet recruiting
Dr. Horst Schmidt Kliniken
Wiesbaden, Germany
Status: Recruiting
Klinikum der Stadt Wolfsburg
Wolfsburg, Germany
Status: Recruiting
University Hospital Würzburg
Würzburg, Germany
Status: Recruiting
Our Lady's Children's Hospital
Dublin, Ireland
Status: Not yet recruiting
Contact: Jane Pears, Dr. - jane.pears@olchc.ie
Fondazione IRCCS Istituto Nazionale Tumori
Milano, Italy
Status: Not yet recruiting
Contact: Maura Massimino, Dr. - maura.massimino@istitutotumori.mi.it
Erasmus Medical Centre
Rotterdam, Netherlands
Status: Not yet recruiting
Contact: Roel E Reddingius, Dr. - r.reddingius@erasmusmc.nl
Rigshospitalet
Oslo, Norway
Status: Not yet recruiting
Contact: Finn Wesenberg, Prof. - finn.wesenberg@rigshospitalet.no
The Children's Memorial Health Institute
Warsaw, Poland
Status: Not yet recruiting
Contact: Marta Perek, Dr. - m.perek-polnik@czd.pl
University Hospital S.Joao
Porto, Portugal
Status: Not yet recruiting
Contact: Maria Joao Gil-da-Costa, Dr. - mjgildacosta@gmail.com
Oncology Hospital Cruces Bilbao
Baracaldo, Spain
Status: Not yet recruiting
Contact: Aurora Navajas Guitierrez, Prof. - anavjas@osakidetza.net
Barncancercentrum Drottning Silvias Barnochungdomssjukhus
Göteburg, Sweden
Status: Not yet recruiting
Contact: Birgitta Lannering, Prof. - birgitta.lannering@vgregion.se
University Children's Hospital
Zürich, Switzerland
Status: Not yet recruiting
Contact: Nicolas Gerber, Dr. - nicolas.gerber@kispi.uzh.ch
Great Ormond Street Hospital
London, United Kingdom
Status: Not yet recruiting
Contact: Antony Michalski, Dr. - antony.michalski@gosh.nhs.uk
Start Date
June 2014
Completion Date
April 2024
Sponsors
Universitätsklinikum Hamburg-Eppendorf
Source
Universitätsklinikum Hamburg-Eppendorf
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page