International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
- Conditions
- Brain Tumors
- Interventions
- Drug: Maintenance chemotherapyRadiation: Radiotherapy without CarboplatinDrug: Induction ChemotherapyDrug: Reduced-intensity maintenance chemotherapyRadiation: Radiotherapy with CarboplatinRadiation: WNT-HR < 16 yearsRadiation: SHH-TP53 M0Radiation: WNT-HR >= 16 yearsRadiation: SHH-TP53 M+ (germline)Radiation: SHH-TP53 (somatic)
- Registration Number
- NCT02066220
- Lead Sponsor
- Universitätsklinikum Hamburg-Eppendorf
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 360
-
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).
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description PNET 5 MB SHH-TP53 Vinblastin Maintenance 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 PNET 5 MB SHH-TP53 SHH-TP53 (somatic) 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 PNET 5 MB WNT-HR Maintenance chemotherapy Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks. PNET 5 MB-LR (low-risk) Radiotherapy without Carboplatin Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks. PNET 5 MB WNT-HR WNT-HR >= 16 years Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks. PNET 5 MB-LR (low-risk) Reduced-intensity maintenance chemotherapy Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks. PNET 5 MB-SR (standard-risk) Radiotherapy with Carboplatin Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks. PNET 5 MB-SR (standard-risk) Maintenance chemotherapy Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks. PNET 5 MB WNT-HR WNT-HR < 16 years Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks. PNET 5 MB SHH-TP53 SHH-TP53 M0 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 PNET 5 MB-SR (standard-risk) Radiotherapy without Carboplatin Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks. PNET 5 MB SHH-TP53 Induction Chemotherapy 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 PNET 5 MB SHH-TP53 SHH-TP53 M+ (germline) 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
- Primary Outcome Measures
Name Time Method 3-year Event-Free Survival (EFS) LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)
- Secondary Outcome Measures
Name Time Method Late effects of therapy on neurology 10 years Measured as
1. presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively)
2. presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy)
3. cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years)
4. 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 10 years measured with standardized questionnaires/ scores:
1. HUI3 (health status)
2. BRIEF (executive functions)
3. SDQ (behavioural outcome)
4. PedsQL (quality of life)
5. QLQ-C30 (quality of life)
6. MEES (neurological function, educational provision)
7. MFI (fatigue) 2 and 5 years after diagnosis and age of 18 yearsProgression-free survival 10 years Feasibility of carboplatin treatment approx. 7 years measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy
Residual tumor 6 years measured by central MRI review postoperatively
Leukoencephalopathy grading 8 years measured 2 years after diagnosis grades 0, 1, 2, 3, 4
Overall survival 10 years Pattern of relapse 10 years Defined in 5 categorical variables:
no relapse, local relapse, distant relapse, local and distant relapse, deathLate effects of therapy on endocrine function 10 years measured as
1. subfertility (FSH \> 15 IU/L)
2. endocrine deficits (hormone supplementation necessary)
3. growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 yearsLate effects of therapy on audiology 8 years measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)
Trial Locations
- Locations (76)
CHU-TOURS - Hôpital Clocheville
🇫🇷Tours, France
University Hospital Gießen and Marburg
🇩🇪Gießen, Germany
Gemeinschaftskrankenhaus Herdecke
🇩🇪Herdecke, Germany
University Hospital Halle/Saale
🇩🇪Halle, Germany
Klinikum Braunschweig
🇩🇪Braunschweig, Germany
Klinikum Duisburg
🇩🇪Duisburg, Germany
UK-SH Campus Kiel
🇩🇪Kiel, Germany
University Hospital Erlangen
🇩🇪Erlangen, Germany
CHU de Grenoble
🇫🇷Grenoble, France
Institute Curie
🇫🇷Paris Cedex 05, France
Hôpital NANCY-BRABOIS
🇫🇷Vandoeuvre Les Nancy, France
Klinikum Augsburg
🇩🇪Augsburg, Germany
Medical University of Graz
🇦🇹Graz, Austria
University Hospital Gasthuisberg
🇧🇪Leuven, Belgium
University Hospital Brno
🇨🇿Brno, Czechia
University Hospital Aachen
🇩🇪Aachen, Germany
Klinikum Chemnitz
🇩🇪Chemnitz, Germany
University Hospital Cologne
🇩🇪Cologne, Germany
Vestische Kinder- und Jugendklinik, University Witten/Herdecke
🇩🇪Datteln, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
University Hospital Göttingen
🇩🇪Göttingen, Germany
University Hospital Homburg/Saar
🇩🇪Homburg, Germany
Klinikum Kassel
🇩🇪Kassel, Germany
University Hospital Jena
🇩🇪Jena, Germany
Gemeinschaftsklinikum Koblenz-Mayen
🇩🇪Koblenz, Germany
Städtisches Klinikum Karlsruhe
🇩🇪Karlsruhe, Germany
Kliniken der Stadt Köln
🇩🇪Köln, Germany
University Hospital München, Dr. von Haunersches Kinderspital
🇩🇪München, Germany
Johannes Wesling Klinikum Minden
🇩🇪Minden, Germany
University Hospital Rostock
🇩🇪Rostock, Germany
University Hospital Mannheim
🇩🇪Mannheim, Germany
Asklepios Klinik Sankt Augustin
🇩🇪Sankt Augustin, Germany
HELIOS-Kliniken Schwerin
🇩🇪Schwerin, Germany
Prinses Máxima Center for Pediatric Oncology
🇳🇱Bilthoven, Netherlands
University Children's Hospital
🇨🇭Zürich, Switzerland
Fondazione IRCCS Istituto Nazionale Tumori
🇮🇹Milano, Italy
Great Ormond Street Hospital
🇬🇧London, United Kingdom
Barncancercentrum Drottning Silvias Barnochungdomssjukhus
🇸🇪Göteburg, Sweden
University Hospital Ulm
🇩🇪Ulm, Germany
Klinikum Stuttgart
🇩🇪Stuttgart, Germany
University Hospital Tübingen
🇩🇪Tübingen, Germany
Oncology Hospital Cruces Bilbao
🇪🇸Baracaldo, Spain
Our Lady's Children's Hospital
🇮🇪Dublin, Ireland
Dr. Horst Schmidt Kliniken
🇩🇪Wiesbaden, Germany
The Children's Memorial Health Institute
🇵🇱Warsaw, Poland
University Hospital S.Joao
🇵🇹Porto, Portugal
Charite Campus, University of Berlin
🇩🇪Berlin, Germany
Evangelisches Krankenhaus Bielefeld
🇩🇪Bielefeld, Germany
University Hospital Bonn
🇩🇪Bonn, Germany
Klinikum Bremen-Mitte
🇩🇪Bremen, Germany
Klinikum Dortmund
🇩🇪Dortmund, Germany
University Hospital Dresden
🇩🇪Dresden, Germany
HELIOS Klinikum-Erfurt
🇩🇪Erfurt, Germany
University Hospital Essen
🇩🇪Essen, Germany
University Medical Center Hamburg-Eppendorf
🇩🇪Hamburg, Germany
University Hospital Frankfurt/Main
🇩🇪Frankfurt, Germany
University Hospital Freiburg
🇩🇪Freiburg, Germany
Angelika-Lautenschläger-Klinik
🇩🇪Heidelberg, Germany
University Hospital Greifswald
🇩🇪Greifswald, Germany
HELIOS Klinikum Krefeld
🇩🇪Krefeld, Germany
University Hospital Lübeck
🇩🇪Lübeck, Germany
University Hospital Leipzig
🇩🇪Leipzig, Germany
University Hospital Magdeburg
🇩🇪Magdeburg, Germany
University Hospital Mainz
🇩🇪Mainz, Germany
Klinikum Schwabing, Pediatric Hospital of Technical University
🇩🇪München, Germany
University Hospital Münster
🇩🇪Münster, Germany
University Hospital Regensburg
🇩🇪Regensburg, Germany
Mutterhaus der Borromäerinnen
🇩🇪Trier, Germany
University Hospital Würzburg
🇩🇪Würzburg, Germany
Klinikum der Stadt Wolfsburg
🇩🇪Wolfsburg, Germany
University Hospital Düsseldorf
🇩🇪Düsseldorf, Germany
Carl-Thiem-Klinikum Cottbus
🇩🇪Cottbus, Germany
Klinikum Oldenburg
🇩🇪Oldenburg, Germany
Cnopf'sche Kinderklinik
🇩🇪Nürnberg, Germany
Rigshospitalet
🇳🇴Oslo, Norway
Helios Klinikum Berlin-Buch
🇩🇪Berlin, Germany