International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

NCT02066220 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: SIOP PNET 5 MB2011-004868-30
• Study Type: interventional
• Target: 360
• Locations: 16 countries
• Sites: 77

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 3-year Event-Free Survival (EFS)

  LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)

Secondary Outcomes (10)

• Overall survival

  10 years

• Pattern of relapse

  10 years

• Late effects of therapy on endocrine function

  10 years

• Late effects of therapy on audiology

  8 years

• Late effects of therapy on neurology

  10 years

Study Arms (4)

PNET 5 MB-LR (low-risk)

EXPERIMENTAL

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

Radiation: Radiotherapy without Carboplatin; Drug: Reduced-intensity maintenance chemotherapy

PNET 5 MB-SR (standard-risk)

EXPERIMENTAL

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

Radiation: Radiotherapy without Carboplatin; Radiation: Radiotherapy with Carboplatin; Drug: Maintenance chemotherapy

PNET 5 MB WNT-HR

EXPERIMENTAL

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

Drug: Maintenance chemotherapy; Radiation: WNT-HR < 16 years; Radiation: WNT-HR >= 16 years

PNET 5 MB SHH-TP53

EXPERIMENTAL

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

Drug: Induction Chemotherapy; Radiation: SHH-TP53 M0; Radiation: SHH-TP53 M+ (germline); Radiation: SHH-TP53 (somatic); Drug: Vinblastin Maintenance

Interventions

Reduced-intensity maintenance chemotherapy DRUG

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.

Also known as: Cisplatin, Lomustin (CCNU), Vincristine, Cyclophosphamide

PNET 5 MB-LR (low-risk)

Radiotherapy without Carboplatin RADIATION

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

PNET 5 MB-LR (low-risk); PNET 5 MB-SR (standard-risk)

Radiotherapy with Carboplatin RADIATION

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.

Also known as: Carboplatin

PNET 5 MB-SR (standard-risk)

Maintenance chemotherapy DRUG

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).

Also known as: Cisplatin, Lomustine (CCNU), Vincristine, Cyclophosphamide

PNET 5 MB WNT-HR; PNET 5 MB-SR (standard-risk)

WNT-HR >= 16 years RADIATION

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

PNET 5 MB WNT-HR

Induction Chemotherapy DRUG

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

PNET 5 MB SHH-TP53

SHH-TP53 M0 RADIATION

* 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)

PNET 5 MB SHH-TP53

SHH-TP53 M+ (germline) RADIATION

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

PNET 5 MB SHH-TP53

SHH-TP53 (somatic) RADIATION

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

PNET 5 MB SHH-TP53

Vinblastin Maintenance DRUG

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

PNET 5 MB SHH-TP53

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead
• Deutsche Kinderkrebsstiftung: collaborator

Study Sites (77)

Medical University of Graz

Graz, 8010, Austria

Location

University Hospital Gasthuisberg

Leuven, 3000, Belgium

Location

University Hospital Brno

Brno, 61300, Czechia

Location

Rigshospitalet

Copenhagen, 2100, Denmark

Location

CHU de Grenoble

Grenoble, 38045, France

Location

Institute Curie

Paris, 75231, France

Location

CHU-TOURS - Hôpital Clocheville

Tours, 37044, France

Location

Hôpital NANCY-BRABOIS

Vandœuvre-lès-Nancy, 54500, France

Location

University Hospital Aachen

Aachen, 52074, Germany

Location

Klinikum Augsburg

Augsburg, 86156, Germany

Location

Helios Klinikum Berlin-Buch

Berlin, 13125, Germany

Location

Charite Campus, University of Berlin

Berlin, 13353, Germany

Location

Evangelisches Krankenhaus Bielefeld

Bielefeld, 33617, Germany

Location

University Hospital Bonn

Bonn, 53113, Germany

Location

Klinikum Braunschweig

Braunschweig, 38118, Germany

Location

Klinikum Bremen-Mitte

Bremen, 28177, Germany

Location

Klinikum Chemnitz

Chemnitz, 09116, Germany

Location

Kliniken der Stadt Köln

Cologne, 50735, Germany

Location

University Hospital Cologne

Cologne, 50924, Germany

Location

Carl-Thiem-Klinikum Cottbus

Cottbus, 03048, Germany

Location

Vestische Kinder- und Jugendklinik, University Witten/Herdecke

Datteln, 45711, Germany

Location

Klinikum Dortmund

Dortmund, 44137, Germany

Location

University Hospital Dresden

Dresden, 01307, Germany

Location

Klinikum Duisburg

Duisburg, 47055, Germany

Location

University Hospital Düsseldorf

Düsseldorf, 40225, Germany

Location

HELIOS Klinikum-Erfurt

Erfurt, 99089, Germany

Location

University Hospital Erlangen

Erlangen, 91054, Germany

Location

University Hospital Essen

Essen, 45147, Germany

Location

University Hospital Frankfurt/Main

Frankfurt, 60590, Germany

Location

University Hospital Freiburg

Freiburg im Breisgau, 79106, Germany

Location

University Hospital Gießen and Marburg

Giessen, 35392, Germany

Location

University Hospital Göttingen

Göttingen, 37075, Germany

Location

University Hospital Greifswald

Greifswald, 17475, Germany

Location

University Hospital Halle/Saale

Halle, 06120, Germany

Location

University Medical Center Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Angelika-Lautenschläger-Klinik

Heidelberg, 69120, Germany

Location

Gemeinschaftskrankenhaus Herdecke

Herdecke, 58313, Germany

Location

University Hospital Homburg/Saar

Homburg, 66421, Germany

Location

University Hospital Jena

Jena, 07740, Germany

Location

Städtisches Klinikum Karlsruhe

Karlsruhe, 76133, Germany

Location

Klinikum Kassel

Kassel, 34125, Germany

Location

UK-SH Campus Kiel

Kiel, 24105, Germany

Location

Gemeinschaftsklinikum Koblenz-Mayen

Koblenz, 56073, Germany

Location

HELIOS Klinikum Krefeld

Krefeld, 47805, Germany

Location

University Hospital Leipzig

Leipzig, 04103, Germany

Location

University Hospital Lübeck

Lübeck, 23538, Germany

Location

University Hospital Magdeburg

Magdeburg, 39120, Germany

Location

University Hospital Mainz

Mainz, 55131, Germany

Location

University Hospital Mannheim

Mannheim, 68167, Germany

Location

Johannes Wesling Klinikum Minden

Minden, 32429, Germany

Location

University Hospital München, Dr. von Haunersches Kinderspital

München, 80337, Germany

Location

Klinikum Schwabing, Pediatric Hospital of Technical University

München, 80804, Germany

Location

University Hospital Münster

Münster, 48149, Germany

Location

Cnopf'sche Kinderklinik

Nuremberg, 90419, Germany

Location

Klinikum Oldenburg

Oldenburg, 26133, Germany

Location

University Hospital Regensburg

Regensburg, 93053, Germany

Location

University Hospital Rostock

Rostock, 18057, Germany

Location

Asklepios Klinik Sankt Augustin

Sankt Augustin, 53757, Germany

Location

HELIOS-Kliniken Schwerin

Schwerin, 19049, Germany

Location

Klinikum Stuttgart

Stuttgart, 70176, Germany

Location

Mutterhaus der Borromäerinnen

Trier, 54290, Germany

Location

University Hospital Tübingen

Tübingen, 72076, Germany

Location

University Hospital Ulm

Ulm, 89075, Germany

Location

Dr. Horst Schmidt Kliniken

Wiesbaden, 65199, Germany

Location

Klinikum der Stadt Wolfsburg

Wolfsburg, 38440, Germany

Location

University Hospital Würzburg

Würzburg, 97080, Germany

Location

Our Lady's Children's Hospital

Dublin, 12, Ireland

Location

Fondazione IRCCS Istituto Nazionale Tumori

Milan, 20133, Italy

Location

Prinses Máxima Center for Pediatric Oncology

Bilthoven, 3720, Netherlands

Location

Rigshospitalet

Oslo, 0424, Norway

Location

The Children's Memorial Health Institute

Warsaw, 04-730, Poland

Location

University Hospital S.Joao

Porto, 4200, Portugal

Location

Oncology Hospital Cruces Bilbao

Barakaldo, 48903, Spain

Location

Barncancercentrum Drottning Silvias Barnochungdomssjukhus

Göteburg, 41685, Sweden

Location

University Children's Hospital

Zurich, 8032, Switzerland

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

MeSH Terms

Conditions

Brain Neoplasms; Medulloblastoma; Neuroectodermal Tumors, Primitive

Interventions

Radiotherapy; Carboplatin; Cisplatin; Lomustine; Vincristine; Cyclophosphamide; Maintenance Chemotherapy; Induction Chemotherapy; Diploidy

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Coordination Complexes; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Drug Therapy; Remission Induction; Ploidies; Genetic Phenomena

Study Officials

• Francois Doz, Prof. Dr.

  Institut Curie Paris, France

  PRINCIPAL INVESTIGATOR

• Till Milde, Dr. med.

  Hopp Children´s Tumor Center at the NCT (KiTZ) and German Cancer Research Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2014
• First Posted: February 19, 2014
• Study Start: June 1, 2014
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 4, 2025

Record last verified: 2025-11

Locations

DE (59); PT (1); CZ (1); SE (1); DK (1); AU (1); CH (1); IE (1); BE (1); PL (1); IT (1); NL (1); ES (1); FR (4); NO (1); GB (1)