Clinical trial NCT02066220: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
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
Lead sponsor: Universitätsklinikum Hamburg-Eppendorf
Sponsor class: OTHER
Collaborators: name: Deutsche Kinderkrebsstiftung
First posted: 2014-02-19
Enrollment: 360
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: 3-year Event-Free Survival (EFS)
timeFrame: LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)
Secondary outcomes:
measure: Overall survival
timeFrame: 10 years
measure: Pattern of relapse
timeFrame: 10 years
measure: Late effects of therapy on endocrine function
timeFrame: 10 years
measure: Late effects of therapy on audiology
timeFrame: 8 years
measure: Late effects of therapy on neurology
timeFrame: 10 years
measure: Late effects of therapy on quality of survival
timeFrame: 10 years
measure: Progression-free survival
timeFrame: 10 years
measure: Feasibility of carboplatin treatment
timeFrame: approx. 7 years
measure: Residual tumor
timeFrame: 6 years
measure: Leukoencephalopathy grading
timeFrame: 8 years
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
city: Brno
country: Czechia
facility: University Hospital Brno
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Grenoble
country: France
facility: CHU de Grenoble
city: Paris Cedex 05
country: France
facility: Institute Curie
city: Tours
country: France
facility: CHU-TOURS - Hôpital Clocheville
city: Vandoeuvre Les Nancy
country: France
facility: Hôpital NANCY-BRABOIS
city: Aachen
country: Germany
facility: University Hospital Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: Charite Campus, University of Berlin
city: Bielefeld
country: Germany
facility: Evangelisches Krankenhaus Bielefeld
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Braunschweig
country: Germany
facility: Klinikum Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz
city: Cologne
country: Germany
facility: University Hospital Cologne
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinder- und Jugendklinik, University Witten/Herdecke
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: University Hospital Dresden
city: Duisburg
country: Germany
facility: Klinikum Duisburg
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf
city: Erfurt
country: Germany
facility: HELIOS Klinikum-Erfurt
city: Erlangen
country: Germany
facility: University Hospital Erlangen
city: Essen
country: Germany
facility: University Hospital Essen
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt/Main
city: Freiburg
country: Germany
facility: University Hospital Freiburg
city: Gießen
country: Germany
facility: University Hospital Gießen and Marburg
city: Greifswald
country: Germany
facility: University Hospital Greifswald
city: Göttingen
country: Germany
facility: University Hospital Göttingen
city: Halle
country: Germany
facility: University Hospital Halle/Saale
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Angelika-Lautenschläger-Klinik
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus Herdecke
city: Homburg
country: Germany
facility: University Hospital Homburg/Saar
city: Jena
country: Germany
facility: University Hospital Jena
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: UK-SH Campus Kiel
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Koblenz-Mayen
city: Krefeld
country: Germany
facility: HELIOS Klinikum Krefeld
city: Köln
country: Germany
facility: Kliniken der Stadt Köln
city: Leipzig
country: Germany
facility: University Hospital Leipzig
city: Lübeck
country: Germany
facility: University Hospital Lübeck
city: Magdeburg
country: Germany
facility: University Hospital Magdeburg
city: Mainz
country: Germany
facility: University Hospital Mainz
city: Mannheim
country: Germany
facility: University Hospital Mannheim
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: University Hospital München, Dr. von Haunersches Kinderspital
city: München
country: Germany
facility: Klinikum Schwabing, Pediatric Hospital of Technical University
city: Münster
country: Germany
facility: University Hospital Münster
city: Nürnberg
country: Germany
facility: Cnopf'sche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Regensburg
country: Germany
facility: University Hospital Regensburg
city: Rostock
country: Germany
facility: University Hospital Rostock
city: Sankt Augustin
country: Germany
facility: Asklepios Klinik Sankt Augustin
city: Schwerin
country: Germany
facility: HELIOS-Kliniken Schwerin
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Ulm
country: Germany
facility: University Hospital Ulm
city: Wiesbaden
country: Germany
facility: Dr. Horst Schmidt Kliniken
city: Wolfsburg
country: Germany
facility: Klinikum der Stadt Wolfsburg
city: Würzburg
country: Germany
facility: University Hospital Würzburg
city: Dublin
country: Ireland
facility: Our Lady's Children's Hospital
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale Tumori
city: Bilthoven
country: Netherlands
facility: Prinses Máxima Center for Pediatric Oncology
city: Oslo
country: Norway
facility: Rigshospitalet
city: Warsaw
country: Poland
facility: The Children's Memorial Health Institute
city: Porto
country: Portugal
facility: University Hospital S.Joao
city: Baracaldo
country: Spain
facility: Oncology Hospital Cruces Bilbao
city: Göteburg
country: Sweden
facility: Barncancercentrum Drottning Silvias Barnochungdomssjukhus
city: Zürich
country: Switzerland
facility: University Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Institut Curie Paris, France
name: Francois Doz, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopp Children´s Tumor Center at the NCT (KiTZ) and German Cancer Research Center
name: Till Milde, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: