International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

Brain Tumors Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02066220
• Other study ID #: SIOP PNET 5 MB
• Secondary ID: 2011-004868-30
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: June 2014
• Est. completion date: December 2026

Study information

• Verified date: April 2022
• Source: Universitätsklinikum Hamburg-Eppendorf
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 360
• Est. completion date: December 2026
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Brain Neoplasms
• Brain Tumors
• Medulloblastoma

Intervention

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
• 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)
• 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
• 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

Locations

Country	Name	City	State
Austria	Medical University of Graz	Graz
Belgium	University Hospital Gasthuisberg	Leuven
Czechia	University Hospital Brno	Brno
Denmark	Rigshospitalet	Copenhagen
France	CHU de Grenoble	Grenoble
France	Institute Curie	Paris Cedex 05
France	CHU-TOURS - Hôpital Clocheville	Tours
France	Hôpital NANCY-BRABOIS	Vandoeuvre Les Nancy
Germany	University Hospital Aachen	Aachen
Germany	Klinikum Augsburg	Augsburg
Germany	Charite Campus, University of Berlin	Berlin
Germany	Helios Klinikum Berlin-Buch	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	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
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	Hannover
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	Kliniken der Stadt Köln	Köln
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	Klinikum Schwabing, Pediatric Hospital of Technical University	München
Germany	University Hospital München, Dr. von Haunersches Kinderspital	München
Germany	University Hospital Münster	Münster
Germany	Cnopf'sche Kinderklinik	Nürnberg
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
Ireland	Our Lady's Children's Hospital	Dublin
Italy	Fondazione IRCCS Istituto Nazionale Tumori	Milano
Netherlands	Prinses Máxima Center for Pediatric Oncology	Bilthoven
Norway	Rigshospitalet	Oslo
Poland	The Children's Memorial Health Institute	Warsaw
Portugal	University Hospital S.Joao	Porto
Spain	Oncology Hospital Cruces Bilbao	Baracaldo
Sweden	Barncancercentrum Drottning Silvias Barnochungdomssjukhus	Göteburg
Switzerland	University Children's Hospital	Zürich
United Kingdom	Great Ormond Street Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
Universitätsklinikum Hamburg-Eppendorf	Deutsche Kinderkrebsstiftung

Countries where clinical trial is conducted

Austria,  Belgium,  Czechia,  Denmark,  France,  Germany,  Ireland,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	3-year Event-Free Survival (EFS)		LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)
Secondary	Overall survival		10 years
Secondary	Pattern of relapse	Defined in 5 categorical variables: no relapse, local relapse, distant relapse, local and distant relapse, death	10 years
Secondary	Late effects of therapy on endocrine function	measured as; subfertility (FSH > 15 IU/L); endocrine deficits (hormone supplementation necessary); growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 years	10 years
Secondary	Late effects of therapy on audiology	measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)	8 years
Secondary	Late effects of therapy on neurology	Measured as; presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively); presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy); cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years); presence of symptoms for brain nerve dysfunction (2 and 5 years after diagnosis and age of 18 years)	10 years
Secondary	Late effects of therapy on quality of survival	measured with standardized questionnaires/ scores: HUI3 (health status); BRIEF (executive functions); SDQ (behavioural outcome); PedsQL (quality of life); QLQ-C30 (quality of life); MEES (neurological function, educational provision); MFI (fatigue) 2 and 5 years after diagnosis and age of 18 years	10 years
Secondary	Progression-free survival		10 years
Secondary	Feasibility of carboplatin treatment	measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy	approx. 7 years
Secondary	Residual tumor	measured by central MRI review postoperatively	6 years
Secondary	Leukoencephalopathy grading	measured 2 years after diagnosis grades 0, 1, 2, 3, 4	8 years