International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma (NCT02066220) — Ireland Trial Details

Condition(s) studied

Brain Tumors

Investigational drug(s) / intervention(s)

Radiotherapy without CarboplatinReduced-intensity maintenance chemotherapyRadiotherapy with CarboplatinMaintenance chemotherapyWNT-HR < 16 yearsWNT-HR >= 16 yearsInduction ChemotherapySHH-TP53 M0SHH-TP53 M+ (germline)SHH-TP53 (somatic)Vinblastin Maintenance

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

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.

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.

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).

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

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

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

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

Study 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.

Eligibility

Sex

ALL

Min age

3 Years

Max age

21 Years

Healthy volunteers

No

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 outcome measure(s)

3-year Event-Free Survival (EFS) — LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)

Trial sites (77)

Facility	City	Region
Medical University of Graz	Graz	Austria
University Hospital Gasthuisberg	Leuven	Belgium
University Hospital Brno	Brno	Czechia
Rigshospitalet	Copenhagen	Denmark
CHU de Grenoble	Grenoble	France
Institute Curie	Paris	France
CHU-TOURS - Hôpital Clocheville	Tours	France
Hôpital NANCY-BRABOIS	Vandœuvre-lès-Nancy	France
University Hospital Aachen	Aachen	Germany
Klinikum Augsburg	Augsburg	Germany
Helios Klinikum Berlin-Buch	Berlin	Germany
Charite Campus, University of Berlin	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
Kliniken der Stadt Köln	Cologne	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 im Breisgau	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	Hanover	Germany
Angelika-Lautenschläger-Klinik	Heidelberg	Germany
Gemeinschaftskrankenhaus Herdecke	Herdecke	Germany
University Hospital Homburg/Saar	Homburg	Germany
University Hospital Jena	Jena	Germany

+ 37 more sites — see the full list on the official registry below.