International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

  • STATUS
    Recruiting
  • End date
    Apr 21, 2024
  • participants needed
    360
  • sponsor
    Universitätsklinikum Hamburg-Eppendorf
Updated on 21 January 2021
residual tumor
metastasis
nervous
medulloblastoma

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 -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.

Description

The aim of the LR-treatment arm 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 -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-arm 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 -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.

Details
Condition Malignant neoplasm of brain, Brain Tumor (Pediatric), Brain Cancer, Brain Tumor, brain tumors
Treatment Maintenance Chemotherapy, Radiotherapy without Carboplatin, Reduced-intensity maintenance chemotherapy, Radiotherapy with Carboplatin
Clinical Study IdentifierNCT02066220
SponsorUniversitätsklinikum Hamburg-Eppendorf
Last Modified on21 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 3 yrs and 21 yrs?
Gender: Male or Female
Do you have Malignant neoplasm of brain?
Do you have any of these conditions: brain tumors or Brain Tumor (Pediatric) or Malignant neoplasm of brain or Brain Tumor or Brain Cancer?
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) -catenin mutation (mandatory testing), or (ii) -catenin nuclear immuno-positivity by IHC (mandatory testing) and -catenin mutation, or (iii) -catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing)
For SR-arm: average-risk biological profile, defined as -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)

Exclusion Criteria

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
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