Clinical Trials /

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

NCT02066220

Description:

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.

Related Conditions:
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
  • Official Title: An International Prospective Study on Clinically Standard-risk Medulloblastoma in Children Older Than 3 to 5 Years With Low-risk Biological Profile (PNET 5 MB-LR) or Average-risk Biological Profile (PNET 5 MB-SR)

Clinical Trial IDs

  • ORG STUDY ID: SIOP PNET 5 MB
  • SECONDARY ID: 2011-004868-30
  • NCT ID: NCT02066220

Conditions

  • Brain Tumors

Interventions

DrugSynonymsArms
Reduced-intensity maintenance chemotherapyCisplatin, Lomustin (CCNU), Vincristine, CyclophosphamidePNET 5 MB-LR (low-risk)
Maintenance chemotherapyCisplatin, Lomustine (CCNU), Vincristine, CyclophosphamidePNET 5 MB-SR (standard-risk)

Purpose

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.

Detailed 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 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-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 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.
    

Trial Arms

NameTypeDescriptionInterventions
PNET 5 MB-LR (low-risk)ExperimentalRadiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.
  • Reduced-intensity maintenance chemotherapy
PNET 5 MB-SR (standard-risk)ExperimentalRadiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks.
  • Maintenance chemotherapy

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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:3-year Event-Free Survival (EFS)
Time Frame:LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall survival
Time Frame:10 years
Safety Issue:
Description:
Measure:Pattern of relapse
Time Frame:10 years
Safety Issue:
Description:Defined in 5 categorical variables: no relapse, local relapse, distant relapse, local and distant relapse, death
Measure:Late effects of therapy on endocrine function
Time Frame:10 years
Safety Issue:
Description: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
Measure:Late effects of therapy on audiology
Time Frame:8 years
Safety Issue:
Description:measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)
Measure:Late effects of therapy on neurology
Time Frame:10 years
Safety Issue:
Description: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)
Measure:Late effects of therapy on quality of survival
Time Frame:10 years
Safety Issue:
Description: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
Measure:Progression-free survival
Time Frame:10 years
Safety Issue:
Description:
Measure:Feasibility of carboplatin treatment
Time Frame:approx. 7 years
Safety Issue:
Description:measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy
Measure:Residual tumor
Time Frame:6 years
Safety Issue:
Description:measured by central MRI review postoperatively
Measure:Leukoencephalopathy grading
Time Frame:8 years
Safety Issue:
Description:measured 2 years after diagnosis grades 0, 1, 2, 3, 4

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Universitätsklinikum Hamburg-Eppendorf

Trial 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

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