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

International Society of Paediatric Oncology (SIOP) PNET 5 <span class="go-doc-concept go-doc-disease">Medulloblastoma</span>

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

    NCT ID: NCT02066220

    ORG ID: SIOP PNET 5 MB

    NCI ID: 2011-004868-30

    Trial Conditions

    Brain Tumors

    Trial Interventions

    Drug Synonyms Arms
    Reduced-intensity maintenance chemotherapy Cisplatin, Lomustin (CCNU), Vincristine, Cyclophosphamide PNET 5 MB-LR (low-risk)
    Maintenance chemotherapy Cisplatin, Lomustine (CCNU), Vincristine, Cyclophosphamide PNET 5 MB-SR (standard-risk)

    Trial 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 -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 -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.

    Trial Arms

    Name Type Description Interventions
    PNET 5 MB-LR (low-risk) Experimental Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks. Reduced-intensity maintenance chemotherapy
    PNET 5 MB-SR (standard-risk) Experimental Radiotherapy 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) -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).

    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.

    Minimum Eligible Age: 3 Years

    Maximum Eligible Age: 21 Years

    Eligible Gender: Both

    Primary Outcome Measures

    3-year Event-Free Survival (EFS)

    Secondary Outcome Measures

    Overall survival

    Pattern of relapse

    Late effects of therapy on endocrine function

    Late effects of therapy on audiology

    Late effects of therapy on neurology

    Late effects of therapy on quality of survival

    Progression-free survival

    Feasibility of carboplatin treatment

    Residual tumor

    Leukoencephalopathy grading

    Trial Keywords

    pediatric brain tumor

    medulloblastoma

    event-free survival (EFS)

    progression-free survival (PFS)

    overall survival (OS)

    PNET

    posterior fossa

    chemotherapy

    radiotherapy

    biological profile

    -catenin