Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00005864

Trial Description

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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)

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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 23.4 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.

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Organizational Data

  •   DRKS00005864
  •   2014/04/29
  •   2014/02/07
  •   yes
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Secondary IDs

  •   2011-004868-30 
  •   NCT02066220  (ClinicalTrials.gov)
  •   SIOP PNET 5 MB  (Universitätsklinikum Hamburg-Eppendorf)
  •   2011-004868-30 
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Health Condition or Problem studied

  •   Brain Tumors
  •   C71 -  Malignant neoplasm of brain
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Interventions/Observational Groups

  •   Radiation: Radiotherapy without Carboplatin
  •   Drug: Reduced-intensity maintenance chemotherapy
  •   Radiation: Radiotherapy with Carboplatin
  •   Drug: Maintenance chemotherapy
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Treatment
  •   Parallel
  •   II-III
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Primary Outcome

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

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Secondary Outcome

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

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Countries of Recruitment

  •   Austria
  •   Belgium
  •   Czech Republic
  •   Denmark
  •   France
  •   Germany
  •   Ireland
  •   Italy
  •   Netherlands
  •   Norway
  •   Poland
  •   Portugal
  •   Spain
  •   Sweden
  •   Switzerland
  •   United Kingdom
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Locations of Recruitment

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Recruitment

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  •   2014/04/30
  •   360
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   3   Years
  •   21   Years
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Additional Inclusion Criteria

1. Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22
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 second surgery is performed within 14 days after first
surgery.

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.

5. No amplification of MYC or MYCN (determined by FISH).

6. For LR-arm: Low-risk biological profile, defined as ß-catenin nuclear
immuno-positivity by IHC (mandatory) and / or mutation analysis (optional); 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. Failure to start
radiotherapy within 40 days after surgery renders patients ineligible for the study.

9. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function

10. 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.

11. 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.

12. No identified Turcot and Li Fraumeni syndrome.

13. Written informed consent (and patient assent where appropriate) for therapy according
to the laws of each participating country.

14. National and local ethical committee approval according to the laws of each
participating country (to include approval for biological studies).

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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.

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 beta-catenin 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.

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Addresses

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    • Universitätsklinikum Hamburg-Eppendorf
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    • Deutsche Kinderkrebsstiftung
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  • start of 1:1-Block address scientific-contact
    • Institut Curie Paris, France
    • Francois Doz, Prof. Dr. 
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    • Stefan Rutkowski, Prof. Dr. med. 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   2
  •   2014/02/23
* This entry means the parameter is not applicable or has not been set.