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Trial record 1 of 1 for:    NCT02066220
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International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02066220
Recruitment Status : Active, not recruiting
First Posted : February 19, 2014
Last Update Posted : April 19, 2022
Sponsor:
Collaborator:
Deutsche Kinderkrebsstiftung
Information provided by (Responsible Party):
Universitätsklinikum Hamburg-Eppendorf

Tracking Information
First Submitted Date  ICMJE February 7, 2014
First Posted Date  ICMJE February 19, 2014
Last Update Posted Date April 19, 2022
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date December 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 16, 2014)
3-year Event-Free Survival (EFS) [ Time Frame: LR-arm after 9 years, SR-arm after 105 events (approx. 10 years) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 16, 2014)
  • 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
    1. subfertility (FSH > 15 IU/L)
    2. endocrine deficits (hormone supplementation necessary)
    3. 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
    1. presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively)
    2. presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy)
    3. cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years)
    4. 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:
    1. HUI3 (health status)
    2. BRIEF (executive functions)
    3. SDQ (behavioural outcome)
    4. PedsQL (quality of life)
    5. QLQ-C30 (quality of life)
    6. MEES (neurological function, educational provision)
    7. 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
Official Title  ICMJE AN INTERNATIONAL PROSPECTIVE TRIAL ON MEDULLOBLASTOMA (MB) IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH WNT BIOLOGICAL PROFILE (PNET 5 MB - LR and PNET 5 MB - WNT-HR), AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR), OR TP53 MUTATION, AND REGISTRY FOR MB OCCURRING IN THE CONTEXT OF GENETIC PREDISPOSITION
Brief 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.

Detailed Description

The aim of the LR-study 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-study 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.

The primary aim of the WNT-HR study is to maintain a 3-year EFS over 80 %. The small number of patients does not allow neither conventional methods of test size and power, nor strict stopping rules. The 3-year EFS will be estimated by the Kaplan-Meier method at the end of the trial and its two-sided 95 % confidence interval will be calculated.

The primary endpoint of the SHH-TP53 study is event-free survival (EFS). The aim of the study is the comparison of EFS between patients receiving a dose reduced induction chemotherapy, radiotherapy and maintenance chemotherapy and a historic population from unpublished data.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Brain Tumors
Intervention  ICMJE
  • Radiation: 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

  • Drug: 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.

    Other Names:
    • Cisplatin
    • Lomustin (CCNU)
    • Vincristine
    • Cyclophosphamide
  • Radiation: 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.
    Other Name: Carboplatin
  • Drug: 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).

    Other Names:
    • Cisplatin
    • Lomustine (CCNU)
    • Vincristine
    • Cyclophosphamide
  • Radiation: 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
  • Radiation: 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
  • Drug: 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
  • Radiation: 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)
  • Radiation: 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
  • Radiation: 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
  • Drug: Vinblastin Maintenance
    Weekly VBL (5mg/m², max. 10mg/dose) for 24 weeks
Study Arms  ICMJE
  • Experimental: PNET 5 MB-LR (low-risk)
    Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.
    Interventions:
    • Radiation: Radiotherapy without Carboplatin
    • Drug: Reduced-intensity maintenance chemotherapy
  • Experimental: PNET 5 MB-SR (standard-risk)

    Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy.

    Total treatment duration is 48 weeks.

    Interventions:
    • Radiation: Radiotherapy without Carboplatin
    • Radiation: Radiotherapy with Carboplatin
    • Drug: Maintenance chemotherapy
  • Experimental: PNET 5 MB WNT-HR

    Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age.

    Total treatment duration is 39 to 48 weeks.

    Interventions:
    • Drug: Maintenance chemotherapy
    • Radiation: WNT-HR < 16 years
    • Radiation: WNT-HR >= 16 years
  • Experimental: PNET 5 MB SHH-TP53

    Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to

    • presence of metastasis
    • germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year
    Interventions:
    • Drug: Induction Chemotherapy
    • Radiation: SHH-TP53 M0
    • Radiation: SHH-TP53 M+ (germline)
    • Radiation: SHH-TP53 (somatic)
    • Drug: Vinblastin Maintenance
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 16, 2014)
360
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Czechia,   Denmark,   France,   Germany,   Ireland,   Italy,   Netherlands,   Norway,   Poland,   Portugal,   Spain,   Sweden,   Switzerland,   United Kingdom
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02066220
Other Study ID Numbers  ICMJE SIOP PNET 5 MB
2011-004868-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Universitätsklinikum Hamburg-Eppendorf
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Universitätsklinikum Hamburg-Eppendorf
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Deutsche Kinderkrebsstiftung
Investigators  ICMJE
Principal Investigator: Francois Doz, Prof. Dr. Institut Curie Paris, France
Principal Investigator: Till Milde, Dr. med. Hopp Children´s Tumor Center at the NCT (KiTZ) and German Cancer Research Center
PRS Account Universitätsklinikum Hamburg-Eppendorf
Verification Date April 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP