SIOP PNET 5 medulloblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Medical Center Hamburg-Eppendorf

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Deutsche Kinderkrebsstiftung

External identifiers

EU CT number

2024-513724-42-00

EudraCT number

2011-004868-30

ClinicalTrials.gov

NCT02066220

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

LR-Arm: to confirm that the 3-year Event-Free Survival (EFS) rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when patients are treated with 18.0 Gy neuraxis irradiation plus boost to the primary tumour, and reduced-intensity chemotherapy.

SR-Arm: to test whether the Event-Free Survival (EFS) in children and adolescents with standard-risk medulloblastoma having an average-risk biological profile is different for patients treated with or without carboplatin concomitantly with radiotherapy (23.4 Gy neuraxis irradiation plus boost to the primary tumour) followed by a modified maintenance chemotherapy.

WNT-HR-Arm: - to confirm the 3-year event-free survival (EFS) of rate of 80 % in children and adolescents with high-risk medulloblastoma having a low-risk biological profile when patients are treated with 23.4 Gy (35.2 Gy) neuraxis irradiation plus boost to the primary tumour (and metastates, if applicable) and reduced-intensity chemotherapy.

SHH-TP53-Arm: to determine the superiority of EFS in MB SHH-TP53-mutant patients receiving treatment adapted to presence of somatic or germline TP53 mutation in comparison to historic MB SHH TP53mut cohort.

Secondary objectives 12

1. All arms: to investigate the Overall Survival (OS) rate, and the pattern of relapse in the respective patient group
2. All arms: to study the late effects of the respective approach, focusing on hearing, endocrine, and neurologic function, and standardized, patients/ parents rated measurments of health status, executive function, behavioural outcome, medical, educational, employment and social situation, and quality of life
3. LR and WNT-HR: to conduct comprehensive studies in a prospective fashion on the biological basis of WNT-subgroup medulloblastoma, with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in this disease subgroup. These investigations will focus on (i). detailed analysis of biological pathways and molecular events established to play a role in medulloblastoma, or that are of potential prognostic significance in this disease group, (ii). comprehensive genome-wide investigations of novel medulloblastoma defects, and (iii). defining diagnostic correlates of WNT pathway activation
4. SR: to investigate the Progession-free survival rates (PFS) in the randomized treatment arms.
5. SR: to test the feasibility of carboplatin treatment concomitantly with radiotherapy
6. SR: to conduct comprehensive studies in a prospective fashion on the biological basis of standard-risk medulloblastoma, with the aim of identification, investigation and validation of biomarkers (diagnostic, prognostic and predictive) and drug targets with therapeutic potential in this disease subgroup. These investigations will focus on (i). detailed analysis of biological pathways and molecular events established to play a role in medulloblastoma, or that have been shown to have potential prognostic significance in this disease subgroup (e.g. chromosome 17 abnormalities), and (ii). comprehensive genome-wide investigations of novel medulloblastoma defects
7. SHH-TP53: response after 1 and 2 cycles chemotherapy
8. SHH-TP53: response after RT
9. SHH-TP53: frequency of second malignancies after treatment
10. SHH-TP53: detection of increased treatment toxicity
11. SHH-TP53: to study late effects of this approach, focusing on second malignancy
12. SHH-TP53: to conduct comprehensive studies on the biological basis of SHH-activated TP53-mutant medulloblastoma in a prospective fashion, with the aim to evaluate germline-somatic correlations, correlations of genotype and phenotype

Conditions and MedDRA coding

Medulloblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 28

1. LR: Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 16 years
2. LR-, SR-, WNT-HR-arm: No significant sensineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing no impairement ≥ 20 dB at 1-3 kHz (best ear). If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit
3. LR-, SR-, WNT-HR-arm: No identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration (evaluation of PALB2 and BRCA2 not mandatory). No unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours
4. All arms: No other medical contraindication to protocol therapy
5. All arms: 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
6. All arms: National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies)
7. SR: Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years
8. SR: Histologically proven and genetically defined medulloblastoma including the following subtypes, as defined in the WHO classification (2016): - medulloblastoma, SHH-activated and TP53-wildtype - medulloblastoma, non-WNT/non-SHH medulloblastoma, group 3 medulloblastoma, group 4 Histologic subtype: - medulloblastoma, classic - medulloblastoma, desmoplastic/nodular Pre-treatment central pathology review, as well as central molecular diagnosis of genetically defined subgroup is mandatory
9. SR: No amplification of MYC or MYCN (determined by FISH or aCGH); MYCN amplification allowed for patients with group 4 medulloblastoma
10. SR: WNT-subgroup negativity
11. SR: For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH and SUFU is required, and recommended for BRCA2 and PALB2. Exclusion of somatic mutation is sufficient for enrolment of the patient. In case of somatic alteration, urgent diagnostic evaluation for germline alteration after appropriate consent is necessary
12. LR: Histologically proven and genetically defined medulloblastoma including the following subgroups, as defined in the WHO classification (2016): medulloblastoma, WNT-activated Histologic subtype: medulloblastoma, classic or medulloblastoma, desmoplastic/nodular; Pre-treatment central pathology review, as well as central molecular confirmation of WNT-activation is considered mandatory
13. WNT-HR, SHH-TP53: Age at diagnosis, at least 3–5 years (depending on the country)
14. WNT-HR: Histologically proven and genetically defined medulloblastoma including the following subgroups, as defined in the WHO classification (2016): medulloblastoma, WNT-activated; Histologic subtype: classic medulloblastoma, desmoplastic/nodular medulloblastoma, large-cell/anaplastic medulloblastoma
15. LR, SR: Clinically standard -risk medulloblastoma
16. All arms: Submission of high quality biological material including fresh frozen tumour samples and blood for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centersSubmission of CSF is recommended
17. LR: No amplification of MYC or MYCN (determined by FISH or aCGH)
18. LR: Low-risk biological profile, defined as presence of β-catenin mutation (mandatory testing) resulting in WNT activation
19. LR, SR, WNT-HR: No prior therapy for medulloblastoma other than surgery
20. All arms: Postoperative therapy aiming to start no more than 28 days after surgery. Foreseeable inability to start therapy within 40 days after surgery renders patients ineligible for the study
21. All arms: CTC grades < 2 for liver, renal, haematological function
22. WNT-HR: Low-risk biological profile, defined as WNT-subgroup positivity
23. WNT-HR: Clinical high risk features
24. SHH-TP53: Histologically proven medulloblastoma, genetically defined as SHH-activated TP53 mutant, as defined in the WHO classification (2016)
25. SHH-TP53: Patients can be included irrespective of histological subtype of medulloblastoma (inclusion of AMB, DMB, CMB, LCMB and MBEN allowed) and irrespective of evidence of MYC/MYCN amplification (inclusion if MYC/MYCN amplification is absent or present)
26. SHH-TP53: Complete postoperative staging investigations according to PNET 5 MB – standards (pre- and postoperative MRI, spinal MRI, cytospin of lumbar CSF with sufficient quality and central review where applicable) is required; patients are eligible irrespective of staging result, i.e. with or without residual tumor, and localized or metastatic disease
27. SHH-TP53: Evaluation of germline TP53 status is required before start of irradiation. Patients with germline TP53 mutation, TP53 mosaicism and/ or somatic TP53 mutation are eligible.
28. SHH-TP53: Diagnosis of SHH-activated TP53-mutant medulloblastoma as first or secondary malignancy

Exclusion criteria 15

1. All arms: One of the inclusion criteria is lacking
2. All arms: Brainstem or supratentorial embryonal tumour
3. All arms: Atypical teratoid rhabdoid tumour
4. All arms: Patients who are pregnant
5. All arms: Female patients who are sexually active and not taking reliable contraception
6. All arms: Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons
7. All arms: Patients in whom non-compliance with toxicity management guidelines can be expected
8. LR, SR: Medulloepithelioma, embryonal tumour with multi-layered rosettes
9. LR, SR: Large cell/anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review
10. LR, SR: Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable
11. LR, SR: Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF)
12. LR, SR, WNT-HR: Patient previously treated for a brain tumour or any type of malignant disease
13. LR, SR, WNT-HR: Identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration. Unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours
14. SR: Identified somatic TP53 mutation in SHH activated tumours
15. SHH-TP53: Patients who refuse testing for germline TP53-mutations

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. All arms: The primary outcome measure is event-free survival (EFS).

Secondary endpoints 13

1. All arms: The rate of overall survival (OS), and the rate of progression-free survival (PFS), estimated by the Kaplan-Meier method, are secondary outcome measures.
2. All arms: Pattern of relapse is a secondary outcome measure. The site and time to local progression will be the measures for local tumour control. Particular attention will be given to posterior fossa relapse, i.e. local relapse within the tumour bed, or metastatic relapse to the posterior fossa outside the tumour bed. The time period begins on the date of surgery and ends on the date of appearance of relapse/progression. The appearance of metastases will not be regarded as local progression.
3. SR: Feasibility of carboplatin treatment concomitantly to radiotherapy is a secondary outcome measure. The timely delivery of maintenance chemotherapy, the number of interruption days, and the grade of weight change, dysphagia and esophagitis, transfusion requirement, haematological toxicities, and infection during therapy, as well as ototoxicity are measures of the feasibility of additional carboplatin.
4. All arms: Indirect measures of quality of survival (QoS) are a secondary outcome measure. Standardized, patients/ parents rated scales for measurement of health status (HUI3), executive function (BRIEF), behavioural outcome (SDQ), medical, educational, employment and social situation (MEES), Fatigue (PedsQL Multidimensional Fatigue Scale and, in adults, the MFI), and quality of life (PedsQL and, in adults, the QLQ-C30) will be the indirect measures for QoS.
5. All arms: Audiological toxicity is a secondary outcome measure. The extent of ototoxicity based dose modifications of maintenance chemotherapy, as well as the results of Pure Tone Audiometry (PTA) graded by the Chang criteria evaluated 2 years after diagnosis will be the measures for audiological toxicity.
6. All arms: Endocrine function is a secondary outcome measure. FSH levels (cut-off level >15 IU/l) will be used as biomarker for subfertility. Growth retardation will be calculated as the difference in height standard deviation score (sds) from diagnosis, and the need for, time to, and duration of hormone supplementation will be used as surrogate markers for endocrine deficits. All measures will be evaluated 2 and 5 years from diagnosis/surgery and again in adulthood at 18 years.
7. All arms: Neurological function is an outcome measure. The occurrence and severity of posterior fossa syndrome (as measured by the cerebellar mutism syndrome survey), and the occurrence and severity of persisting cerebellar symptoms (measured by the brief ataxia rating scale) will be the measures for neurological function.
8. All arms: The prognostic value of biological tumour markers is an outcome measure. Results of protein expression (including immunohistochemistry), RNA expression, and DNA analysis assays undertaken on tumour, blood or CSF material will be the measures for biological properties.
9. SHH-TP53: Response rate
10. SHH-TP53: Duration of response
11. SHH-TP53: Incidence of secondary malignancies
12. SHH-TP53: Incidence of local, metastastatic and combined relapses in relation to radiation field (inside or outside of radiation field)
13. SHH-TP53: Incidence of somatic, germline, and mosaic TP53 mutations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Medical Center Hamburg-Eppendorf

Sponsor organisation

University Medical Center Hamburg-Eppendorf

Address

Martinistrasse 52, Eppendorf Eppendorf

City

Hamburg

Postcode

20246

Country

Germany

Scientific contact point

Organisation

University Medical Center Hamburg-Eppendorf

Contact name

Prof. Dr. Stefan Rutkowski

Public contact point

Organisation

University Medical Center Hamburg-Eppendorf

Contact name

Regine Riechers

Locations

10 EU/EEA countries · 116 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 260 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications