Comparison of neurocognitive outcome in two standard regimen for treatment of low-risk medulloblastoma (COGNITO-MB)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GPOH gGmbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-08-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Bundesministerium für Bildung und Forschung (BMBF)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others

To compare neurocognitive outcomes 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified MB randomized to the interventional arms A (“Head Start” 4) and B (HITSKK)

Secondary objectives 16

1. Progression-free survival (PFS) compared between randomized groups
2. Radiotherapy-free/progression-free survival (rtPFS) compared between randomized groups
3. Overall survival (OS) compared between randomized groups
4. Incidence of second malignancies compared between randomized groups
5. Acute toxicities compared between randomized groups
6. Incidence of therapy-related deaths compared between randomized groups
7. Neurocognitive outcomes at baseline and 5 years after diagnosis compared between randomized groups
8. Subdomain-specific neurocognitive outcome parameters (2.5 and 5 years after diagnosis) compared between randomized groups
9. Development and adaptive functioning (at diagnosis, 2.5 and 5 years after diagnosis) compared between randomized groups
10. QoL (at diagnosis, 2.5 and 5 years after diagnosis) between randomized groups
11. Longitudinal development of neurocognitive, QoL, and behavioral outcomes 5 years after diagnosis compared between randomized groups
12. Ototoxicity at 2.5 years and 5 years after diagnosis compared between randomized groups
13. LEP 2.5 and 5 years after diagnosis compared between randomized groups
14. To compare PFS, rtPFS,OS between randomized groups in patients in CR at end of study therapy
15. To compare PFS, rtPFS, OS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher)
16. To assess the rate of patients with genetically confirmed ba-sal-cell nevus syndrome (BCNS, Gorlin-Syndrome, OMIM: 109400), ELP1 and GPR161 cancer predisposition syndromes among eligible enrolled patients

Conditions and MedDRA coding

newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified medulloblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age at diagnosis < 5 years
2. Patients with institutional suspicion or diagnosis of SHH-activated MB
3. Patient and family in social circumstances that will allow neuropsychological follow-up
4. Ability of parents/legal representatives to understand the patient information and to personal-ly sign and date the informed consent to participate in screening procedures
5. Patient and the parents/legal representatives are able and willing to participate in the entire study (if patient is eligible)

Exclusion criteria 7

1. Patient previously treated for a brain tumor or any type of malignant disease
2. Patients, in whom compliance with toxicity management guidelines and study procedures cannot be assured
3. History of hypersensitivity to an investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of an investigational medicinal product
4. Patients/parents who do not wish to abstain from treatment with live vaccines during study participation
5. Patients with a language barrier too extensive to complete neuropsychological tests based on the investigator’s judgment
6. Patients with severe premorbid developmental delay (based on the investigator’s judgment), which will not allow WPPSI-IV assessment after 2.5 years
7. Patients that cannot undergo MRI

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Full-Scale Intelligence Quotient (IQ) as measured by the Wechsler Pre-school and Primary Scale of Intelligence (WPPSI-IV) administered to those between the ages of 2 years and 6 months to 7 years and 7 months old at 2.5 years after diagnosis (+/- 6 months)

Secondary endpoints 23

1. Progression-free survival (PFS): time from diagnosis to first re-lapse, first disease pro-gression or death, whichever occurs first. Censored at the time of last contact in patients with-out event
2. Survival free of radiotherapy and progression (rtPFS): Time from diagnosis to first radiotherapy, first relapse, first disease progression or death, whatever is first. Censored at last contact in patients without event
3. Overall survival (OS): time from diagnosis to death due to any cause. Censored at the time of last contact in alive patients
4. Time to first second malignancy: time from diagnosis to first second malignancy. Death for other reasons will be used as competing event. A second malignancy is any malignant tumor disease defined by the International Classification of Childhood Cancer (ICCC)-3. Benign diseases except ICCC-3 included CNS-tumors are not being considered
5. Toxicity will be defined according to CTCAE Version 5.0
6. Time to death due to toxicity: time from diagnosis to death re-lated to therapy (as defined by investigator assessment). In or-der to describe the toxic death rate for the regimens under in-vestigation, deaths occurring in patients after relapse are ex-cluded, even if they occur due to toxicity from relapse therapy. Deaths from reasons other than toxicity will be used as a competing event
7. WPPSI-IV on therapy (all children >2.5 years at diagnosis), and WISC-V at 5 years after diag-nosis (+/- 12 months range allowed; WPPSI-IV if younger than 6;0 years)
8. Subdomain-specific neurocognitive outcome parameters from WPPSI-IV and WISC-V (primary index scales): Verbal Comprehension Index (all children ≥ 2.5 years old), Visual Spatial Index (all children ≥ 2.5 years old), Fluid Reasoning Index (all children ≥ 4.0 years old), Working Memory Index (all children ≥ 2.5 years old), Processing Speed Index (all children 4 years and older)
9. Subdomain-specific neurocognitive outcome parameters from Beery Visual Motor Integration (VMI) Test (all children ≥ 2.0 years old)
10. Subdomain-specific neurocognitive outcome parameters from Purdue Pegboard Test (all children ≥ 5.0 years old)
11. Development and Adaptive Functioning: Adaptive Behavior Assessment System (ABAS, versions II or 3) at diagnosis, 2.5- and 5 years after diagnosis
12. Quality of Life (QoL): - PedsQL Infant Scale or PedsQL 4.0 parent-report measure at diagnosis, followed by Ped-sQL 4.0 and PedsQL Fatigue Scale at 2.5 and 5 years after diagnosis by Parent- and Self-report
13. Quality of Life (QoL): - BRIEF-P or BRIEF or BRIEF 2 parent-report measure based on age at 2.5 and 5 years after diagnosis by Parent-report
14. Quality of Life (QoL): Strengths and Difficulties Questionnaire (SDQ) parent-report at 2.5 and 5 years after diagnosis
15. Longitudinal development of neurocognitive, QoL and behavioral outcomes to evaluate potential change over time, change in: ABAS (II or 3) between diagnosis, 2.5 years and 5 years
16. Longitudinal development of neurocognitive, QoL and behavioral outcomes to evaluate potential change over time, change in: WPPSI-IV (including subtests) between baseline and 2.5 years and WISC-V (including subtests) at 5 years
17. Longitudinal development of neurocognitive, QoL and behavioral outcomes to evaluate potential change over time, change in: PedsQL between diagnosis, 2.5 years and 5 years af-ter diagnosis
18. Longitudinal development of neurocognitive, QoL and behavioral outcomes to evaluate potential change over time, change in: BRIEF-P or BRIEF or BRIEF-2 between 2.5 years and 5 years after diagnosis
19. Longitudinal development of neurocognitive, QoL and behavioral outcomes to evaluate potential change over time, change in: SDQ between 2.5 years and 5 years after diagnosis
20. Ototoxicity: Hearing evaluation according to SIOP Boston Scales and Chang-Scale 2.5 years and 5 years after diagnosis (patients with normal Distortion-Product Otoacoustic Emissions (DPOAE) will be considered as not having hearing loss)
21. Leukoencephalopathy: modified Fazekas scale: 2.5 and 5 years after diagnosis
22. To compare PFS, rtPFS, OS between epigenetically defined subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher): Independent variable = subtyp, dependent variables : PFS, rtPFS, and OS
23. Rate of patients with genetically confirmed basal cell nevus syndrome (BCNS, Gorlin-Syndrome, OMIM: 109400): Defined by central sequencing of relevant genes from germline material

Investigational products

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

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GPOH gGmbH

Sponsor organisation

GPOH gGmbH

Address

Chausseestrasse 128-129, Mitte Mitte

City

Berlin

Postcode

10115

Country

Germany

Scientific contact point

Organisation

GPOH gGmbH

Contact name

Katharina Waack-Buchholz

Public contact point

Organisation

GPOH gGmbH

Contact name

Katharina Waack-Buchholz

Third parties 4

Locations

5 EU/EEA countries · 43 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 56 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