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MedulloblastomaPhase 3NCT07291102

Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma

A Phase 3 study testing Bridging Chemotherapy, Induction Cycles A1-A3 and Induction Cycles A4-5 in people with Medulloblastoma, run by Nationwide Children's Hospital at 2 sites in United States.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial summary

This is a trial to compare neurocognitive outcomes in the intent-to-treat population 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified MF randomized to the interventional arms A ("Head Start 4") or B (HIT-SKK). Read more about this study

Who is it for?
Ages Up to 5 years
Conditions the study is for
Medulloblastoma
What is being tested?
Bridging Chemotherapy, Induction Cycles A1-A3 and Induction Cycles A4-5
Could I receive a placebo?
No, everyone receives an active treatment
How many people
96 participants
Where
2 sitesUnited States
Study dates
1 Jan 2027to Oct 2038
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 5 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Age at diagnosis < 5 years
  • Patients with institutional suspicion or diagnosis of SHH-activated MB
  • Patient and family in social circumstances that will allow neuropsychological follow-up
  • Ability of parents/legal representatives to understand the patient information and to personally sign and date the informed consent to participate in screening procedures
  • Patient and the parents/legal representative are able and willing to participate in the entire study (if patient is eligible)
  • Patient has received bridging chemotherapy as described in this protocol
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  • Patients with centrally reviewed SHH-activated MB, TP53-wt, according to WHO classification 2021
  • Absence of metastatic disease on central radiology review
  • Exclusion of TP53-mutation by DNA sequencing of the TP53-gene from tumor tissue by central review. Results from local institution will be accepted if raw data of this analysis is forwarded to the national central review institution
  • Confirmation of SHH activation by DNA methylation-based classification on central review. Results from local institution will be accepted if raw data of this analysis is forwarded to the national central review institution
  • No amplification of MYC (amplification of MYCN allowed). Array-based technologies (850k array, molecular inversion probe assay (MIP)), array-based comparative genomic hybridization (array-CGH) or next generation sequencing (NGS) DNA sequencing coverage MYC locus will be used. If these alternative assays give any indication of possible amplification, FISH will be performed on central review.
  • No other medical contraindications to chemotherapy:
  • No uncontrolled invasive fungal infection or other severe systemic infection requiring system/parental therapy
  • No other severe organ dysfunctions, which cannot be clinically controlled
  • No concomitant use with yellow fever vaccine and with live virus and bacterial vaccines
  • No demyelinating form of Charcot-Marie-Tooth syndrome
  • Retrospective assessment of pre-operative health-related QoL (HR-QoL) measured by Pediatric Quality of Life Inventory
  • Provided written informed consent by parent(s)/parent representative(s) for randomization

Who cannot join

  • Patients previously treated for any other brain tumor or any type of malignant disease
  • Patients, in whom compliance with toxicity management guidelines and study procedures cannot be assured
  • 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.
  • Patients/parents who do not wish to abstain from treatment with live vaccines during study participation
  • Patients with a language barrier too extensive to complete neuropsychological tests based on the investigator's judgement
  • Patients with severe premorbid developmental delay (based on the investigator's judgement), which will not allow WPPSI-IV assessment after 2.5 years
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  • Patients cannot undergo MRI
  • Inclusion Criteria for Bridging chemotherapy (carboplatin/etopiside) in interventional arms:
  • Patients with SHH-activated MB, TP53-wt demonstrated by IHC for Gab1 or p75-NGFR, Yap1, beta-catenin, and TP53 (lack of strong and widespread nuclear p53 positivity) on central review according to WHO classification 2021.
  • No clinical evidence of extra-CNS metastases
  • Negative CSF cytology
  • No prior therapy for MB other than surgery
  • No other medical contraindications to chemotherapy:
  • No uncontrolled invasive fungal infection or other severe systemic infection requiring system/parental therapy
  • No other severe organ dysfunctions, which cannot be clinically controlled
  • No concomitant use with yellow fever vaccine and with live virus and bacterial vaccines
  • No demyelinating form of Charcot-Marie-Tooth syndrome
  • Assessment of hearing function completed
  • No evidence of cancer predisposition syndromes other than Gorlin syndrome or ELP1, GPR161 germline alterations.
  • Provided written informed consent by parent(s)/parent representative(s) by bridging chemotherapy
  • Patient should be enrolled within 28 days after diagnosis. Bridging chemotherapy can start as early as criteria for enrollment are met, and must start no later than 33 days after diagnosis
  • One or more of the inclusion criteria for bridging chemotherapy are lacking
  • Other histology than SHH MB
  • -Patients are excluded from the interventional study if any of the following criteria are met:
  • One or more of the inclusion criteria for randomization are lacking
  • Patients with metastatic disease
  • TP53-mutated SHH MB
  • MYC amplified MB
  • Pre-existing condition incompatible with scheduled therapy (e.g. Fanconi anemia)
  • Patients with non-communicating hydrocephalus, e.g. due to perinatal intracranial haemorrhage, adueductal stenosis, or meningitis
  • Contraindication for any components of the randomized therapies, including HDCT and intraventricular chemotherapy. Note: postperative hydrocephalus is not a contraindication for i.ventr. MTX.

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Kelsey Troyer, PhD contact

16147228566

kelsey.troyer@nationwidechildrens.org

United States2 sites

  • Children's of Alabama

    Birmingham, Alabama, 35233

    Girish Dhall, MD, (205) 638-9100, gdhall@uabmc.edu

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

    Maryam Fouladi, MD, 6147225758, Maryam.Fouladi@nationwidechildrens.org

Other trials in United States

About this study

This is a trial to compare neurocognitive outcomes in the intent-to-treat population 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt, non-MYC amplified MF randomized to the interventional arms A ("Head Start 4") or B (HIT-SKK).

Read the detailed description

In this study, two highly effective irradiation-sparing treatment regimens are being compared in patients with low-risk early childhood MB:

  1. Arm A: The "Head Start" 4 regimen developed by the North American Head Start Consortium. This approach uses intensive Induction chemotherapy and Consolidation with HDCT and has led to equally favorable results in this subgroup -- 3y PFS was 96% for infants and young children with M0, SHH MB; 5y EFS was 93% for M0, DMB on the predecessor "Head Start" 3 study.
  2. Arm B: The HIT-SKK regimen developed within the GPOH. This regimen combines systemic chemotherapy with intraventricular MTX, leading to 93% 5-year PFS in low-risk patients.

Both treatment regimens use high-dose i.v. MTX, but only the HIT-SKK regimen also uses intraventricular administration of MTX directly into the CSF in addition to i.v. MTX. Given the long-term neurocognitive deficits of MTX have been described in childhood leukemia, and the pathogenesis of MTX-induced CNS-damage has been described, this has raised some concerns. Similarly, highly intensive, HDCT containing "Head Start" chemotherapy carries specific risks for the neurocognitive outcomes. Encouragingly, five years after HIT-SKK treatment including intraventricular MTX, young children with MB have a mean fluid intelligence score of 93.8 points. The full-scale IQ after "Head Start" chemotherapy is 95.4 and likewise within normal range. On the other hand, highly intensive, HDCT/AuHCR containing "Head Start" chemotherapy carries specific risks for the neurocognitive outcomes. However, neurocognitive outcomes after the HIT-SKK and "Head Start" chemotherapy regimens are difficult to compare from existing data, because of small sample sizes and inhomogeneous assessment tools used in prior studies. Therefore, a confirmatory study utilizing the same measures administered at the same time points is required to identify clinically relevant differences. In addition, survival, occurrence of second malignancies, neurological and endocrine deficits, hearing loss, and psychosocial comorbidities are also of high relevance in survivors of MB and may differ after both regimens. Since these also severely limit the survivors' potential for activity and participation in everyday life and affect their parents and siblings as well, this information will also be recorded.

Conditions
Medulloblastoma
Being tested
Bridging Chemotherapy, Induction Cycles A1-A3, Induction Cycles A4-5, Consolidation Cycle A6, HIT-SKK Chemotherapy Cycles B1-3
Medical subject headings
Medulloblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bridging ChemotherapyDrug

    One bridging chemotherapy cycle consists of five days of therapy using Carboplatin and etoposide

  • Induction Cycles A1-A3Drug

    Cisplatin, vincristin, etoposide, cyclophosphamide, high-dose methotrexate

  • Induction Cycles A4-5Drug

    Cisplatin, etoposide, cyclophosphamide, high-dose methotrexate

  • Consolidation Cycle A6Drug

    Carboplatin, thiotepa, etoposide

  • HIT-SKK Chemotherapy Cycles B1-3Drug

    Cyclophosphamide, vincristine, high-dose methotrexate, carboplatin, etoposide, i.ventri. methotrexate

  • Modified HIT-SKK Cycle B4-5Drug

    Cyclophosphamide, vincristine, carboplatin, etoposide

Study groups in NCT07291102
Study groupRoleWhat they receive
Arm A: "Head Start" 4ExperimentalArm A consists of 3 to 5 Induction chemotherapy cycles and one high-dose chemotherapy cycle evaluated in the "Head Start" 4 study.
Receives: Drug: Bridging Chemotherapy; Drug: Induction Cycles A1-A3; Drug: Induction Cycles A4-5; Drug: Consolidation Cycle A6
Arm B: HIT-SKKExperimentalArm B consists of 3 to 5 cycles of chemotherapy evaluated in the HIT-SKK'92 (Rutkowski et al. 2005) and HIT-2000 (NCT00303810) clinical studies.
Receives: Drug: Bridging Chemotherapy; Drug: HIT-SKK Chemotherapy Cycles B1-3; Drug: Modified HIT-SKK Cycle B4-5

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Neurocognitive Outcomes using WPPSIIV

    To compare neurocognitive outcomes 2.5 years after diagnosis between patients randomized to the interventional arms A ("Head Start" 4) and B (HIT-SKK). Full-Scale Intelligence Quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence (WPPSIIV) 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).

    Measured: 105 months

Secondary outcomes (21)

  1. PFS

    Progression-free survival (PFS) compared between randomized groups

    Measured: 152 months

  2. rtPFS

    Radiotherapy-free/progression-free survival (rtPFS) compared between randomized groups

    Measured: 152 months

  3. OS

    Overall survival (OS) compared between randomized groups

    Measured: 152 months

  4. Second malignancies

    Incidence of second malignancies compared between randomized groups

    Measured: 152 months

  5. Number of patients with treatment-related adverse events as assessed by CTCAE v5.0

    Acute toxicities compared between randomized groups

    Measured: 152 months

  6. Incidence of therapy-related deaths

    Incidence of therapy-related deaths compared between randomized groups

    Measured: 152 months

  7. Assessment of IQ in patients randomized to Head Start or HIT-SKK

    Wechsler Intelligence Scale for Children (WISC-V) Full Scale IQ at 5 years after diagnosis (+/- 12 months range allowed), with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) Full Scale IQ Score used only for children < 6 years old.

    Measured: 152 months

  8. Assessment of Development and Adaptive Functioning using ABAS v2 or v3

    Adaptive Behavior Assessment System (ABAS, versions II or 3) at diagnosis, 2.5- and 5 years after diagnosis will be used to compare patients randomized to Head Start or HIT-SKK.

    Measured: 152 months

  9. Quality of Life Assessment using PedsQL Infant or PedsQL 4.0 parent-reported Quality of Life Measure

    PedsQL Infant or PedsQL 4.0 parent-report QoL measure depending upon current age at the treatment timepoints. Questionnaires are quantified on a scale of 0-100 where higher scores indicate better outcomes/quality of life.

    Measured: 152 months

  10. Correlation between neurocognitive outcomes and QoL

    Correlation of neurocognitive outcomes (measured using WISC-V Full Scale IQ at 5 years after diagnosis) and quality of life (measured using PedsQL Infant) 5 years after diagnosis will be achieved using a regression for linear mixed model.

    Measured: 152 months

  11. Assessment of impact on hearing using SIOP Boston scale

    Ototoxicity will be assessed through hearing evaluation according to SIOP Boston scale (patients with normal Distortion-Product Otoacoustic Emissions (DPOAE) will be considered as not having hearing loss).

    Measured: 152 months

  12. Number of patients with Leukoencephalopathy

    LEP will be assessed 2.5 and 5 years after diagnosis compared between randomized groups using the modified Fazekas scale.

    Measured: 152 months

  13. Compare PFS

    To compare PFS between randomized groups in patients in CR at end of study therapy

    Measured: 152 months

  14. Compare PFS

    To compare PFS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher)

    Measured: 152 months

  15. Assess rate of patients with cancer predisposition syndromes

    To assess the rate of patients with genetically confirmed basal cell nevus syndrome (BCNS, Gorlin-Syndrome, OMIM: 109400), ELP1 and GPR161 cancer predisposition syndromes among eligible enrolled patients

    Measured: 152 months

  16. Compare rtPFS

    To compare rtPFS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher)

    Measured: 152 months

  17. Compare OS

    To compare OS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher)

    Measured: 152 months

  18. Compare rtPFS

    To compare rtPFS between randomized groups in patients in CR at end of study therapy

    Measured: 152 months

  19. Compare OS

    To compare OS between randomized groups in patients in CR at end of study therapy

    Measured: 152 months

  20. Assessment of impact on hearing using Chang scales

    Ototoxicity will be assessed through hearing evaluation according to Chang Scale (patients with normal Distortion-Product Otoacoustic Emissions (DPOAE) will be considered as not having hearing loss).

    Measured: 152 months

  21. Association between neurocognitive and behavioral outcomes

    Association of neurocognitive (measured using WISC-V Full Scale IQ at 5 years after diagnosis and WPPSI Full Scale IQ Score used only for children < 6 years old) outcomes and behavioral outcomes (measured using ABAS v2 or v3) 5 years after diagnosis compared between randomized groups

    Measured: 152 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Dec 2025
  2. Study start1 Jan 2027 (estimated)
  3. Primary completionOct 2034 (estimated)
  4. Study completionOct 2038 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
96 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07291102
Sponsor's protocol ID
COGNITO-MB
Other IDs
2024-517133-40-00
Status last verified
Oct 2026
First submitted
21 Nov 2025
Last updated
20 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: This study is considered for publication in the scientific literature in a peer re-viewed journal, irrespective of the results. Study results may also be presented at one or more medical congresses and may be used for scientific exchange and teaching purposes. Additionally, this study and its results may be submitted for inclusion in all appropriate health authority study registries, as well as publication on health authority study registry websites, as required by local health authority regulations.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Bridging Chemotherapy, Induction Cycles A1-A3 and Induction Cycles A4-5 in people with Medulloblastoma, run by Nationwide Children's Hospital at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 20 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Kelsey Troyer, PhD (16147228566, kelsey.troyer@nationwidechildrens.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Neurocognitive Outcomes using WPPSIIV (time frame: 105 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07291102.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2026; AzTrials last refreshed its copy on 8 Nov 2026.

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