Medulloblastoma
Conditions
Brief 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).
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.
Interventions
DRUGBridging Chemotherapy
One bridging chemotherapy cycle consists of five days of therapy using Carboplatin and etoposide
DRUGInduction Cycles A1-A3
Cisplatin, vincristin, etoposide, cyclophosphamide, high-dose methotrexate
DRUGInduction Cycles A4-5
Cisplatin, etoposide, cyclophosphamide, high-dose methotrexate
DRUGConsolidation Cycle A6
Carboplatin, thiotepa, etoposide
DRUGHIT-SKK Chemotherapy Cycles B1-3
Cyclophosphamide, vincristine, high-dose methotrexate, carboplatin, etoposide, i.ventri. methotrexate
DRUGModified HIT-SKK Cycle B4-5
Cyclophosphamide, vincristine, carboplatin, etoposide
Sponsors
German Society of Paediatric Oncology and Hematology (GPOH gGmbH)
Children's of Alabama
Nationwide Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 5 Years
Healthy volunteers
No
Inclusion criteria
for screening: * 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)
Exclusion criteria
for overall study: * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Outcomes using WPPSIIV | 105 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| rtPFS | 152 months | Radiotherapy-free/progression-free survival (rtPFS) compared between randomized groups |
| OS | 152 months | Overall survival (OS) compared between randomized groups |
| Second malignancies | 152 months | Incidence of second malignancies compared between randomized groups |
| Number of patients with treatment-related adverse events as assessed by CTCAE v5.0 | 152 months | Acute toxicities compared between randomized groups |
| Incidence of therapy-related deaths | 152 months | Incidence of therapy-related deaths compared between randomized groups |
| Assessment of IQ in patients randomized to Head Start or HIT-SKK | 152 months | 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. |
| Assessment of Development and Adaptive Functioning using ABAS v2 or v3 | 152 months | 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. |
| Quality of Life Assessment using PedsQL Infant or PedsQL 4.0 parent-reported Quality of Life Measure | 152 months | 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. |
| PFS | 152 months | Progression-free survival (PFS) compared between randomized groups |
| Assessment of impact on hearing using SIOP Boston scale | 152 months | 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). |
| Number of patients with Leukoencephalopathy | 152 months | LEP will be assessed 2.5 and 5 years after diagnosis compared between randomized groups using the modified Fazekas scale. |
| Compare PFS | 152 months | To compare PFS between randomized groups in patients in CR at end of study therapy |
| Assess rate of patients with cancer predisposition syndromes | 152 months | 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 |
| Compare rtPFS | 152 months | To compare rtPFS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher) |
| Compare OS | 152 months | To compare OS between subtypes of SHH-MB as defined by classification based on the Heidelberg brain tumor classifier Version 11 (or higher) |
| Assessment of impact on hearing using Chang scales | 152 months | 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). |
| Association between neurocognitive and behavioral outcomes | 152 months | 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 |
| Correlation between neurocognitive outcomes and QoL | 152 months | 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. |
Countries
United States
Contacts
Primary ContactKelsey Troyer, PhD
Outcome results
None listed