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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
96
One bridging chemotherapy cycle consists of five days of therapy using Carboplatin and etoposide
Cisplatin, vincristin, etoposide, cyclophosphamide, high-dose methotrexate
Cisplatin, etoposide, cyclophosphamide, high-dose methotrexate
Children's of Alabama
Birmingham, Alabama, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
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).
Time frame: 105 months
PFS
Progression-free survival (PFS) compared between randomized groups
Time frame: 152 months
rtPFS
Radiotherapy-free/progression-free survival (rtPFS) compared between randomized groups
Time frame: 152 months
OS
Overall survival (OS) compared between randomized groups
Time frame: 152 months
Second malignancies
Incidence of second malignancies compared between randomized groups
Time frame: 152 months
Number of patients with treatment-related adverse events as assessed by CTCAE v5.0
Acute toxicities compared between randomized groups
Time frame: 152 months
Incidence of therapy-related deaths
Incidence of therapy-related deaths compared between randomized groups
Time frame: 152 months
Assessment of IQ in patients randomized to Head Start or HIT-SKK
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Carboplatin, thiotepa, etoposide
Cyclophosphamide, vincristine, high-dose methotrexate, carboplatin, etoposide, i.ventri. methotrexate
Cyclophosphamide, vincristine, carboplatin, etoposide
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.
Time frame: 152 months
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.
Time frame: 152 months
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.
Time frame: 152 months
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.
Time frame: 152 months
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).
Time frame: 152 months
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.
Time frame: 152 months
Compare PFS
To compare PFS between randomized groups in patients in CR at end of study therapy
Time frame: 152 months
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)
Time frame: 152 months
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
Time frame: 152 months
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)
Time frame: 152 months
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)
Time frame: 152 months
Compare rtPFS
To compare rtPFS between randomized groups in patients in CR at end of study therapy
Time frame: 152 months
Compare OS
To compare OS between randomized groups in patients in CR at end of study therapy
Time frame: 152 months
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).
Time frame: 152 months
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
Time frame: 152 months