Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
- Conditions
- Medulloblastoma
- Interventions
- Procedure: Surgical resectionOther: Educational and Media InterventionOther: SOC, Educational and Media InterventionProcedure: Ommaya/VPSRadiation: Irradiation
- Registration Number
- NCT05535166
- Lead Sponsor
- St. Jude Children's Research Hospital
- Brief Summary
This is a multi-center, multinational phase 2 trial that aims to explore the use of molecular and clinical risk-directed therapy in treatment of children 0-4.99 years of age with newly diagnosed medulloblastoma.
- Detailed Description
The objectives of this study are:
Primary Objectives
* To estimate the progression free survival of SHH-2 infant (0-2.99 years) and young child (3-4.99 years) medulloblastoma patients treated with systemic HD-MTX- based chemotherapy only.
* To estimate the progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy augmented with IVT-MTX.
* To estimate the progression free survival of G3/G4 infant (0-2.99 years) medulloblastoma patients treated with systemic chemotherapy and delayed risk- adapted CSI augmented with carboplatin.
* To compare cognitive outcomes among infants (0-2.99 years) and young children (3-4.99 years) treated with systemic chemotherapy only to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk- adapted craniospinal irradiation.
Secondary Objectives
* To investigate change in neurocognitive performance among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma, and examine the impact of demographic factors (e.g., age at treatment, gender, and socioeconomic status), disease-related factors (e.g., presence of hydrocephalus, posterior fossa syndrome) and variants of proposed treatment regimen (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) on cognitive late effects.
* To investigate which familial factors (e.g., family cohesion, family coping with medical management, parent-child interaction style) and environmental factors (e.g., parental verbal abilities, home literacy, adherence with rehabilitative therapies, participation in early intervention, school advocacy) associate with socioeconomic status and examine the impact of these factors on cognitive late effects.
* To evaluate the feasibility and acceptability of a caregiver education program paired with interactive neurodevelopmental games used to improve parent-child interactions, cognitive and social-emotional functioning in infants undergoing treatment for medulloblastoma. (funded by NCI via the R21CA280187)
* To estimate the magnitude of change in parent-child interactions following participation in a caregiver education paired with interactive neurodevelopmental games. (funded by NCI via the R21CA280187)
* To estimate the magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games. (funded by NCI via the R21CA280187)
* To determine the extent of inter- and intra-patient variability in the plasma pharmacokinetics of high-dose systemic methotrexate, cyclophosphamide, vincristine, and topotecan in infants and young children with medulloblastoma, to assess potential covariates to explain this variability, and to explore associations between clinical effects and methotrexate, cyclophosphamide, vincristine, and topotecan pharmacokinetics.
* To determine the extent of inter- and intra-patient pharmacokinetic variability of methotrexate in ventricular CSF after intraventricular methotrexate dose administration in infants with medulloblastoma, and to explore associations between methotrexate CSF pharmacokinetics and clinical effects.
All participants enrolled will be treated with systemic chemotherapy post-surgical resection of the tumor. Participants will be assigned to treatment strata based first on tumor molecular group and subgroup assignment \[SHH (including SHH-1, SHH-2, SHH-3, SHH-4 and SHH-NOS), G3, G4, (including NWNS NOS, or indeterminate cases\] and then by clinical risk stratification (age and metastatic state).
Infants and young children on Stratum S-2 and infants on Stratum S-1 will be treated with chemotherapy-only strategies.
* Stratum S-2:
Patients on S-2 will receive 8 courses of chemotherapy consisting of:
* 4 Course A (A1A2A3A4)
* 2 Course B (B1B2)
* 2 Course C (C1C2) Courses repeats every 28 days/4 weeks.
* Stratum S-1:
Patients on S-1 will receive the same systemic chemotherapy regimen as S-2, with the addition of intraventricular (IVT)- MTX, administered via Ommaya reservoir, with each systemic MTX infusion. Each S-1 patient is scheduled to receive 12 doses of IVT-MTX. Each patient on S-1 will also receive 8 courses of combination chemotherapy. (4 Course A with IVT, 2 Course B with IVT and 2 Course C). Courses repeats every 28 days/4 weeks.
* Stratum N:
Stratum N participants will be treated with post-surgery chemotherapy until 36-months-of age followed by radiation CSI with Boost. There is no defined maximum number of systemic chemotherapy courses in stratum N. The length of chemotherapy (number of courses) will depend on the patient's age at enrollment. The chemotherapy plan for stratum N is divided into 5 sub-cohorts:
* Age ≥34 months and \< 36 months: 4 cycles - 2 cycles (A1A2) prior to radiation and 2 cycles (E1, E2) post-radiation
* Age: ≥32 to \<34 months-old: 4 cycles (A1A2A3A4)
* Age: ≥30 to \<32 months-old: 6 cycles (A1A2A3A4B1B2)
* Age: ≥28 to \<30-months-old: 8 cycles (A1A2A3A4B1B2C1C2)
* Age: \< 28 months-old: 8 cycles + multiple cycles of Course D until 36 months old (A1A2A3A4 B1B2 C1C2D1D2D3D4...)
Courses A, B, C and E repeats every 28 days/4 weeks and Course D repeats every 42 days.
Prior to radiation therapy, around when stratum N patients achieve 36 months of age, they will be re-stratified onto substratum N-1, N-2 or N-3 based on their response to chemotherapy.
Patients who receive less than or equal to 4 cycles of systemic chemotherapy prior to CSI regardless of their substratum assignment (N-1, N-2 or N-3) will have their radiation therapy augmented by IV carboplatin. Carboplatin will be given to each of these patients 1-4 hours before each radiation fraction is delivered.
Patients enrolled in stratum N who have received only 2 courses of pre-radiation chemotherapy will receive 2 additional courses of adjuvant chemotherapy after completing CSI . The adjuvant chemotherapy consists of Cisplatin, Cyclophosphamide, and Vincristine. The patients receiving 4 or more courses of chemotherapy prior to radiation will not receive additional adjuvant chemotherapy after completing CSI.
Patients will be followed for 84 months following enrollment.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 120
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stratum N Pegfilgrastim Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum S-1 Ommaya/VPS Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Surgical resection Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Surgical resection Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Filgrastim Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Cognitive Study Group I (educational video and games) Educational and Media Intervention Educational video and games Stratum N Irradiation Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Surgical resection Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Cognitive Study Group II (standard-of-care control) SOC, Educational and Media Intervention Standard-of-care (SOC) followed by educational video and games Stratum S-2 Cyclophosphamide Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Methotrexate Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Cisplatin Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Carboplatin Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Vincristine Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Topotecan Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-2 Pegfilgrastim Patients with Sonic Hedgehog subgroup 2 (SHH-2), 0-2.99 years, or M0 and 3-4.99 years, will receive systemic high-dose methotrexate (HD-MTX) and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Methotrexate Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Cisplatin Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Vincristine Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Topotecan Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Cyclophosphamide Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum N Methotrexate Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum S-1 Carboplatin Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Pegfilgrastim Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum S-1 Filgrastim Patients with SHH-1, SHH-3, SHH-4, or SHH-Not otherwise specified (NOS), 0-2.99 years, will receive intraventricular methotrexate (IVT-MTX) in parallel with systemic HD-MTX and conventional chemotherapy. Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Pegfilgrastim, Filgrastim Stratum N Vincristine Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Cyclophosphamide Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Cisplatin Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Carboplatin Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Topotecan Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Etoposide Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation Stratum N Filgrastim Patients with Medulloblastoma (MB) group 3 or group 4 (G3/G4) or MB \[including Non-WNT non-SHH medulloblastoma (NWNS) NOS or otherwise indeterminate cases\] (0-2.99 years) will receive systemic HD-MTX and conventional chemotherapy only for radiation delaying purposes. At 3 years of age, these patients will receive risk-stratified craniospinal irradiation (CSI). Interventions: Surgery, Methotrexate, Cisplatin, Vincristine, Cyclophosphamide, Carboplatin, Topotecan, Etoposide, Pegfilgrastim, Filgrastim, Radiation
- Primary Outcome Measures
Name Time Method Progression free survival of G3/G4 infant (0-2.99 years) medulloblastoma patients treated with systemic chemotherapy and delayed risk-adapted CSI augmented with carboplatin. Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient Progression free survival (PFS) will be measured from treatment initiation to the earliest of disease progression or death from any cause in stratum S-N eligible patients who receive at least 1 dose of the chemotherapy regimen. Patients who have not experienced one of these events will be censored at their last date of contact. The Kaplan-Meier estimate of PFS at two years will be computed. PFS will be compared to St. Jude historical cohorts using hazard ratios with 95% confidence intervals.
Executive function among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation Baseline through 5 years after enrollment Change from baseline over time in executive functions will be assessed using different instruments as age appropriate. The Behavior Rating Inventory of Executive Function \[BRIEF-P (ages 2-5:11) and BRIEF-2 (ages 6-18)\] will assess behavioral manifestations of executive function. Longitudinal analyses will be conducted using mixed models.
Progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy augmented with IVT-MTX. Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient Progression free survival (PFS) will be measured from treatment initiation to the earliest of disease progression or death from any cause in stratum S-1 eligible SHH-1 patients who receive at least 1 dose of the chemotherapy regimen. Patients who have not experienced one of these events will be censored at their last date of contact. The Kaplan-Meier estimate of PFS at two years will be computed. PFS will be compared to St. Jude historical cohorts using hazard ratios with 95% confidence intervals.
IQ among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation Baseline through 5 years after enrollment Change from baseline over time in intellectual function (IQ) will be assessed using different instruments as age appropriate. IQ will be measured in children 0-3:6 years of age using Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4), in children 3.0-5.11 years of age using Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV), and in children 6-10 years of age using Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V). Longitudinal analyses will be conducted using mixed models.
Health-related quality of life among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation Baseline through 5 years after enrollment Changes from baseline over time in health-related quality of life will be assessed using the PedsQL (ages 2 and older). Longitudinal analyses will be conducted using mixed models.
Progression free survival of SHH-2 infant (0-2.99 years) and young child (3-4.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy only. Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient Progression free survival (PFS) will be measured from treatment initiation to the earliest of disease progression or death from any cause in stratum S-2 eligible M0 patients who receive at least 1 dose of the chemotherapy regimen. Patients who have not experienced one of these events will be censored at their last date of contact. The Kaplan-Meier estimate of PFS at two years will be computed. PFS will be compared to St. Jude historical cohorts using hazard ratios with 95% confidence intervals.
- Secondary Outcome Measures
Name Time Method Change in executive function among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma Baseline through 5 years after enrollment This will be assessed using different instruments as age appropriate (The Behavior Rating Inventory of Executive Function \[BRIEF-P (ages 2-5:11) and BRIEF-2 (ages 6-10)\] will assess behavioral manifestations of executive function. A linear mixed-effects regression model will be used to examine changes in executive function from baseline over time as related to demographic (e.g., age at treatment, gender, and socioeconomic status), disease-related (e.g., presence of hydrocephalus, posterior fossa syndrome), and treatment (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) factors.
Evaluate intervention feasibility by measuring the rate of participants completing a caregiver education combined with interactive. neurodevelopmental games. Baseline through 6 months after enrollment The neurocognitive intervention consists of the Working for Kids (WFK) education, which is designed to improve parent understanding of the importance of the early learning environment on brain development, and First Pathways Game (FPG), which is an interactive neurodevelopmental games designed for parents to play with their children to strengthen brain pathways for specific skills including communication, problem-solving and social emotional skills, motor skills, math skills and early science learning. Intervention feasibility will be measured by the proportion of randomized participants completing at least 10 neurodevelopmental games.
Change in health-related quality of life among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma Baseline through 5 years after enrollment Health-related quality of life will be assessed using the PedsQL (ages 2 and older). A linear mixed-effects regression model will be used to examine changes in health-related quality of life from baseline over time as related to demographic (e.g., age at treatment, gender, and socioeconomic status), disease-related (e.g., presence of hydrocephalus, posterior fossa syndrome), and treatment (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) factors.
Association of familial factors and environmental factors with socioeconomic status Baseline through 5 years after enrollment Socioeconomic status will be measured using the Barratt Simplified Measure of Social Status (BSMSS). Generalized linear models will be used to investigate the association of socioeconomic status with familial factors (e.g., family cohesion, family coping with medical management, parent-child interaction style) and environmental factors (e.g., parental verbal abilities, home literacy, adherence with rehabilitative therapies, participation in early intervention, school advocacy)
Association of familial factors and environmental factors with cognitive late effects. Baseline through 5 years after enrollment Linear mixed-effects models will be used to examine changes from baseline over time in cognitive outcomes (as described above) with familiar and environmental factors (as described above).
Evaluate family interest in caregiver education combined with interactive neurodevelopmental games. Baseline through 6 months after enrollment The neurocognitive intervention consists of the Working for Kids (WFK) education, which is designed to improve parent understanding of the importance of the early learning environment on brain development, and First Pathways Game (FPG), which are interactive neurodevelopmental games designed for parents to play with their children to strengthen brain pathways for specific skills including communication, problem-solving and social emotional skills, motor skills, math skills and early science learning. Family interest in this intervention will be measured by the proportion of families approached enrolling on study.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in in the plasma systemic clearance (CL) of CTX in infants and young children with medulloblastoma receiving CTX. Data for CTX from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. A covariate analysis will be performed to investigate potential associations between the CTX CL pharmacokinetic parameter (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in CTX CL values in infants and young children with medulloblastoma receiving CTX.
To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide (CEPM) in infants and young children with medulloblastoma receiving cyclophosphamide. Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. Carboxyethylphosphoramide will be included in above described population pharmacokinetic approach. Based on the results of the population pharmacokinetic analysis, the CEPM AUC0-24h can be calculated.
To characterize the plasma systemic methotrexate (MTX) clearance (CL) in infants and young children with medulloblastoma. Day 1 of each course A, AIVT, B, and BIVT. Drug plasma concentrations will be simultaneously analyzed with a population pharmacokinetic approach, which permits characterizing typical pharmacokinetics and interindividual variability within the population. We will use a similar approach to what we have used in our previously published manuscripts. Methotrexate CL will be estimated based on serial samples acquired during the first day of each course of therapy.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in MTX PK parameter CL in infants and young children with medulloblastoma receiving MTX. Day 1 of each course A, AIVT, B, and BIVT. A covariate analysis will be performed to investigate potential associations between the MTX pharmacokinetic parameter CL (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in MTX CL values in infants and young children with medulloblastoma receiving MTX.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in 7OHMTX PK parameter AUC0-24h in infants and young children with medulloblastoma receiving MTX. Day 1 of each course A, AIVT, B, and BIVT. A covariate analysis will be performed to investigate potential associations between the MTX pharmacokinetic parameter AUC (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in 7OHMTX AUC values in infants and young children with medulloblastoma receiving MTX.
Change in IQ among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma Baseline through 5 years after enrollment IQ will be assessed using different instruments as age appropriate. IQ will be measured in children 0-3:6 years of age using Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4), in children 3.0-5.11 years of age using Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV), and in children 6-10 years of age using Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V). The multiple instruments will be combined across all ages into one measure of standardized Full-Scale IQ. A linear mixed-effects regression model will be used to examine changes in IQ from baseline over time as related to demographic (e.g., age at treatment, gender, and socioeconomic status), disease-related (e.g., presence of hydrocephalus, posterior fossa syndrome), and treatment (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) factors.
Evaluate the acceptability of a caregiver education combined with interactive neurodevelopmental games. Baseline through 6 months after enrollment The neurocognitive intervention consists of the Working for Kids (WFK) education, which is designed to improve parent understanding of the importance of the early learning environment on brain development, and First Pathways Game (FPG), which is an interactive neurodevelopmental games designed for parents to play with their children to strengthen brain pathways for specific skills including communication, problem-solving and social emotional skills, motor skills, math skills and early science learning. Acceptability will be measured as the proportion of caregivers reporting benefit from the intervention participation on a satisfaction questionnaire.
Magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games. Baseline and 6 months after enrollment Mean six-month change from baseline in cognition and social-emotional development as measured by DAYC-2 (parent interview) will be computed for families randomized to the intervention (described above) and for families randomized to the standard care control group.
To characterize the plasma systemic clearance (CL) of cyclophosphamide (CTX) in infants and young children with medulloblastoma. Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. Drug plasma concentrations will be simultaneously analyzed with a population pharmacokinetic approach, which permits characterizing typical pharmacokinetics and interindividual variability within the population. We will use a similar approach to what we have used in our previously published manuscripts. Cyclophosphamide CL will be estimated based on serial samples acquired during therapy.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in VCR PK parameter (CL) in infants and young children with medulloblastoma receiving VCR. Beginning on Day 8 of the first course of A or AIVT and B or BIVT (or E). A covariate analysis will be performed to investigate potential associations between the VCR CL pharmacokinetic parameter (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in VCR CL values in infants and young children with medulloblastoma receiving VCR.
To characterize the area under the concentration-time curve (AUC0-24h) of 4-hydroxy-cyclophosphamide (4OHCTX) in infants and young children with medulloblastoma receiving cyclophosphamide. Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. In a similar manner to the CEPM AUC0-24h, the 4-hydroxy-cyclophosphamide area under the curve AUC0-24h can be estimated based on the results of the population pharmacokinetic analysis.
To characterize the plasma systemic clearance (CL) of vincristine (VCR) in infants and young children with medulloblastoma. Beginning on Day 8 of the first course of A or AIVT and B or BIVT (or E). As with cyclophosphamide, the vincristine drug plasma concentrations will be analyzed with a population pharmacokinetic approach, which permits characterizing typical pharmacokinetics and interindividual variability within the population. Vincristine CL will be estimated based on serial samples acquired during therapy.
To characterize the plasma systemic clearance (CL) of topotecan (TPT) in infants and young children with medulloblastoma. All samples acquired during each course C for domestic patients and patients at St. Jude only. The topotecan drug plasma concentrations will be analyzed with a population pharmacokinetic approach, which permits characterizing typical pharmacokinetics and interindividual variability within the population. Topotecan CL will be estimated based on serial samples acquired during course C of therapy.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in TPT PK parameter (CL) in infants and young children with medulloblastoma receiving TPT. All samples acquired during each course C for domestic patients and patients at St. Jude, only. A covariate analysis will be performed to investigate potential associations between the TPT CL pharmacokinetic parameter (outcome measure) and demographics and clinical chemistry data (covariates). Also included in this analysis will be concomitant medications given at the same as topotecan (i.e., cyclophosphamide), as well as concomitant adjuvant drugs given within 48 hr of topotecan dose in at least 30% of patients included in the analysis. Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Patient age will be tested according to a Hill equation to reflect potential maturation process. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, and a covariate was considered significant at P\<0.05 for the forward addition and at the 0.01 for the backward addition.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in CEPM AUC0-24h in infants and young children with medulloblastoma receiving CTX. Data for CEPM from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. A covariate analysis will be performed to investigate potential associations between the CTX AUC pharmacokinetic parameter (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in CEPM AUC values in infants and young children with medulloblastoma receiving CTX.
To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in 4OHCTX AUC0-24h in infants and young children with medulloblastoma receiving CTX. Data for 4OHCTX from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E. A covariate analysis will be performed to investigate potential associations between the 4OHCTX AUC pharmacokinetic parameter (outcome measure) and demographics and clinical chemistry data (covariates). Continuous covariates will be implemented according to a power model scaled to the population median covariate value. Categorical covariates will be modeled using an exponential change due to the covariate value. Significant covariates will be selected by using a classic forward/backward stepwise approach, with criteria P values of 0.05 and 0.01 for the forward and backward steps, respectively. Wald tests will be also used to test whether covariates should be kept in the model (criteria p-value\<0.05) to explain the inter- and intra-patient variability in 4OHCTX AUC values in infants and young children with medulloblastoma receiving CTX.
To characterize the area under the concentration-time curve (AUC0-24h) of 7-hydroxymethotrexate (7OHMTX) in infants and young children with medulloblastoma receiving methotrexate. Day 1 of each course A, AIVT, B, and BIVT. 7-hydroxymethotrexate will be included in above described population pharmacokinetic approach. Based on the results of the population pharmacokinetic analysis, the 7OHMTX AUC0-24h will be calculated.
Trial Locations
- Locations (10)
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Lucille Packard Children's Hospital at Stanford University
🇺🇸Palo Alto, California, United States
Orlando Health Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
St. Joseph's Children's Hospital
🇺🇸Tampa, Florida, United States
C.S. MOTT Children's Hospital, University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital and Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
UT Southwestern/Simmons Cancer Center
🇺🇸Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States