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Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05535166
Recruitment Status : Recruiting
First Posted : September 10, 2022
Last Update Posted : April 15, 2024
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Study Description
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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.

Condition or disease Intervention/treatment Phase
Medulloblastoma Procedure: Surgical resection Procedure: Ommaya/VPS Drug: Methotrexate Drug: Cisplatin Drug: Vincristine Drug: Cyclophosphamide Drug: Carboplatin Drug: Topotecan Drug: Etoposide Drug: Pegfilgrastim Drug: Filgrastim Radiation: Irradiation Other: Educational and Media Intervention Other: SOC, Educational and Media Intervention Phase 2

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Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: SJiMB21: Phase 2 Study of Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
Actual Study Start Date : December 20, 2022
Estimated Primary Completion Date : July 2035
Estimated Study Completion Date : July 2035

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Stratum S-2

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

 Procedure: Surgical resection
All participants enrolled will undergo surgical resection prior to treatment. The maximal resection that can be achieved without undue risk to the patient will be attempted, with decisions about feasibility and extent of resection left to the discretion of the neurosurgeon. In instances where an STR is the best extent of resection achieved prior to start of therapy, a "second-look" surgery may be performed between cycles of chemotherapy after discussion with the principal investigator.
Other Name: surgical management

Drug: Methotrexate
Route of administration: Intravenously (IV)
Other Names:
  • MTX
  • amethopterin
  • Rexall®

Drug: Cisplatin
Route of administration: Intravenously (IV)
Other Names:
  • CDDP
  • cis-DDP
  • Platinol-AQ®

Drug: Vincristine
Route of administration: Intravenously (IV)
Other Name: Oncovin®

Drug: Cyclophosphamide
Route of administration: Intravenously (IV)
Other Name: Cytoxan®

Drug: Carboplatin
Route of administration: Intravenously (IV)
Other Name: Paraplatin®

Drug: Topotecan
Route of administration: Intravenously (IV)
Other Name: Hycamtin®

Drug: Pegfilgrastim
Route of administration: subcutaneous (SQ)
Other Name: Udenyca®

Drug: Filgrastim
Route of administration: subcutaneous (SQ) or Intravenously (IV)
Other Names:
  • GCSF
  • Neupogen®
Experimental: Stratum S-1

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

 Procedure: Surgical resection
All participants enrolled will undergo surgical resection prior to treatment. The maximal resection that can be achieved without undue risk to the patient will be attempted, with decisions about feasibility and extent of resection left to the discretion of the neurosurgeon. In instances where an STR is the best extent of resection achieved prior to start of therapy, a "second-look" surgery may be performed between cycles of chemotherapy after discussion with the principal investigator.
Other Name: surgical management

Procedure: Ommaya/VPS
All participants enrolled on S-1 will undergo
Other Name: surgical management

Drug: Methotrexate
Route of administration: Intravenously (IV)
Other Names:
  • MTX
  • amethopterin
  • Rexall®

Drug: Cisplatin
Route of administration: Intravenously (IV)
Other Names:
  • CDDP
  • cis-DDP
  • Platinol-AQ®

Drug: Vincristine
Route of administration: Intravenously (IV)
Other Name: Oncovin®

Drug: Cyclophosphamide
Route of administration: Intravenously (IV)
Other Name: Cytoxan®

Drug: Carboplatin
Route of administration: Intravenously (IV)
Other Name: Paraplatin®

Drug: Topotecan
Route of administration: Intravenously (IV)
Other Name: Hycamtin®

Drug: Pegfilgrastim
Route of administration: subcutaneous (SQ)
Other Name: Udenyca®

Drug: Filgrastim
Route of administration: subcutaneous (SQ) or Intravenously (IV)
Other Names:
  • GCSF
  • Neupogen®
Experimental: Stratum N

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

 Procedure: Surgical resection
All participants enrolled will undergo surgical resection prior to treatment. The maximal resection that can be achieved without undue risk to the patient will be attempted, with decisions about feasibility and extent of resection left to the discretion of the neurosurgeon. In instances where an STR is the best extent of resection achieved prior to start of therapy, a "second-look" surgery may be performed between cycles of chemotherapy after discussion with the principal investigator.
Other Name: surgical management

Drug: Methotrexate
Route of administration: Intravenously (IV)
Other Names:
  • MTX
  • amethopterin
  • Rexall®

Drug: Cisplatin
Route of administration: Intravenously (IV)
Other Names:
  • CDDP
  • cis-DDP
  • Platinol-AQ®

Drug: Vincristine
Route of administration: Intravenously (IV)
Other Name: Oncovin®

Drug: Cyclophosphamide
Route of administration: Intravenously (IV)
Other Name: Cytoxan®

Drug: Carboplatin
Route of administration: Intravenously (IV)
Other Name: Paraplatin®

Drug: Topotecan
Route of administration: Intravenously (IV)
Other Name: Hycamtin®

Drug: Etoposide
Route of administration: Intravenously (IV)
Other Names:
  • VP-16
  • Vepesid®

Drug: Pegfilgrastim
Route of administration: subcutaneous (SQ)
Other Name: Udenyca®

Drug: Filgrastim
Route of administration: subcutaneous (SQ) or Intravenously (IV)
Other Names:
  • GCSF
  • Neupogen®

Radiation: Irradiation
All participants in stratum N will undergo craniospinal irradiation (CSI) with boost to the primary tumor site once they reach 36 months of age. The dose given is based on the molecular risk group and disease response to chemotherapy as noted in the arm descriptions. The type of radiation used includes conformal radiation therapy (photons) or intensity modulated radiation therapy (IMRT) or proton beam therapy.
Other Name: Radiotherapy
Experimental: Cognitive Study Group I (educational video and games)
Educational video and games
 Other: Educational and Media Intervention
Participants watch a 75-minute caregiver education video program and receive access to interactive games on a smartphone or tablet throughout the optional cognitive study.
Active Comparator: Cognitive Study Group II (standard-of-care control)
Standard-of-care (SOC) followed by educational video and games
 Other: SOC, Educational and Media Intervention
Standard-of-care (SOC) treatment during main cognitive study. After the one-year serial cognitive evaluation, participants will be offered participation in the cognitive study group I intervention.


Outcome Measures
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Primary Outcome Measures :
  1. 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. [ Time Frame: 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.

  2. Progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy augmented with IVT-MTX. [ Time Frame: 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.

  3. 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. [ Time Frame: 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.

  4. 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 [ Time Frame: 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.

  5. 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 [ Time Frame: 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.

  6. 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 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Change in IQ among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma [ Time Frame: 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.

  2. Change in executive function among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma [ Time Frame: 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.

  3. Change in health-related quality of life among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma [ Time Frame: 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.

  4. Association of familial factors and environmental factors with socioeconomic status [ Time Frame: 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)

  5. Association of familial factors and environmental factors with cognitive late effects. [ Time Frame: 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).

  6. Evaluate family interest in caregiver education combined with interactive neurodevelopmental games. [ Time Frame: 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.

  7. Evaluate intervention feasibility by measuring the rate of participants completing a caregiver education combined with interactive. neurodevelopmental games. [ Time Frame: 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.

  8. Evaluate the acceptability of a caregiver education combined with interactive neurodevelopmental games. [ Time Frame: 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.

  9. Magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games. [ Time Frame: 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.

  10. To characterize the plasma systemic clearance (CL) of cyclophosphamide (CTX) in infants and young children with medulloblastoma. [ Time Frame: 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.

  11. To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide (CEPM) in infants and young children with medulloblastoma receiving cyclophosphamide. [ Time Frame: 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.

  12. 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. [ Time Frame: 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.

  13. 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. [ Time Frame: 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.

  14. 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. [ Time Frame: 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.

  15. 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. [ Time Frame: 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.

  16. To characterize the plasma systemic clearance (CL) of vincristine (VCR) in infants and young children with medulloblastoma. [ Time Frame: 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.

  17. 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. [ Time Frame: 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.

  18. To characterize the plasma systemic clearance (CL) of topotecan (TPT) in infants and young children with medulloblastoma. [ Time Frame: 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.

  19. 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. [ Time Frame: 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.

  20. To characterize the plasma systemic methotrexate (MTX) clearance (CL) in infants and young children with medulloblastoma. [ Time Frame: 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.

  21. To characterize the area under the concentration-time curve (AUC0-24h) of 7-hydroxymethotrexate (7OHMTX) in infants and young children with medulloblastoma receiving methotrexate. [ Time Frame: 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.

  22. 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. [ Time Frame: 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.

  23. 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. [ Time Frame: 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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 59 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - Screening Phase (All Patients)

  • Participants with presumptive/suspected newly diagnosed medulloblastoma.

  • Participant meets one of the following criteria at the time of screening:

    • Age < 36 months OR Age ≥ 36 months and < 60 months with presumptive/suspected non-metastatic disease
  • Participant must have adequate tumor tissue from primary tumor for central review of pathology and molecular classification by methylation and IHC
  • Participant must be able to begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is Day 0). In case a second surgery is clinically indicated to remove the residual tumor prior to starting treatment, the second surgery will be considered as the definitive surgery (Day 0).
  • Parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines.

Exclusion Criteria - Screening Phase

  • Participants with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedure.

Inclusion Criteria - Study Enrollment (All Patients)

  • Participant must be < 60 months of age at time of enrollment.

    • Note: Each treatment stratum has additional specific age requirements

  • Participant must have confirmation of newly diagnosed medulloblastoma per Central Review:

    • Central review includes histopathology, IHC and St. Jude Clinical Genomic Methylation Profiling conducted on MLPNet. If tissue or the extracted DNA does not meet quality control criteria for methylation analysis or if methylation classifier is unable assign molecular group/subgroup within the assigned classifier (MLPNet) parameters, then IHC will be used to define molecular group of these cases. IHC cannot be used to determine molecular subgroup. Therefore, IHC defined SHH patients will be enrolled on Stratum S-1 under "SHH-NOS", and all NWNS and indeterminate molecular group will be enrolled on stratum N.
    • Note: Diagnosis of medulloblastoma, as well as group and subgroup assignment, will be done by central pathology review at St. Jude only. No outside testing is allowed for trial enrollment.

  • Participant must have disease staged by MRI of the brain and spine and by cytologic examination of CSF* and be placed into the following categories:

    • M0: no evidence of metastatic disease.

      • must include a negative CSF cytology result
    • M1: Tumor cells found in the CSF but no other evidence of metastasis
    • M2: Intracranial tumor beyond the primary tumor site
    • M3: Metastatic disease in the spine
    • M4: Extraneural metastatic disease
    • *All participants are to undergo CSF cytologic examination regardless of presence or absence of gross metastatic disease unless procedure is medically contraindicated. CSF is to be obtained by lumbar puncture (LP) performed at least 10 days after surgery. If LP is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used for staging but this is not the preferred option due to lower sensitivity. If LP is medically contraindicated and the patient doesn't have a shunt or reservoir for CSF sampling, the treating physician should reach out to PI or Co-PI regarding decision on enrollment to SJiMB21. The decision to enroll without CSF cytology will be made on case-by-case basis.
    • Note: Participants who have M2 disease and positive CSF will be assigned to M3.
    • Note: Participants will be assigned to the highest stage number for which they meet eligibility.
    • Note: Treatment stratums may have additional stage requirements.
  • Patient must have received no previous radiotherapy, chemotherapy, or other brain tumor-directed therapy other than corticosteroid therapy and surgery.
  • Participant must have a Lansky performance score of > 30 (except for patients with posterior fossa syndrome.

  • Participant must have adequate organ function prior to study entry, as defined by:

    • Absolute neutrophil counts (ANC) >750/mm^3
    • Platelet count ≥ 50,000/mm^3 without support of a platelet transfusion within 7 days
    • Hemoglobin ≥8.0 g/dL (with or without support of a blood transfusion).
    • Normal liver function as defined by Alanine aminotransferase (ALT) concentration ≤ 3 x 45 U/L and total bilirubin ≤ 3 x 1.0.

  • Adequate renal function as defined by a serum creatinine concentration:

    • Age - 0 to <1year; Maximum Serum Creatinine (mg/dl) - Male 0.5; Female 0.5
    • Age - 1 to < 2years; Maximum Serum Creatinine (mg/dl) - Male 0.6; Female 0.6
    • Age - 1 to < 2yearsr; Maximum Serum Creatinine (mg/dl) - Male 0.8; Female 0.8
  • Participant's parent or legal guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.

Inclusion Criteria - Stratum S-2

  • Participant must have confirmed diagnosis of the following medulloblastoma molecular group and subgroup per Central Review.

    • Medulloblastoma SHH-2

  • Participant must meet one of the following criteria at time of enrollment:

    • Age <36 months OR Age ≥ 36 months and < 60 months with non-metastatic disease (M0) Inclusion Criteria - Stratum S-1

  • Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.

    • Medulloblastoma SHH-1
    • Medulloblastoma SHH-3
    • Medulloblastoma SHH-4

    • Medulloblastoma SHH-NOS

      • Includes medulloblastoma cases that could not be assigned to a molecular subgroup using the DNA methylation classifier, but which are in the SHH group and/or cases defined as SHH by IHC.

  • Participant must be < 36 months of age at time of enrollment

    • Note: Patients who are < 36 months of age, regardless of metastatic status (M0/M+), are eligible for enrollment on stratum S-1.

Inclusion Criteria - Stratum N

  • Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.

    • Medulloblastoma G3
    • Medulloblastoma G4

    • Medulloblastoma - Not classified into SHH (i.e., NWNS or indeterminate)

      • Includes medulloblastoma cases that could not be assigned to a molecular group using the DNA methylation classifier but which are in the NWNS class and/or defined as NWNS by IHC.
  • Participant must be <36 months of age at time of enrollment
  • All NWNS patients (M+ and M0) are eligible for enrollment in stratum N

Exclusion Criteria - All Patients

  • CNS embryonal tumor other than medulloblastoma, for example, patients with diagnosis of Atypical Teratoid/Rhabdoid Tumor (ATRT), PNET, Pineoblastoma, Ependymoma, and ETMR are excluded.

  • Participant with prior treatment for medulloblastoma, including:

    • Radiotherapy
    • Chemotherapy
    • Cancer directed immunotherapy
    • Targeted agents
    • NOTE: Corticosteroid therapy is acceptable; prior treatment with chemotherapy, immunotherapy or targeted agents for non-cancer directed indications are acceptable as long as these have been stopped at least 14 days prior to start of therapy or 2 half-lives from last dose. (i.e., methotrexate for juvenile rheumatoid arthritis, JAK inhibitor therapy for eczema, etc.)
  • Participant who is actively receiving any other investigational agents.
  • Participant with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05535166


Contacts
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Contact: Tabatha E. Doyle, RN 901-595-2544 tabatha.doyle@stjude.org
Contact: Jean Laboe, MSN, RN 901-595-1693 jean.laboe@stjude.org

Locations
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United States, California
Lucille Packard Children's Hospital at Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Sonia Partap, MD, MS,    650-723-5535    spartap@stanford.edu   
Principal Investigator: Sonia Partap, MD, MS,         
United States, Florida
Orlando Health Arnold Palmer Hospital for Children Recruiting
Orlando, Florida, United States, 32806
Contact: Ana Aguilar-Bonilla, MD    321-841-8588    ana.aguilar-bonilla@orlandohealth.com   
Principal Investigator: Ana Aguilar-Bonilla, MD         
United States, Michigan
C.S. MOTT Children's Hospital, University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Santhosh Upadhyaya, MD    734-615-7920    saupadhy@med.umich.edu   
Principal Investigator: Santhosh Upadhyaya, MD         
United States, Minnesota
Children's Hospital and Clinics of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Anne Bendel, MD    612-813-5913    Anne.bendel@childrensmn.org   
Principal Investigator: Anne Bendel, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tabatha E. Doyle, RN    901-595-2544    tabatha.doyle@stjude.org   
Principal Investigator: Giles W. Robinson, MD         
Principal Investigator: Aditi Bagchi, MD, PhD         
United States, Texas
Cook Children's Medical Center Recruiting
Fort Worth, Texas, United States, 76104
Contact: Sibo Zhao, MD    682-885-4007    sibo.zhao@cookchildrens.org   
Principal Investigator: Sibo Zhao, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Giles W. Robinson, MD St. Jude Children's Research Hospital
Principal Investigator: Aditi Bagchi, MD, PhD St. Jude Children's Research Hospital
More Information
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Additional Information:

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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT05535166    
Other Study ID Numbers: SJiMB21
NCI-2022-07099 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: September 10, 2022    Key Record Dates
Last Update Posted: April 15, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available at the time of article publication.
Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by St. Jude Children's Research Hospital:
SJiMB21
Brain Cancer
Brain Tumors in Children
Medulloblastoma Sonic Hedgehog subgroup 1
Medulloblastoma Sonic Hedgehog subgroup 2
Medulloblastoma Sonic Hedgehog subgroup 3
Medulloblastoma Sonic Hedgehog subgroup 4
Medulloblastoma Sonic Hedgehog-not otherwise specified
Medulloblastoma G3
 Medulloblastoma G4
Medulloblastoma indeterminate
MLPNet
Neural Net Classification Pipeline
Non-WNT non-SHH medulloblastoma
Posterior fossa syndrome
St. Jude Brain Tumor Studies
Treatment for Brain Tumors in Infants and Young Children
Untreated Childhood Medulloblastoma
Additional relevant MeSH terms:
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Medulloblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Carboplatin
Methotrexate
Etoposide
Vincristine
 Topotecan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites