NCT01878617 · CITED IN SOURCE DOCUMENTS

A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE2
Status at capture: ACTIVE NOT RECRUITING
Registry last update: 2025-11-13

Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following: * To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects. * To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors. * To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors. * To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study. All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers: * WNT (Strata W): positive for WNT biomarkers * SHH (Strata S): positive for SHH biomarkers * Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of: * How much tumor is left after surgery * If the cancer has spread to other sites outside the brain \[i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)\] * The appearance of the tumor cells under the microscope * Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility Criteria: INCLUSION CRITERIA * Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist. * Participant's age meets one of the following: (1) Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis (may enroll on Strata W, S or N), OR (2) age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma (must enroll on Stratum S). * No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery. * Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor). * Adequate performance status: children \< 10-Lansky Score ≥ 30; children ≥ 10-Karnofsky ≥ 30 (except for posterior fossa syndrome). * Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants \> 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment. * Biological parent(s) of participant (child) enrolling on this protocol. These parents will be assigned to cohort P. The exclusion criteria below do not apply to this cohort. EXCLUSION CRITERIA * CNS embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, ETANTR are excluded. * Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history. Participants in the Stratum S maintenance chemotherapy portion of the study must meet the criteria below prior to start of vismodegib therapy: * Participants must be Stratum S (SHH) * Participants must be skeletally mature defined as females with a bone age ≥ 15 years and males with a bone age ≥ 17 years. * Must be able to swallow pills * BSA must be \>0.67 and \<2.5 m2 * Male and female participants of reproductive potential must agree to effective contraception during and after study treatment. See Appendices I and II for further guidance for participants receiving vismodegib * ANC ≥ 1000/mm\^3 (after G-CSF discontinued) * Platelets ≥ 50,000/mm\^3 (without support) * Hgb ≥ 8 g/dL (with or without transfusion support) * Serum creatinine ≤ 1.5 mg/dL * Total bilirubin ≤ 1.5X the institutional ULN * SGPT (ALT) ≤ 2.5X the institutional ULN * SGOT (AST) ≤ 2.5X the institutional ULN * Alkaline Phosphatase ≤ 1.5X the institutional ULN * Serum albumin ≥ 2.5 g/dL Participants in the exercise intervention portion of the study must meet all criteria below: * Must be ≥ 5 years and \< 22 years at the time of enrollment * Must have no congenital heart disease * Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician. Participants in the cognitive remediation intervention portion of the study must meet all criteria below: * Completed protocol-directed radiation therapy * ≥5 years at the time of remediation intervention consent or age is greater than or equal to 22 years and less than 40 years and patient has SHH medulloblastoma * English as primary language and training aide who speaks English available to participate in required sessions * No significant cognitive impairment operationalized as either an IQ \< 70 for children with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ missing * No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)
healthy Volunteers: false
maximum Age: 39 Years
minimum Age: 3 Years
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
Participants in stratum W1 will undergo reduced dose Craniospinal Irradiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum W1: Low Risk
type
EXPERIMENTAL
description
Participants in stratum W2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum W2: Atypical
type
EXPERIMENTAL
description
Participants in stratum W3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum W3: High Risk
type
EXPERIMENTAL
description
Participants in stratum S1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Drug: Vismodegib
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum S1: Standard Risk
type
EXPERIMENTAL
description
Participants in stratum S2 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Drug: Vismodegib
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum S2: High Risk
type
EXPERIMENTAL
description
Participants in stratum N1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum N1: Standard Risk
type
EXPERIMENTAL
description
Participants in stratum N2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Drug: Pemetrexed
Drug: Gemcitabine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum N2: Intermediate Risk
type
EXPERIMENTAL
description
Participants in stratum N3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.
intervention Names
Radiation: Craniospinal Irradiation with boost to the primary tumor site
Drug: Cyclophosphamide
Drug: Cisplatin
Drug: Vincristine
Drug: Pemetrexed
Drug: Gemcitabine
Other: Aerobic Training
Other: Neurocognitive Remediation
label
Stratum N3: High Risk
type
EXPERIMENTAL

interventions

arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
description
All participants will undergo craniospinal irradiation (CSI) with boost to the primary tumor site. The dose given is based on the molecular and risk group 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.
name
Craniospinal Irradiation with boost to the primary tumor site
other Names
CSI
Radiation treatments
type
RADIATION
arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
description
Route of Administration (ROA): Intravenously (IV)
name
Cyclophosphamide
other Names
Cytoxan(R)
type
DRUG
arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
description
ROA: IV
name
Cisplatin
other Names
Platinol-AQ(R)
type
DRUG
arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
description
ROA: IV
name
Vincristine
other Names
Oncovin(R)
type
DRUG
arm Group Labels
Stratum S1: Standard Risk
Stratum S2: High Risk
description
ROA: Orally (PO)
name
Vismodegib
other Names
Erivedge(TM)
GDC-0449
type
DRUG
arm Group Labels
Stratum N2: Intermediate Risk
Stratum N3: High Risk
description
ROA: IV
name
Pemetrexed
other Names
Almita(R)
type
DRUG
arm Group Labels
Stratum N2: Intermediate Risk
Stratum N3: High Risk
description
ROA: IV
name
Gemcitabine
other Names
Gemzar
type
DRUG
arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
name
Aerobic Training
other Names
Exercise
type
OTHER
arm Group Labels
Stratum N1: Standard Risk
Stratum N2: Intermediate Risk
Stratum N3: High Risk
Stratum S1: Standard Risk
Stratum S2: High Risk
Stratum W1: Low Risk
Stratum W2: Atypical
Stratum W3: High Risk
name
Neurocognitive Remediation
other Names
Computer-based working memory intervention
Cogmed
type
OTHER

Study design

allocation

NON_RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 660
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact.
measure
Progression-free Survival in Stratum W1
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact.
measure
Progression-free Survival in Stratum N1
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S1 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Progression-free Survival in Stratum S1 Skeletally Mature Cohort
time Frame
2 years after diagnosis
description
To evaluate the effect of an aerobic training intervention on cardiopulmonary fitness.
measure
Change in VO2 Peak Value
time Frame
baseline and 12 weeks post-randomization
description
To assess the impact of a computer-based working memory intervention, relative to standard of care, on a performance-based measure of working memory.
measure
Change in Spatial Span Backward Standard Score
time Frame
baseline and 10-12 weeks post baseline

secondary Outcomes

description
Progression-free survival (PFS) in stratum W1 will be compared to historical controls from SJMB03 using log-rank test.
measure
Progression-free Survival in Stratum W1 Compared to Historical Controls
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum W1 will be compared to historical controls from SJMB03 using log-rank test.
measure
Overall Survival in Stratum W1
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S1 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Progression-free Survival in Stratum S1 Skeletally Immature Cohort
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S2 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Progression-free Survival in Stratum S2 Skeletally Mature Cohort
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S2 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Progression-free Survival in Stratum S2 Skeletally Immature Cohort
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S1 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Overall Survival in Stratum S1 Skeletally Mature Cohort
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S1 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Overall Survival in Stratum S1 Skeletally Immature Cohort
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S2 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Overall Survival in Stratum S2 Skeletally Mature Cohort
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S2 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.
measure
Overall Survival in Stratum S2 Skeletally Immature Cohort
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum N2 will be compared to historical controls from SJMB03 using log-rank test.
measure
Progression-free Survival in Stratum N2
time Frame
2 years after diagnosis
description
Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum N2 will be compared to historical controls from SJMB03 using log-rank test.
measure
Overall Survival in Stratum N2
time Frame
2 years after diagnosis
description
Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum N3 will be compared to historical controls from SJMB03 using log-rank test.
measure
Progression-free Survival in Stratum N3
time Frame
2 years after diagnosis

Full study description

brief Summary: Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following: * To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects. * To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors. * To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors. * To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study. All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers: * WNT (Strata W): positive for WNT biomarkers * SHH (Strata S): positive for SHH biomarkers * Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of: * How much tumor is left after surgery * If the cancer has spread to other sites outside the brain \[i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)\] * The appearance of the tumor cells under the microscope * Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)
detailed Description: Primary Objectives: * To estimate the progression free survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide. * To estimate progression-free survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide. * To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts. * To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness. * To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory. Secondary Objectives: * To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study. * To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts. * To estimate the progression free and overall survival distributions of Non-WNT Non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study separately for each stratum. * To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study. * To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH medulloblastoma patients (Strata N2 and N3). * To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete. * To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors. * To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance, fatigue, health related quality of life, memory, attention and executive function at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma. * To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma. * To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma. * To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome). * To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions. * To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions. * To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program. Outline: This is a multicenter study. Patients are stratified according to molecular subgroup assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent of resection, M stage, histologic subtype, and cytogenetic features). All patients will be treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1, N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2, or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4 cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype (Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance therapy with vismodegib. Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies. Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the SHH signaling pathway, validation of novel patterns of gene expression via immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of gene expression profiles via microarray analysis; construction of DNA methylation profiling via microarrays; single nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal proteins implicated in the biology of medulloblastoma via western blot; expression of additional proteins encoded by genes associated through SNP and gene expression array analysis with clinical disease behavior. Blood samples are analyzed from patients whose tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumor markers. Parents may consent to have blood samples analyzed for inheritable gene mutations associated with medulloblastoma. Patients may also consent to exploratory research that include additional functional MRI imaging to investigate damage to neural connections from therapy; additional psychological testing to identify neurocognitive effects of therapy; additional heart and lung testing to identify treatment effects; additional endocrine studies to identify treatment effect on growth and development. After completion of study treatment, patients are followed every 6 months for 5 years.

Source references

references

citation
Gajjar A, Mahajan A, Bale T, Bowers DC, Canan L, Chi S, Cluster A, Cohen K, Cole B, Coven S, Darlington W, Dorris K, Elster J, Ermoian R, Franson A, George E, Helgager J, Landi D, Lin C, Metrock L, Nanda R, Palmer J, Partap S, Plant A, Pruthi S, Reynolds R, Stearns D, Storm P, Wang A, Wang LD, Whipple N, Zaky W, McMillian N, Ramakrishnan S. Pediatric Central Nervous System Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw. 2025 Mar;23(3):113-130. doi: 10.6004/jnccn.2025.0012.
pmid
40073837
type
DERIVED
citation
Khan RB, Patay Z, Klimo P, Huang J, Kumar R, Boop FA, Raches D, Conklin HM, Sharma R, Simmons A, Sadighi ZS, Onar-Thomas A, Gajjar A, Robinson GW. Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol. 2021 Sep 1;23(9):1586-1596. doi: 10.1093/neuonc/noab030.
pmid
33823018
type
DERIVED