A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
NCT ID: NCT01878617
Last Updated: 2025-11-13
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE2
660 participants
INTERVENTIONAL
2013-06-23
2031-10-13
Brief Summary
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* 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
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* 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.
Conditions
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Keywords
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Stratum W1: Low Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Stratum W2: Atypical
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Stratum W3: High Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Stratum S1: Standard Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Vismodegib
ROA: Orally (PO)
Aerobic Training
Neurocognitive Remediation
Stratum S2: High Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Vismodegib
ROA: Orally (PO)
Aerobic Training
Neurocognitive Remediation
Stratum N1: Standard Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Stratum N2: Intermediate Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Pemetrexed
ROA: IV
Gemcitabine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Stratum N3: High Risk
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.
Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Pemetrexed
ROA: IV
Gemcitabine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Interventions
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Craniospinal Irradiation with boost to the primary tumor site
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.
Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Cisplatin
ROA: IV
Vincristine
ROA: IV
Vismodegib
ROA: Orally (PO)
Pemetrexed
ROA: IV
Gemcitabine
ROA: IV
Aerobic Training
Neurocognitive Remediation
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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.
Exclusion Criteria
* 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)
3 Years
39 Years
ALL
No
Sponsors
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Genentech, Inc.
INDUSTRY
National Cancer Institute (NCI)
NIH
St. Jude Children's Research Hospital
OTHER
Responsible Party
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Principal Investigators
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Amar Gajjar, MD
Role: PRINCIPAL_INVESTIGATOR
St. Jude Children's Research Hospital
Giles Robinson, MD
Role: PRINCIPAL_INVESTIGATOR
St. Jude Children's Research Hospital
Locations
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Lucille Packard Children's Hospital at Stanford University Medical Center
Palo Alto, California, United States
Rady Children's Hospital
San Diego, California, United States
Yale University
New Haven, Connecticut, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
University of Florida
Gainesville, Florida, United States
Arnold Palmer Hospital for Children
Orlando, Florida, United States
Children's Hospital and Clinics of Minnesota
Minneapolis, Minnesota, United States
Duke Children's Hospital and Health Center
Durham, North Carolina, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Cook Children's Medical Center
Fort Worth, Texas, United States
Texas Children's Cancer Center
Houston, Texas, United States
Sydney Children's Hospital
Randwick, New South Wales, Australia
Children's Hospital at Westmead
Westmead, New South Wales, Australia
Queensland Children's Hospital
Brisbane, Queensland, Australia
Royal Children's Hospital, Melbourne
Melbourne, Victoria, Australia
Perth Children's Hospital
Perth, Western Australia, Australia
Alberta Children's Hospital
Calgary, Alberta, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, Canada
Starship Children's Hospital
Auckland, , New Zealand
Countries
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References
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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.
Related Links
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St. Jude Children's Research Hospital
Clinical Trials Open at St. Jude
Other Identifiers
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NCI-2013-01125
Identifier Type: REGISTRY
Identifier Source: secondary_id
SJMB12
Identifier Type: -
Identifier Source: org_study_id