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

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ClinicalTrials.gov Identifier: NCT01878617
Recruitment Status : Recruiting
First Posted : June 17, 2013
Last Update Posted : December 18, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

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)

Condition or disease Intervention/treatment Phase
Medulloblastoma Radiation: Craniospinal Irradiation with boost to the primary tumor site Drug: Cyclophosphamide Drug: Cisplatin Drug: Vincristine Drug: Vismodegib Drug: Pemetrexed Drug: Gemcitabine Other: Aerobic Training Other: Neurocognitive Remediation Phase 2

  Show Detailed Description

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
Actual Study Start Date : June 23, 2013
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : December 2026


Arms and Interventions

Arm Intervention/treatment
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Drug: Vismodegib
ROA: Orally (PO)
Other Names:
  • Erivedge(TM)
  • GDC-0449
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Drug: Vismodegib
ROA: Orally (PO)
Other Names:
  • Erivedge(TM)
  • GDC-0449
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Drug: Pemetrexed
ROA: IV
Other Name: Almita(R)
Drug: Gemcitabine
ROA: IV
Other Name: Gemzar
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed
Experimental: 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.
Radiation: 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.
Other Names:
  • CSI
  • Radiation treatments
Drug: Cyclophosphamide
Route of Administration (ROA): Intravenously (IV)
Other Name: Cytoxan(R)
Drug: Cisplatin
ROA: IV
Other Name: Platinol-AQ(R)
Drug: Vincristine
ROA: IV
Other Name: Oncovin(R)
Drug: Pemetrexed
ROA: IV
Other Name: Almita(R)
Drug: Gemcitabine
ROA: IV
Other Name: Gemzar
Other: Aerobic Training
Other Name: Exercise
Other: Neurocognitive Remediation
Other Names:
  • Computer-based working memory intervention
  • Cogmed


Outcome Measures

Primary Outcome Measures :
  1. Progression-free survival distribution (Stratum W1) [ Time Frame: 2 years after last patient enrollment ]
    Progression-free survival 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.)

  2. Progression free survival distribution (Stratum N1) [ Time Frame: 2 years after last patient enrollment ]
    Progression-free survival 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.)

  3. Change in VO2 peak values [ Time Frame: baseline and 12 weeks post-randomization ]
    To evaluate the effect of an aerobic training intervention on cardiopulmonary fitness.

  4. Change in spatial span backward standard score [ Time Frame: baseline and 10-12 weeks post baseline ]
    To assess the impact of a computer-based working memory intervention, relative to standard of care, on a performance-based measure of working memory.


Secondary Outcome Measures :
  1. Compare progression-free survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
    To estimate progression-free survival distribution and compare by strata to molecularly and clinically matched historical controls from St. Jude SJMB03 study.

  2. Compare overall survival by strata with prior St. Jude SJMB03 study participants [ Time Frame: 2 years after last patient enrollment ]
    To estimate overall survival distribution by strata and compare to molecularly and clinically matched historical controls from St. Jude SJMB03 study.

  3. Proportion of patients able to complete protocol therapy [ Time Frame: 10 months after the last patient enrollment ]
    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).

  4. Number of patients who go off treatment for reasons other than progressive disease [ Time Frame: 20 months after the last patient enrollment ]
    To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.

  5. Number of local failures [ Time Frame: 2 and 5 years after the last patient enrollment ]
    To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.

  6. Change in hand grip strength [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    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 hand grip strength as measured using a hand-held dynamometer among children treated for medulloblastoma. Participants will be seated with the shoulder at 0-10 degrees and the elbow in 90 degrees of flexion. The forearm will be positioned in neutral. Each participant will complete three trials, the average used for analysis.

  7. Change in range of motion [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    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 range of motion as measured with a goniometer among children treated for medulloblastoma. The goniometer is a reliable and valid measure of active and passive range of motion with standard procedures.

  8. Change in overall flexibility [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    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 overall flexibility among children treated for medulloblastoma. Flexibility will be measured by having participants perform a "sit and reach test." A yardstick is placed on a firm flat surface and tape is placed across it at a right angle to the 15 inch mark. The participant sits with the yardstick between the legs, with legs extended at right angles to the taped line on the floor. The heels of the feet touch the edge of the taped line and are 10-12 inches apart. The participant reaches forward with both hands as far as possible, and the best value for three trials, in centimeters, at the fingertips is recorded.

  9. Change in motor proficiency [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    Measured by the Bruininks-Oseretsky Test of Motor Proficiency, Version 2 (BOT-2). 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 motor proficiency among children treated for medulloblastoma.

  10. Change in quality of life (QOL) score [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    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 health related quality of life (QoL) among children treated for medulloblastoma. QoL will be assessed using the 23-item PedsQL(TM) 4.0 Generic Core Scales which encompasses four subscales (1) physical functioning (eight items), (2) emotional functioning (five items), (3) social functioning (five items), and (4) school functioning (five items) and the 24-item PedsQL(TM) Brain Tumor Module which encompasses six scales: (1) cognitive problems (seven items), (2) pain and hurt (three items), (3) movement and balance (three items), (4) procedural anxiety (three items), (5) nausea (five items), and (6) worry (three items).

  11. Change in fatigue score [ Time Frame: Baseline (at enrollment), 12 weeks, at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3), and 1, 2, and 5 years after the last patient enrollment ]
    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 fatigue among children treated for medulloblastoma. Fatigue will be assessed using the 18-item PedsQL(TM) Multidimensional Fatigue Scale which encompasses three subscales: (1) general fatigue (six items), (2) sleep/rest fatigue (six items), and (3) cognitive fatigue (six items).

  12. Change in measure of memory function [ Time Frame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3). ]
    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 memory function at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Memory will be measured using different instruments as age appropriate: CogStage for age 5 and older (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for age 6 to < 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for age ≥17 years.

  13. Change in measure of attention [ Time Frame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3). ]
    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 attention at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to < 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to < 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to < 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks).

  14. Change in executive function score [ Time Frame: Baseline (at enrollment), 12 weeks, and at end of adjuvant chemotherapy (28 weeks for strata W1/W2/W3/N1/S1/S2 and 40 weeks for strata N2/N3). ]
    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 executive function at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Executive function is measured as age-appropriate by the following: BRIEF-P (age 3 to <6 years), BRIEF (age 6 to <19 years) and BREIF-A (age ≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for age 6 to <19 years, as well as CogState One-Back and Groton Maze tasks for age ≥5 years.

  15. Change in sleep [ Time Frame: Baseline and 10-12 weeks post randomization ]
    To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma. Sleep quality and quantity will be measured by Actigraph accelerometer as well as a sleep diary.

  16. Association between baseline cognitive performance and sleep quality [ Time Frame: Baseline and approximately 7-10 months after treatment ]
    To evaluate the relation between baseline cognitive performance and sleep quality in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between sleep quality as measured by Actigraph accelerometer and a sleep diary with measures of cognitive performance (memory, attention and executive function (detailed above) and internalizing and externalizing behavior. Internalizing and externalizing behaviors will be measured using the Behavior Assessment System for Children, 2nd Edition (BASC-2). There are Preschool, Child and Adolescent versions.

  17. Association between baseline cognitive performance and sleep quantity [ Time Frame: Baseline and approximately 7-10 months after treatment ]
    To evaluate the relation between baseline cognitive performance and sleep quantity in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between sleep quantity as measured by a sleep diary with measures of cognitive performance (memory, attention and executive function and internalizing and externalizing behavior (detailed above).

  18. Association between baseline cognitive performance and fatigue [ Time Frame: Baseline and approximately 7-10 months after treatment ]
    To evaluate the relation between baseline cognitive performance and fatigue in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between fatigue score as measured by the Multidimensional Fatigue Scale with measures of cognitive performance (memory, attention and executive function and internalizing and externalizing behavior (detailed above).

  19. Longitudinal change in measure of intellectual function [ Time Frame: Baseline through 5 years after enrollment ]
    Intellectual function will be measured as age-appropriate using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for age 3 to < 6 years, Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for age 6 to < 17 years, and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for age ≥17 years. Linear mixed-effects models will be used to model change in intellectual function over time.

  20. Association of demographic and clinical factors with change in intellectual function [ Time Frame: Baseline through 5 years after enrollment ]
    Intellectual function will be measured as age-appropriate using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for age 3 to < 6 years, Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for age 6 to < 17 years, and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for age ≥17 years. Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in intellectual function with demographic and clinical factors.

  21. Longitudinal change in measure of academic ability [ Time Frame: Baseline through 5 years after enrollment ]
    Academic ability will be measured using the Woodcock Johnson Tests of Academic Achievement-Third Edition (WJ-III-ACH) which has six subsets: Letter-Word Identification, Passage Comprehension, Reading Fluency, Calculation, Applied Problems, and Math Fluency. Academic ability will also be measured using the Comprehensive Test of Phonological Processing (CTOPP) which has three subsets: Elision, Blending Words, and Rapid Naming. Linear mixed-effects models will be used to model change in academic ability over time.

  22. Association of demographic and clinical factors with change in academic ability [ Time Frame: Baseline through 5 years after enrollment ]
    Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in academic ability (measured as described above) with demographic and clinical factors.

  23. Longitudinal change in measure of attention [ Time Frame: Baseline through 5 years after enrollment ]
    Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to < 6 years old (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to < 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to < 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). Linear mixed-effects models will be used to model change in the measure of attention over time.

  24. Association of demographic and clinical factors with change in attention [ Time Frame: Baseline through 5 years after enrollment ]
    Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in attention (measured as described above) with demographic and clinical factors.

  25. Longitudinal change in measure of memory [ Time Frame: Baseline through 5 years after enrollment ]
    Memory will be measured using different instruments as age appropriate: CogStage for age 5 and older (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for age 6 to < 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for age ≥17 years. Linear mixed-effects models will be used to model change in memory over time.

  26. Association of demographic and clinical factors with change in memory [ Time Frame: Baseline through 5 years after enrollment ]
    Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in memory (measured as described above) with demographic and clinical factors.

  27. Longitudinal change in measure of cognitive processing speed function [ Time Frame: Baseline through 5 years after enrollment ]
    Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for age 3 to < 6 years old; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to < 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for age ≥17 years. Linear mixed-effects models will be used to model change in cognitive processing speed over time.

  28. Association of demographic and clinical factors with change in cognitive processing speed [ Time Frame: Baseline through 5 years after enrollment ]
    Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in cognitive processing speed (measured as described above) with demographic and clinical factors.

  29. Longitudinal change in measure of neurocognitive executive function [ Time Frame: Baseline through 5 years after enrollment ]
    Neurocognitive executive function will be measured using the Behavioral rating inventory of executive function (BRIEF). There are age-appropriate versions: BRIEF-P for age 3 to < 6 years, BRIEF for age 6 to <19 years, and BRIEF-A for age ≥19 years. Executive function will also be measured using Conner's Parent Rating Scale, Third Edition (CPRS-III), for age 6 to < 19 years and also CogState, for age ≥5 years, One-Back and Groton Maze tasks. Linear mixed-effects models will be used to model change in executive function over time.

  30. Association of demographic and clinical factors with change in neurocognitive executive function [ Time Frame: Baseline through 5 years after enrollment ]
    Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in executive function (measured as described above) with demographic and clinical factors.

  31. Change in measure of attention [ Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline ]
    To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of attention. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to < 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to < 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to < 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). T tests will be used to compare changes in attention between the intervention and standard of care groups.

  32. Change in measure of processing speed [ Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline ]
    To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of processing speed. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for age 3 to < 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to < 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for age ≥17 years. T tests will be used to compare changes in processing speed between the intervention and standard of care groups.

  33. Change in measure of executive function ability [ Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline ]
    To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of executive function. Executive function is measured as age-appropriate by the following: BRIEF-P (age 3 to <6 years), BRIEF (age 6 to <19 years) and BREIF-A (age ≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for age 6 to <19 years, as well as CogState One-Back and Groton Maze tasks for age ≥5 years. T tests will be used to compare changes in executive function between the intervention and standard of care groups.

  34. Change in measure of attention among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone) [ Time Frame: Baseline and at 3 months after baseline ]
    Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for 3 to < 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for 6 to < 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for 4 to < 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). ANOVA will be used to compare changes in memory among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

  35. Change in measure of processing speed among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone) [ Time Frame: Baseline and at 3 months after baseline ]
    Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for 3 to < 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to < 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for ≥17 years. ANOVA will be used to compare changes in processing speed among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

  36. Change in measure of executive function among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone) [ Time Frame: Baseline and at 3 months after baseline ]
    Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Executive function is measured as age-appropriate by the following: BRIEF-P (3 to <6 years), BRIEF (6 to <19 years) and BREIF-A (≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for 6 to <19 years, as well as CogState One-Back and Groton Maze tasks for ≥5 years. ANOVA will be used to compare changes in executive function among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

  37. Change in measure of attention between participants who received computer-based intervention VS. those who did not [ Time Frame: Baseline (at 7-10 months after on treatment) through 6 months after baseline. ]
    Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for 3 to < 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for 6 to < 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for 4 to < 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ≥6 years, in addition to Cog Stage for ≥5 years (Detection and Identification tasks). Differences between 6 months following assessment and immediate post-intervention testing, and difference between 6 months following assessment and pre-intervention testing, will be calculated for each subject and then group difference (intervention group vs. control group) will be examined using t-tests.

  38. Change in measure of working memory between participants who received computer-based intervention VS. those who did not [ Time Frame: Baseline (at 7-10 months after on treatment) through 6 months after baseline. ]
    To evaluate the maintenance of improvements in working memory three months following participation in the computer-based working memory intervention program. Memory will be measured using different instruments as age appropriate: CogStage for ≥5 years (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for 6 to < 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for ≥17 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.

  39. Change in measure of processing speed between participants who received computer-based intervention VS. those who did not [ Time Frame: Baseline (at 7-10 months after on treatment) through 6 months after baseline. ]
    To evaluate the maintenance of improvements on processing speed three months following participation in the computer-based working memory intervention program. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for 3 to < 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to < 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for ≥17 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.

  40. Change in measure of executive function between participants who received computer-based intervention VS. those who did not [ Time Frame: Baseline (at 7-10 months after on treatment) through 6 months after baseline. ]
    To evaluate the maintenance of improvements in executive function three months following participation in the computer-based working memory intervention program. Executive function is measured as age-appropriate by the following: BRIEF-P (3 to <6 years), BRIEF (6 to <19 years) and BREIF-A (≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for 6 to <19 years, as well as CogState One-Back and Groton Maze tasks for ≥5 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 39 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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
  • 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)
Contacts and Locations

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): NCT01878617


Contacts
Contact: Tabatha E. Doyle, RN 901-595-2544 tabatha.doyle@stjude.org

  Show 22 Study Locations
Sponsors and Collaborators
St. Jude Children's Research Hospital
Genentech, Inc.
National Cancer Institute (NCI)
Investigators
Principal Investigator: Amar Gajjar, MD St. Jude Children's Research Hospital
Principal Investigator: Giles Robinson, MD St. Jude Children's Research Hospital
More Information

Additional Information:
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01878617     History of Changes
Other Study ID Numbers: SJMB12
NCI-2013-01125 ( Registry Identifier: NCI Clinical Trials Reporting Program )
R01CA187079 ( U.S. NIH Grant/Contract )
First Posted: June 17, 2013    Key Record Dates
Last Update Posted: December 18, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:
SJMB12
Brain Cancer
Brain Tumors in Children
Cisplatin
Cyclophosphamide
Embryonal Tumors of CNS
GDC-0449
Gemcitabine
Hedgehog Pathway Inhibitor
Infratentorial
Mass in Brain
Medulloblastoma
Medulloblastoma Brain Tumor
Medulloblastoma Tumor
Molecular
Neuroectodermal Tumor, Primitive
Newly Diagnosed Childhood Medulloblastoma
Non-SHH Non-WNT
Pediatric Brain Tumor
Pemetrexed
Posterior Fossa Tumor
Proton Beam Therapy
Radiation Therapy
Rare Brain Tumor
Risk
SHH
Sonic Hedgehog Pathway
St Jude Medullo
St. Jude Brain Tumor Studies
St. Jude Medullo

Additional relevant MeSH terms:
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
Gemcitabine
Cisplatin
Cyclophosphamide
Pemetrexed
Vincristine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Folic Acid Antagonists