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

Brief Summary

Official Title: “A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma”

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).

  • Study Type: Interventional
  • Study Design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: June 2023

Detailed Clinical Trial 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 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 and overall survival distributions of SHH medulloblastoma patients treated on Stratum S1 with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.

- 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 three 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) 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.

Interventions Used in this Clinical Trial

  • 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.
  • Drug: Cyclophosphamide
    • Route of Administration (ROA): Intravenously (IV)
  • Drug: Cisplatin
    • ROA: IV
  • Drug: Vincristine
    • ROA: IV
  • Drug: Vismodegib
    • ROA: Orally (PO)
  • Drug: Pemetrexed
    • ROA: IV
  • Drug: Gemcitabine
    • ROA: IV
  • Other: Aerobic Training
  • Other: Neurocognitive Remediation

Arms, Groups and Cohorts in this Clinical Trial

  • 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.
  • 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.
  • 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.
  • 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 chemotherapy, participants will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.
  • 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 chemotherapy, participants will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.
  • 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.
  • 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.
  • 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.

Outcome Measures for this Clinical Trial

Primary Measures

  • Progression-free survival distribution (Stratum W1)
    • Time Frame: 2 years after last patient enrollment
      Safety Issue?: No
  • Progression free survival distribution (Stratum N1)
    • Time Frame: 2 years after last patient enrollment
      Safety Issue?: No
  • Change in VO2 peak values
    • Time Frame: baseline and 12 weeks post-randomization
      Safety Issue?: No
  • Change in spatial span backward standard score
    • Time Frame: baseline and 10-12 weeks post baseline
      Safety Issue?: No

Secondary Measures

  • Compare progression-free survival by strata with prior St. Jude SJMB03 study participants
    • Time Frame: 2 years after last patient enrollment
      Safety Issue?: No
  • Compare overall survival by strata with prior St. Jude SJMB03 study participants
    • Time Frame: 2 years after last patient enrollment
      Safety Issue?: No
  • Proportion of patients able to complete protocol therapy
    • Time Frame: 10 months after the last patient enrollment
      Safety Issue?: Yes
  • Number of patients who go off treatment for reasons other than progressive disease
    • Time Frame: 20 months after the last patient enrollment
      Safety Issue?: Yes
  • Number of local failures
    • Time Frame: 2 and 5 years after the last patient enrollment
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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).
      Safety Issue?: No
  • 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).
      Safety Issue?: No
  • 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).
      Safety Issue?: No
  • Change in sleep
    • Time Frame: Baseline and 10-12 weeks post randomization
      Safety Issue?: No
  • Association between baseline cognitive performance and sleep quality
    • Time Frame: Baseline and approximately 7-10 months after treatment
      Safety Issue?: No
  • Association between baseline cognitive performance and sleep quantity
    • Time Frame: Baseline and approximately 7-10 months after treatment
      Safety Issue?: No
  • Association between baseline cognitive performance and fatigue
    • Time Frame: Baseline and approximately 7-10 months after treatment
      Safety Issue?: No
  • Longitudinal change in measure of intellectual function
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in intellectual function
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Longitudinal change in measure of academic ability
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in academic ability
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Longitudinal change in measure of attention
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in attention
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Longitudinal change in measure of memory
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in memory
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Longitudinal change in measure of cognitive processing speed function
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in cognitive processing speed
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Longitudinal change in measure of neurocognitive executive function
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Association of demographic and clinical factors with change in neurocognitive executive function
    • Time Frame: Baseline through 5 years after enrollment
      Safety Issue?: No
  • Change in measure of attention
    • Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
      Safety Issue?: No
  • Change in measure of processing speed
    • Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
      Safety Issue?: No
  • Change in measure of executive function ability
    • Time Frame: Baseline (at 7-10 months after start of therapy) and at 3 months after baseline
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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.
      Safety Issue?: No
  • 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.
      Safety Issue?: No
  • 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.
      Safety Issue?: No
  • 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.
      Safety Issue?: No

Criteria for Participation in this Clinical Trial

Inclusion Criteria

  • Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist.
  • Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis.
  • 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

  • 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 exercise intervention portion of the study must meet all criteria below:

  • Must be > 5 years at the time of enrollment
  • Must have no congenital heart disease or posterior fossa syndrome

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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 3 Years

Maximum Age for this Clinical Trial: 21 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • St. Jude Children’s Research Hospital
  • Collaborator
    • Genentech, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Amar Gajjar, MD, Principal Investigator, St. Jude Children’s Research Hospital
  • Overall Contact(s)
    • Tabatha E. Doyle, RN, 901-595-2544, tabatha.doyle@stjude.org

Source

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The URL of this page is:
http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01878617