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

Official Title

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

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 tumours 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 tumours. - 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 tumours. - To define the cure rate for standard risk Non-WNT Non-SHH tumours 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 tumour 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 tumour's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumour tissue for tumour 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 tumour 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 tumour cells under the microscope - Whether or not there are chromosomal abnormalities in the tumour, and if present, what type (also called cytogenetics analysis)

Trial Description

Primary Outcome:

• Progression-free Survival in Stratum W1
• Progression-free Survival in Stratum N1
• Progression-free Survival in Stratum S1 Skeletally Mature Cohort
• Change in VO2 Peak Value
• Change in Spatial Span Backward Standard Score

• Progression-free Survival in Stratum W1 Compared to Historical Controls
• Overall Survival in Stratum W1
• Progression-free Survival in Stratum S1 Skeletally Immature Cohort
• Progression-free Survival in Stratum S2 Skeletally Mature Cohort
• Progression-free Survival in Stratum S2 Skeletally Immature Cohort
• Overall Survival in Stratum S1 Skeletally Mature Cohort
• Overall Survival in Stratum S1 Skeletally Immature Cohort
• Overall Survival in Stratum S2 Skeletally Mature Cohort
• Overall Survival in Stratum S2 Skeletally Immature Cohort
• Progression-free Survival in Stratum N2
• Overall Survival in Stratum N2
• Progression-free Survival in Stratum N3
• Overall Survival in Stratum N3
• Progression-free Survival in Stratum N1 Compared to Historical Controls
• Overall Survival in Stratum N1
• Percentage of Participants Who Complete Pemetrexed and Gemcitabine Therapy
• Percentage of Participants Who Complete Vismodegib Therapy
• Number of Local Failures
• Change in hand grip strength
• Change in range of motion
• Change in overall flexibility
• Change in motor proficiency
• Change in quality of life (QOL) score
• Change in fatigue score
• Change in measure of memory function
• Change in measure of attention
• Change in executive function score
• Change in sleep
• Association between baseline cognitive performance and sleep quality
• Association between baseline cognitive performance and sleep quantity
• Association between baseline cognitive performance and fatigue
• Longitudinal change in measure of intellectual function
• Association of demographic and clinical factors with change in intellectual function
• Longitudinal change in measure of academic ability
• Association of demographic and clinical factors with change in academic ability
• Longitudinal change in measure of attention
• Association of demographic and clinical factors with change in attention
• Longitudinal change in measure of memory
• Association of demographic and clinical factors with change in memory
• Longitudinal change in measure of cognitive processing speed function
• Association of demographic and clinical factors with change in cognitive processing speed
• Longitudinal change in measure of neurocognitive executive function
• Association of demographic and clinical factors with change in neurocognitive executive function
• Change in measure of attention
• Change in measure of processing speed
• Change in measure of executive function ability
• Change in measure of attention among 3 groups (working memory intervention + physical exercise intervention VS. working memory intervention alone VS. physical training intervention alone)
• 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)
• 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)
• Change in measure of attention between participants who received computer-based intervention VS. those who did not
• Change in measure of working memory between participants who received computer-based intervention VS. those who did not
• Change in measure of processing speed between participants who received computer-based intervention VS. those who did not
• Change in measure of executive function between participants who received computer-based intervention VS. those who did not

• 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 multicentre 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 tumour tissue, blood, and CSF samples for biological studies. Tumour 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 tumour 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 behaviour. Blood samples are analyzed from patients whose tumours contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumour 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.

View this trial on ClinicalTrials.gov