Trial Information

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

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.