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 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 the progression-free and overall
survival distributions to molecularly and clinically matched historical controls from
St. Jude SJMB03 study as well as outcome from other published cohorts.

- To estimate the progression free and overall survival distributions of Non-WNT Non-SHH
medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and
gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare
the progression-free and overall survival distributions to molecularly and clinically
matched historical controls from St. Jude SJMB03 study separately for each stratum.

- To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma
patients treated on Stratum N1 with reduced dose cyclophosphamide and compare
progression free and overall survival distributions to molecularly and clinically
matched historical controls from St. Jude SJMB03 study.

- To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to
adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH
medulloblastoma patients (Strata N2 and N3).

- To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted
SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.

- To estimate the cumulative incidence of local disease failure at 2 and 5 years based on
treatment regimen, strata, and clinical and treatment factors.

- To evaluate the effects of an aerobic training intervention, delivered during the
radiation therapy period and at home, prior to the start of chemotherapy, on physical
performance, fatigue, health related quality of life, memory, attention and executive
function at the end of the intervention, at the end of adjuvant chemotherapy, and one,
two and five years off adjuvant chemotherapy, among children treated for
medulloblastoma.

- To evaluate the impact of an aerobic training intervention on sleep quality and quantity
in children with medulloblastoma.

- To evaluate the relation between baseline cognitive performance and the variables of
sleep quality and quantity, and fatigue in children with medulloblastoma.

- To estimate change in neurocognitive performance using a comprehensive assessment
battery (e.g., measures of intellectual function, academic abilities, attention, memory,
processing speed and executive functions) and investigate the relationship of change to
relevant demographic factors (e.g., gender, age at treatment, time since treatment and
socioeconomic status) and clinical factors (e.g., treatment intensity/risk group,
posterior fossa syndrome).

- To assess the impact of a computer-based working memory intervention, relative to
standard of care, on additional performance- and rater-based measures of attention,
processing speed and executive functions.

- To compare the impact of a computer-based working memory intervention in conjunction
with an aerobic training intervention, relative to either intervention in isolation, on
measures of attention, processing speed and executive functions.

- To evaluate the maintenance of improvements on measures of attention, working memory,
processing speed and executive functions six months following participation in the
computer-based working memory intervention program.

Outline: This is a multicenter study. Patients are stratified according to molecular subgroup
assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent
of resection, M stage, histologic subtype, and cytogenetic features). All patients will be
treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to
Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1,
N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2,
or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4
cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine
for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk
factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy
intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype
(Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance
therapy with vismodegib.

Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies.
Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the
SHH signaling pathway, validation of novel patterns of gene expression via
immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase
fluorescence in situ hybridization (iFISH); construction of gene expression profiles via
microarray analysis; construction of DNA methylation profiling via microarrays; single
nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes
and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal
proteins implicated in the biology of medulloblastoma via western blot; expression of
additional proteins encoded by genes associated through SNP and gene expression array
analysis with clinical disease behavior. Blood samples are analyzed from patients whose
tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood
samples are analyzed for identification of potential tumor markers. Parents may consent to
have blood samples analyzed for inheritable gene mutations associated with medulloblastoma.

Patients may also consent to exploratory research that include additional functional MRI
imaging to investigate damage to neural connections from therapy; additional psychological
testing to identify neurocognitive effects of therapy; additional heart and lung testing to
identify treatment effects; additional endocrine studies to identify treatment effect on
growth and development.

After completion of study treatment, patients are followed every 6 months for 5 years.

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 or age is greater than or
equal to 22 years and less than 40 years and patient has SHH medulloblastoma

- English as primary language and training aide who speaks English available to
participate in required sessions

- No significant cognitive impairment operationalized as either an IQ < 70 for children
with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ
missing

- No major sensory or motor impairment that would preclude valid cognitive testing
(e.g., unresolved posterior fossa syndrome, blindness, poorly controlled
seizures/photosensitive epilepsy, psychosis) or a major psychological condition that
would preclude completion of the intervention (e.g., significant oppositionality,
autism spectrum disorder, severe anxiety or depressive symptoms)