Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma

Study ID

Cancer Related

Healthy Volunteers

Study Sites

  • UT Southwestern-Other
  • Children’s Medical Center (Dallas, Plano, Southlake)

Natasha Anderson

Principal Investigator
Daniel Bowers, M.D.

Official Title

Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma

Brief Overview

RATIONALE: In this study a combination of anti-cancer drugs (chemotherapy) is used to treat
brain tumors in young children. Using chemotherapy gives the brain more time to develop
before radiation is given. The chemotherapy in this study includes the drug methotrexate.
This drug was an important part of the two clinical trials which resulted in the best
survival results for children less than 3 years of age with medulloblastoma. Most patients
treated on this trial will also receive radiation which is carefully targeted to the area of
the tumor. This type of radiation (focal conformal or proton beam radiotherapy) may result
in fewer problems with thinking and learning than radiation to the whole brain and spinal

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together
with radiation therapy works in treating young patients with newly diagnosed central nervous
system tumors.


All patients with medulloblastoma who were diagnosed prior to their 3rd birthday will
contribute to both the biology and therapeutic primary objectives of this protocol.
Furthermore patients who were ≥3 and <5 years old at the time of diagnosis will also be
included in the cohort for these primary objectives as long as they meet the eligibility
criteria as outlined in Amendment 8.0 of this protocol. Patients in the 3-5 year old age
cohort who enrolled on previous versions of this protocol and who do not meet the criteria
as outlined in Amendment 8.0 of this protocol will be excluded from the outcome analyses of
the biology and therapeutic primary objectives of the protocol.



- To identify patterns of methylation profiling that are associated with progression-free
survival among young pediatric patients with medulloblastoma treated with risk-adapted

- To estimate the event-free survival distribution of young medulloblastoma patients
treated with risk-adapted therapy.


- To perform high-resolution genome-wide analyses of chromosomal abnormalities and gene
expression patterns, and evaluate the relationship of these to other
clinicopathological variables.

- To evaluate specific tumor types for molecular abnormalities with suspected prognostic
or therapeutic significance.

- To evaluate the feasibility of collecting frozen and fixed tumor samples for analysis
using high-resolution molecular biology tools.

- To estimate the event-free and overall survival of patients treated with the proposed
risk-adapted therapy regimen, and to descriptively compare these survival rates to
historical controls.

- To estimate the rates of local and distant disease progression in patients treated with
focal radiotherapy (RT) to the post-operative tumor bed using a 5 mm clinical target
volume margin.

- To estimate the objective response rate (sustained for 8 weeks) to induction
chemotherapy including high-dose intravenous methotrexate for patients with residual or
metastatic disease.

- To evaluate the feasibility and toxicity of administering low-dose intravenous
vinblastine in conjunction with induction chemotherapy to patients with metastatic

- To evaluate the feasibility and toxicity of administering consolidation therapy
including cyclophosphamide and pharmacokinetically targeted topotecan to patients with
metastatic disease, and to estimate the sustained (for 8 weeks) objective response rate
(complete response and partial response) to such therapy in patients with measurable
residual disease after induction.

- To evaluate the feasibility and toxicity of administering oral maintenance therapy in
young children.

- To use quantitative magnetic resonance (MR) measures (volumetric, diffusion, and
perfusion) of young brain tumor patients receiving chemotherapy including high-dose
intravenous methotrexate to assess impact of treatment on developing brain.

OUTLINE: This is a multicenter study. Patients are stratified according to disease risk
(low-risk vs intermediate-risk vs high-risk). Therapy consists of risk adapted induction,
consolidation and maintenance chemotherapy. Focal irradiation is given to intermediate risk
patients who have reached at least 12 months of age upon completion of induction.
Intermediate risk patients who have not will receive low risk chemotherapy to delay RT until
the age of 12 months.

Patients may consent to provide tumor tissue and blood samples for biological studies. Tumor
tissues are analyzed for the activation of the wnt signaling pathway (β-catenin), activation
of the shh signaling pathway (Gli-1/SFRP1), and ERBB2; validation of novel patterns of gene
expression via immunohistochemical (IHC) analysis; loss of chromosomes 6, 8p, 9q22,
isochromosome 17q; amplification of MYCC, MYCN, and MYCL; validation of genetic
abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of
gene expression profiles via microarray analysis; single nucleotide polymorphism (SNP)
analysis for DNA purity and integrity using UV spectrophotometry and agarose gel
electrophoresis; amplification of DNA via PCR and a combination of previously published and
'in-house' generated primers; 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;
and differential expression pattern of genes detected using microarray analysis via RT-PCR.
DNA extraction and construction of tissue microarrays (TMAs) from tumor tissue will also be
used for future IHC and FISH analysis. Blood samples are analyzed for constitutional DNA
from patients whose tumors contain gene mutations via sequence analysis of constitutional
DNA; cyclophosphamide and its metabolites via liquid chromatography mass spectroscopy
method; topotecan lactone via isocratic high-performance liquid chromatography assay with
fluorescence detection; and alpha-1-acid glycoprotein (AAGP) concentrations via
immunoturbidimetric assay.

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

Participant Eligibility

Histologically confirmed newly diagnosed CNS tumors of any of the following :

- Medulloblastoma (all histologic subtypes, including medullomyoblastoma and melanotic

- Supratentorial primitive neuroectodermal tumor (PNET) (including CNS neuroblastoma or
ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma)

- Pineoblastoma

- Atypical teratoid rhabdoid tumor (ATRT)

- Choroid plexus carcinoma

- High grade glioma (including anaplastic astrocytoma, anaplastic oligodendroglioma,
anaplastic ganglioglioma, pleomorphic xanthoastrocytoma with anaplastic features,
high-grade astroblastoma , anaplastic pilocytic astrocytoma, malignant glioneuronal
tumor, glioblastoma multiforme), or gliosarcoma,

- Ependymoma (including all ependymoma histological variants)

- Age < 3 years at time of diagnosis for all histological diagnosis. Medulloblastoma
patients ≥ 3 and < 5years old at diagnosis who have non-metastatic disease with no
more than 1cm2 of residual tumor are also eligible.

- Meets criteria for 1 of the following risk groups:

- Low-risk group:

- Histologically confirmed nodular desmoplastic medulloblastoma, including
medulloblastoma with extensive nodularity

- Focal areas of anaplasia or other atypical features suggesting more
aggressive phenotype in a tumor otherwise considered nodular desmoplastic
should be treated on the intermediate-risk group, with final risk
stratification at the discretion of principal investigator and study

- No evidence of CNS metastasis 7 to 28 days after surgery by MRI and cytologic
examination of lumbar cerebrospinal fluid (CSF)

- Ventricular CSF from a shunt or Ommaya reservoir may be used to rule out M1
disease when lumbar puncture is medically contraindicated

- Intermediate-risk group assignment when there is no other evidence of
metastasis and CSF sampling is not possible

- Gross total resection, defined as residual tumor or imaging abnormality (not
definitive for residual tumor) with a size of < 1 cm2 confirmed on postoperative
CT scan or MRI

- Brain stem invasion by the tumor in the absence of imaging evidence of residual
tumor (tumor size < 1 cm2) and otherwise meets criteria for the low-risk group,
the patient will be classified as low-risk

- Desmoplastic medulloblastoma patients who are ≥3 -<5 years of age will NOT be
eligible for the low risk arm of the protocol.

- Intermediate-risk group:

- Histologically confirmed nodular desmoplastic medulloblastoma with less than
gross total resection and no evidence of metastasis

- Any eligible histologic diagnosis other than desmoplastic medulloblastoma with
no evidence of CNS metastasis

- Medulloblastoma patients who are ≥3 and < 5 yrs of age irrespective of histology
and with no evidence of CNS metastasis

- High-risk group:

- Any eligible histologic diagnosis with evidence of CNS metastasis

- Patients with extraneural metastasis are eligible for treatment on the high-risk


- Lansky performance status ≥ 30 (except for posterior fossa syndrome)

- WBC > 2,000/mm3

- Platelets > 50,000/mm3 (without support)

- Hemoglobin > 8 g/dL (with or without support)

- ANC > 500/mm3

- Serum creatinine < 3 times upper limit of normal (ULN)

- ALT < 5 times ULN

- Total bilirubin < 3 times ULN


- See Disease Characteristics

- No more than 31 days since prior definitive surgery

- No prior radiotherapy or chemotherapy other than corticosteroid therapy