Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
- To identify patterns of tumor gene expression that are associated with progression-free
survival among young pediatric patients with newly diagnosed medulloblastoma treated
with risk-adapted therapy.
- 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
- 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 compare these survival rates to historical controls.
- To estimate the rates of local and distant disease progression in patients treated with
focal radiotherapy to the post-operative tumor bed using a 5 mm clinical target volume
- To estimate the objective response rate (sustained for 8 weeks) to induction
chemotherapy including high-dose intravenous methotrexate for patients with residual or
- 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
- 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.
- To estimate the event free survival of average risk (M0 with gross total resection)
medulloblastoma patients who were ≥3-<5 years of age at the time of diagnosis and
treated on the intermediate risk arm of the study.
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
After completion of study treatment, patients are followed every 6 months for 5 years.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To identify patterns of tumor gene expression that are associated with progression-free survival among patients with medulloblastoma younger than three years of age at diagnosis treated with risk-adapted therapy.
Amar Gajjar, MD
St. Jude Children's Research Hospital
United States: Food and Drug Administration
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Lucile Packard Children's Hospital at Stanford University Medical Center||Palo Alto, California 95798|
|Children's Hospitals and Clinics of Minnesota - St. Paul||St. Paul, Minnesota 55102-2392|
|University of Texas Southwestern Medical Center at Dallas||Dallas, Texas 75235-8897|
|Rady Children's Hospital||San Diego, California 92123|