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

This study is currently recruiting participants.
Verified November 2013 by St. Jude Children's Research Hospital
Sponsor:
Collaborator:
University of Florida
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00602667
First received: January 10, 2008
Last updated: November 7, 2013
Last verified: November 2013

January 10, 2008
November 7, 2013
November 2007
December 2015   (final data collection date for primary outcome measure)
  • 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. [ Time Frame: 7 Years ] [ Designated as safety issue: Yes ]
  • To estimate the event free survival distribution of medulloblastoma patients younger than three years of age at diagnosis treated with risk-adapted therapy. [ Time Frame: 12 Years ] [ Designated as safety issue: Yes ]
  • Progression-free survival [ Designated as safety issue: Yes ]
  • Event-free survival [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00602667 on ClinicalTrials.gov Archive Site
Not Provided
  • Relationship of chromosomal abnormalities and gene expression patterns to other clinicopathological variables [ Designated as safety issue: No ]
  • Presence of molecular abnormalities with suspected prognostic or therapeutic significance [ Designated as safety issue: No ]
  • Collection of frozen and fixed tumor samples for analysis [ Designated as safety issue: No ]
  • Event-free and overall survival of study patients compared to historical controls [ Designated as safety issue: Yes ]
  • Rates of local and distant disease progression in patients treated with focal radiotherapy [ Designated as safety issue: No ]
  • Objective response rate (sustained for 8 weeks) to induction chemotherapy including high-dose intravenous methotrexate for patients with residual or metastatic disease [ Designated as safety issue: No ]
  • Feasibility and toxicity of administering low-dose intravenous vinblastine in patients with metastatic disease [ Designated as safety issue: Yes ]
  • Feasibility and toxicity of administering consolidation therapy including cyclophosphamide and pharmacokinetically targeted topotecan to patients with metastatic disease [ Designated as safety issue: Yes ]
  • Sustained (for 8 weeks) objective response rate (complete response and partial response) to such therapy in patients with measurable residual disease after induction [ Designated as safety issue: No ]
  • Feasibility and toxicity of administering oral maintenance therapy in children younger than three years of age at diagnosis [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma

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 cord.

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.

OBJECTIVES:

Primary

  • 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.

Secondary

  • 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 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 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 disease.
  • 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.
  • 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 immunoturbidimetric assay.

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

Interventional
Not Provided
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: Induction Chemotherapy
    All patients will receive 4 identical cycles of induction chemotherapy including highdose (5 g/m2 or 2.5g/m2 for patients less than or equal to 31 days of age at enrollment) intravenous methotrexate and standard dose vincristine, cisplatin, and cyclophosphamide.
    Other Names:
    • MTX (methotrexate)
    • Oncovin(R) (vincristine)
    • Platinol-AQ(R) (cisplatin)
    • Cytoxan(R) (cyclophosphamide)
  • Drug: Low-Risk Therapy
    Induction will be followed by further conventional chemotherapy with carboplatin, cyclophosphamide, and etoposide. After consolidation, patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
    Other Names:
    • Cytoxan(R) (cyclophosphamide)
    • Paraplatin(R) (carboplatin)
    • Vepesid(R), VP-16 (etoposide)
    • Hycamptin(R) (topotecan)
    • Tarceva(TM) (erlotinib)
  • Drug: High-Risk Therapy
    High risk patients will also receive vinblastine with each course of induction chemotherapy. Induction will be followed by either chemotherapy with targeted intravenous topotecan and cyclophosphamide or optional craniospinal irradiation (CSI). CSI will be offered only to patients who reach 3 years of age by the end of induction only. After consolidation, all patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
    Other Names:
    • Velban(R) (vinblastine)
    • Cytoxan(R) (cyclophosphamide)
    • Hycamptin(R) (topotecan)
    • Tarceva(TM) (erlotinib)
    • Vepesid(R), VP-16 (etoposide)
  • Drug: Intermediate-Risk Therapy
    Induction will be followed by consolidation focal radiotherapy (RT) to the tumor bed. Patients less than 12 months old upon completion of induction will receive low risk chemotherapy to delay RT until the age of 12 months. After consolidation, patients will receive 6 cycles of oral maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, either erlotinib or etoposide (VP-16).
    Other Names:
    • Cytoxan(R) (cyclophosphamide)
    • Hycamptin(R) (topotecan)
    • Tarceva(TM) (erlotinib)
    • Vepesid(R), VP-16 (etoposide)
  • Experimental: Low-Risk Patients
    Patients with GTR/M0 medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-risk therapy.
    Interventions:
    • Drug: Induction Chemotherapy
    • Drug: Low-Risk Therapy
  • Experimental: High-Risk Patients
    Patients with CNS metastatic disease will receive induction chemotherapy and high-risk therapy.
    Interventions:
    • Drug: Induction Chemotherapy
    • Drug: High-Risk Therapy
  • Experimental: Intermediate-Risk Therapy
    Patients with M0 medulloblastoma or nodular desmoplastic histology with less than a GTR, other histologic diagnoses with no metastatic disease, will receive induction chemotherapy and intermediate-risk therapy.
    Interventions:
    • Drug: Induction Chemotherapy
    • Drug: Intermediate-Risk Therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
400
December 2020
December 2015   (final data collection date for primary outcome measure)

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

  • Medulloblastoma (all histologic subtypes, including medullomyoblastoma and melanotic medulloblastoma)
  • 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 pathologist
    • 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 group

PATIENT CHARACTERISTICS:

  • 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

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No more than 31 days since prior definitive surgery
  • No prior radiotherapy or chemotherapy other than corticosteroid therapy
Both
up to 5 Years
No
Contact: Amar Gajjar, MD 1-866-278-5833 info@stjude.org
United States,   Australia
 
NCT00602667
SJYC07
No
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
University of Florida
Study Chair: Amar Gajjar, MD St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP