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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

Brief Summary:

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.


Detailed Summary:

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.

OBJECTIVES:

Primary

  • To identify patterns of methylation profiling that are associated with progression-free survival among young pediatric patients with 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 ove
    Sponsor: St. Jude Children's Research Hospital

    Current Primary Outcome:

    • Progression-free survival [ Time Frame: 1 year after treatment initiation of the last patient ]
      Defined as the time interval from date on treatment until the date of first progression, medulloblastoma-related death or date of last contact for patients who have not experienced an event. All eligible patients who receive any methotrexate will be included in the analysis.
    • DNA methylation in peripheral blood or tissue [ Time Frame: 1 year after treatment initiation date of the last patient enrolled ]
      Sample and array processing of tumor tissue samples from all participants will be completed at one time following the collection of the sample from the last subject enrolled. Design and analysis will utilize the latest sample and array processing methodologies available at that time. Statistical methodology will also utilize the latest approach at the time of analysis.
    • Event-free survival [ Time Frame: 1 year after treatment initiation date of the last patient enrolled ]
      Defined as the time interval from date on treatment until the date of first progression, second malignancy or death due to any cause; or date of last contact for patients who have not experienced an event. All eligible patients who receive any methotrexate will be included in the analysis.


    Original Primary Outcome:

    • Progression-free survival
    • Event-free survival


    Current Secondary Outcome:

    • Chromosomal abnormalities [ Time Frame: After the treatment initiation date of the last patient enrolled on the study ]
      For patients from whom fresh frozen tumor is available at the time of surgery microarray analysis will be performed on the tumor sample obtained at initial or repeat surgery prior to treatment. The association between clinicopathological variables (e.g., M-stage, desmoplasia, age etc.) and presence of mutations as well as gene expression profiles will be explored.
    • Gene expression patterns [ Time Frame: After the treatment initiation date of the last patient enrolled on the study ]
    • Molecular abnormalities by tumor type [ Time Frame: After the treatment initiation date of the last patient enrolled on the study ]
    • Number of successful collections for frozen and fixed tumor samples [ Time Frame: After the treatment initiation date of the last patient enrolled on the study ]
      Successful collections will be defined as the number of patients who have frozen tissue available and the number of available frozen tumor tissue which will be suitable for high-quality RNA extraction, high-quality protein, and high-quality DNA.
    • Event free survival compared to historical controls [ Time Frame: 1 year after the treatment initiation date of the last patient enrolled ]
      We will estimate event-free survival (EFS) using the method of Kaplan and Meier for all eligible patients who received at least one dose of methotrexate. EFS will be measured from the date of initial treatment to the earliest date of disease progression, second malignancy or death for patients who fail; and to the date of last contact for patients who remain at risk for failure. EFS will be compared to a St. Jude historical cohort.
    • Overall survival compared to historical controls [ Time Frame: 1 year after the treatment initiation date of the last patient enrolled ]
      We will estimate survival using the method of Kaplan and Meier for all eligible patients who received at least one dose of methotrexate. Survival will be compared to a St. Jude historical cohort.
    • Rate of disease progression [ Time Frame: 1 year after completion of radiation therapy for last patient ]
      We will estimate the rate of local and distant disease progression in patients treated in the intermediate risk stratum (M0 non-desmoplastic medulloblastoma and other eligible tumors) after focal irradiation of the post-operative tumor bed using a 5 mm clinical target volume margin. This analysis will be done once all patients in this stratum have been followed for at least 1 year from the end of their radiation treatment.
    • Objective response rate [ Time Frame: From on-study date to 2 months after completion of induction chemotherapy (up to 4 months after on-study date) ]
      For patients treated in the intermediate and high risk strata with residual or metastatic disease we will estimate the stratum-specific objective response rate (CR or PR). All patients who receive at least 1-dose of methotrexate are evaluable for response. Objective responses must be sustained for at least eight weeks.
    • Number of participants who successfully complete induction therapy [ Time Frame: From on-study date up to 4 months after on-study date ]
      During induction, the proportion of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity will be calculated.
    • Number of participants who successfully complete consolidation therapy [ Time Frame: At completion of consolidation therapy (up to 6 months after on-study date) ]
      During consolidation, we will estimate the proportion of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity.
    • Sustained objective response rate [ Time Frame: 8 weeks after completion of consolidation therapy (up to 8 months after on-study date) ]
      Objective responses must be sustained for at least eight weeks.
    • Percent of total scheduled doses received during oral maintenance therapy [ Time Frame: From start of oral maintenance therapy (approximately 6 months after on-study date) to completion of oral maintenance therapy (up to 1 year after on-study date) ]
      These data are based on patient diaries. If the average number of doses successfully administered per course is less than 75% of the scheduled number of doses due to toxicity or patient refusal to take the agent, then the feasibility of administering oral maintenance therapy may be in question.
    • Change in neurostructure, especially white matter volume and integrity [ Time Frame: From baseline to 60 months off therapy ]
      Quantitative MRI measures of change in neurostructure (especially white matter volume and integrity) over time will be assessed using a random effec

      Original Secondary Outcome:

      • Relationship of chromosomal abnormalities and gene expression patterns to other clinicopathological variables
      • Presence of molecular abnormalities with suspected prognostic or therapeutic significance
      • Collection of frozen and fixed tumor samples for analysis
      • Event-free and overall survival of study patients compared to historical controls
      • Rates of local and distant disease progression in patients treated with focal radiotherapy
      • Objective response rate (sustained for 8 weeks) to induction chemotherapy including high-dose intravenous methotrexate for patients with residual or metastatic disease
      • Feasibility and toxicity of administering low-dose intravenous vinblastine in patients with metastatic disease
      • Feasibility and toxicity of administering consolidation therapy including cyclophosphamide and pharmacokinetically targeted topotecan to patients with metastatic disease
      • Sustained (for 8 weeks) objective response rate (complete response and partial response) to such therapy in patients with measurable residual disease after induction
      • Feasibility and toxicity of administering oral maintenance therapy in children younger than three years of age at diagnosis


      Information By: St. Jude Children's Research Hospital

      Dates:
      Date Received: January 10, 2008
      Date Started: December 17, 2007
      Date Completion: December 31, 2023
      Last Updated: May 3, 2017
      Last Verified: December 2016