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

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ClinicalTrials.gov Identifier: NCT00602667
Recruitment Status : Active, not recruiting
First Posted : January 28, 2008
Results First Posted : January 30, 2019
Last Update Posted : September 11, 2019
Sponsor:
Collaborators:
University of Florida
National Cancer Institute (NCI)
The Pew Charitable Trusts
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

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.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: Induction Chemotherapy Drug: Low-Risk Therapy Drug: High-Risk Therapy Drug: Intermediate-Risk Therapy Phase 2

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 293 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Actual Study Start Date : December 17, 2007
Actual Primary Completion Date : September 27, 2017
Estimated Study Completion Date : April 30, 2023


Arm Intervention/treatment
Experimental: Low-Risk Patients

Patients with GTR/M0 medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-risk therapy.

Note: Accrual to the low-risk medulloblastoma cohort is closed as of 12/2/2015. Accrual to the low-risk high grade glioma remains open.

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)

Experimental: High-Risk Patients
Patients with CNS metastatic disease will receive induction chemotherapy and high-risk therapy.
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: 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)

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.
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: 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).

Note: The option to receive focal proton beam irradiation was suspended 10/29/2015. Focal photon beam irradiation continues as part of the treatment plan.

Other Names:
  • Cytoxan(R) (cyclophosphamide)
  • Hycamptin(R) (topotecan)
  • Tarceva(TM) (erlotinib)
  • Vepesid(R), VP-16 (etoposide)




Primary Outcome Measures :
  1. Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients [ Time Frame: From date on treatment until date of first progression or relapse or disease related death or date of last contact, estimated at 1 year after treatment ]
    Progression was defined as 25% increase in the size of any measurable lesion; the appearance of a new lesion; or the conversion of negative cerebrospinal fluid (CSF) cytology to positive. 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 medulloblastoma patients who received any methotrexate are included in this analysis.

  2. Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients by DNA Methylation Subgroup [ Time Frame: From date on treatment to date of first progression or relapse or disease related death or date of last contact, estimated at 1 year after treatment ]
    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. Eligible medulloblastoma patients who received any methotrexate and had molecularly confirmed medulloblastoma are included in this analysis. Five patients were excluded as 3 had no archival tissue available and 2 were found to not be medulloblastoma by methylation profile.

  3. Percent Probability of Event-free Survival (EFS) for Medulloblastoma Patients [ Time Frame: From date on treatment to date of first progression, relapse, second malignancy or death from any cause or to date of last contact, estimated at 1 year after ]
    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 medulloblastoma patients who received any methotrexate are included in this analysis.


Secondary Outcome Measures :
  1. Number of Participants With Chromosomal Abnormalities [ Time Frame: Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment ]
    Amplifications and deletions (gains and losses) for chromosomes of interest are shown in the table of measured values.

  2. Numbers of Patients With Gene Alterations [ Time Frame: Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment ]
    Gene alterations, which include single nucleotide variants (SNPs), amplifications, deletions, translocations, indels, and germline alterations are shown for specific genes of interest in the results table.

  3. Numbers of Patients With Molecular Abnormalities by Tumor Type [ Time Frame: Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment ]
    Alterations included single nucleotide variants (SNPs), amplifications, deletions, translocations, indels, and germline alterations. Cytogenetic information shows gains and losses as specified in the table of measured values.

  4. Number of Successful Collections for Frozen and Fixed Tumor Samples [ Time Frame: Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment ]
    Successful collections will be defined as the number of patients who have frozen/fixed tumor samples available.

  5. Event-free Survival (EFS) Compared to Historical Controls [ Time Frame: From date on treatment until date of first event (progression, second malignancy or death) or until date of last contact, assessed up to 10 years ]
    EFS was 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. 1-year EFS estimates are reported by risk group. EFS was compared to St. Jude historical cohorts by risk group using hazard ratios with 95% confidence intervals.

  6. Overall Survival (OS) Compared to Historical Controls [ Time Frame: 1 year after treatment initiation of last patient ]
    OS was measured from the date of initial treatment to date of death or to date of last contact for survivors. 1-year OS estimates were reported by risk group. OS was compared to St. Jude historical cohorts by risk group using hazard ratios with 95% confidence intervals.

  7. Percentage of Patients With Objective Responses Rate to Induction Chemotherapy [ 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 (complete response (CR) or partial response [ 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.

  8. Feasibility and Toxicity of Administering Vinblastine With Induction Chemotherapy for Patients With Metastatic Disease as Measured by the Percentage of Courses Delayed for More Than 7 Days Due to Toxicity [ Time Frame: From on-study date up to 4 months after on-study date ]
    For the subset of patients with metastatic disease (high-risk group patients), during induction, the proportion percentage of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity will be calculated. Patients were to receive 4 courses of induction and then consolidation chemotherapy.

  9. Feasibility and Toxicity of Administering Consolidation Therapy Including Cyclophosphamide and Pharmacokinetically Targeted Topotecan to Patients With Metastatic Disease Based on the Percentage of Courses Delayed for More Than 7 Days Due to Toxicity [ Time Frame: At completion of consolidation therapy (up to 6 months after on-study date) ]
    For the subset of patients with metastatic disease (high-risk group patients), during consolidation, we will calculate the number and proportion of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity. Patients were to received 2 courses of consolidation chemotherapy and then maintenance therapy.

  10. Percent of Patients With Sustained Objective Responses Rate After Consolidation [ Time Frame: 8 weeks after completion of consolidation therapy (up to 8 months after on-study date) ]
    For patients enrolled on the high-risk arm with measurable residual disease after induction treated with consolidation therapy, we will estimate the objective response (complete response (CR)/partial response (PR)) rate after consolidation therapy with a 95% confidence interval. Objective responses must be sustained for at least eight weeks. All patients who receive at least 1 dose of cyclophosphamide or topotecan during consolidation are evaluable for response.

  11. Feasibility and Toxicity of Administering Oral Maintenance Therapy in Children <3 Years of Age as Measured by the Percentage of Total Scheduled Maintenance Doses Received [ 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. For children <3 years of age, we will calculate the percentage of total scheduled doses each patient received per course for each of the oral maintenance courses and report the overall average number percentage of doses received per course across patients. If patients received all planned doses, their percentage would be 100%. If the average percentage was less than 75%, then feasibility would be in question.

  12. 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 effects model incorporating various covariates. Covariates to be considered include age at diagnosis, time since diagnosis and risk-arm. Differences in quantitative MRI measures of neurostructure volume and integrity between patient groups will be evaluated as a metric of structural neurotoxicity of therapy.

  13. Percent of PET Scans With Loss of Signal Intensity [ Time Frame: Up to 3 times during RT consolidation ]
    Measures will be analyzed for intermediate risk participants who receive proton beam therapy (PBT) and who consent. This objective aims to assess the feasibility of using post-proton beam therapy (PBT) positron emission tomography (PET) as an in-vivo dosimetric and distal edge verification system in this patient population. To this end we will estimate the percentage of PET scans where loss of signal intensity or resolution were observed. In addition the differences observed between the measured and simulated parameters such as positron activation locations and intensities will be estimated.

  14. Change in Concentration of Cerebrospinal Fluid (CSF) Neurotransmitters [ Time Frame: Baseline, at the completion of therapy, and every 12 months up to 36 months after off therapy date ]
  15. Change in Neurocognitive Performance [ Time Frame: Baseline, at the completion of therapy, and every 12 months up to 60 months off therapy ]
    Age standardized performance on measures of global cognitive functioning, attention, processing speed and executive functions.

  16. Number and Type of Genetic Polymorphisms [ Time Frame: At study enrollment (Day 0) ]
  17. Pharmacogenetic Variation on CNS Transmitters [ Time Frame: At study enrollment (Day 0) ]
  18. Change in Neuropsychological Performance [ Time Frame: Baseline, 6- and 12-months from treatment initiation, and yearly after the first year (up to 5 years) ]
    The primary interest is in global cognitive functioning. This is measured using the SB-V Routing subtests.

  19. Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe [ Time Frame: Baseline and up to 60 months after completion of therapy. ]
  20. Change in Neurocognitive Performance in Attention, Working Memory, and Fluency [ Time Frame: Baseline and prior to cycle A1 (~6 months) and at end of therapy and at 12, 24, 36, 48 and 60 months after completion of therapy. ]
    Neurocognitive performance is assessed using a comprehensive battery of standard tests. Sustained attention is measured using the TOVA; selective auditory attention is measured using the WJIII; nonverbal attention span is measured using the SB-V Block Span subset. Working memory is measured using the WJIII. Fluency is measured using is also measured using the WJIII.

  21. Change in Quantitative MR Measures in the Right Frontal-parietal Regions [ Time Frame: Baseline and up to 5 years after completion of therapy ]
  22. Change in Neurocognitive Performance in Visual-spatial Reasoning and Processing Speed [ Time Frame: Baseline and up to 5 years after completion of therapy. ]
    Processing speed will be measured using the WJIII. Visual perception and visual-motor integration will be measured using the Beery VMI.

  23. Number of Participants With Endocrinopathy [ Time Frame: Baseline, end of therapy, and at 6- and 24-months after completion of therapy ]
    Serial GH testing (at baseline, the end of therapy, and at 6 and 24 months after completion of therapy) will be performed on consenting patients in order to estimate longitudinal change in GH secretion as measured by mean peak GH values, with the intent to explore associations with radiation dose to the hypothalamus. Since determination of proton- or photon-based radiotherapy is not based on randomization, it will not be possible to compare the endocrine outcome between the patients with and without PBT. However, the differences between these two clinical cohorts with respect to clinical and demographic variables of interest will be summarized via descriptive statistics.

  24. Longitudinal Change in Growth Hormone Secretion [ Time Frame: Baseline, end of therapy, and at 6- and 24-months after completion of therapy ]
    The intent of this objective is to estimate the longitudinal change in abnormal GH secretion as measured by mean peak GH values via a mixed effects model for the patients who receive PBT.

  25. Methotrexate Clearance in Induction Cycle 1 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of Methotrexate (MTX) ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.

  26. Methotrexate Clearance in Induction Cycle 2 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.

  27. Methotrexate Clearance in Induction Cycle 3 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.

  28. Methotrexate Clearance in Induction Cycle 4 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.

  29. Methotrexate Volume of Central Compartment in Induction Cycle 1 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.

  30. Methotrexate Volume of Central Compartment in Induction Cycle 2 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.

  31. Methotrexate Volume of Central Compartment in Induction Cycle 3 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.

  32. Methotrexate Volume of Central Compartment in Induction Cycle 4 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.

  33. Methotrexate AUC0-66h in Induction Cycle 1 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.

  34. Methotrexate AUC0-66h in Induction Cycle 2 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.

  35. Methotrexate AUC0-66h in Induction Cycle 3 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.

  36. Methotrexate AUC0-66h in Induction Cycle 4 [ Time Frame: Pre-infusion and 6, 23, 42, 66 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.

  37. Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 1 [ Time Frame: 42 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.

  38. Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 2 [ Time Frame: 42 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.

  39. Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 3 [ Time Frame: 42 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.

  40. Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 4 [ Time Frame: 42 hours from start of MTX ]
    Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.

  41. Cyclophosphamide Clearance in Induction Chemotherapy [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.

  42. Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 1 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.

  43. Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 2 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.

  44. Cyclophosphamide Apparent Oral Clearance in Maintenance Chemotherapy Cycle A1 [ Time Frame: Pre-dose, 0.5, 1.75, 3 and 6 hours post-dose ]
    Cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of cyclophosphamide apparent oral clearance are obtained using post hoc analysis.

  45. Cyclophosphamide AUC0-24h in Induction Chemotherapy [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  46. Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  47. Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  48. Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1 [ Time Frame: Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose ]
    Cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of cyclophosphamide AUC0-24h are obtained using post hoc analysis.

  49. 4-OH Cyclophosphamide AUC0-24h in Induction Chemotherapy [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    4-OH cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  50. 4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    4-OH cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  51. 4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    4-OH cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  52. 4-OH Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1 [ Time Frame: Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose ]
    4-OH cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  53. CEPM AUC0-24h in Induction Chemotherapy [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected on day 9 in one induction cycle. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  54. CEPM AUC0-24h in Consolidation Chemotherapy Cycle 1 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  55. CEPM AUC0-24h in Consolidation Chemotherapy Cycle 2 [ Time Frame: Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion ]
    Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  56. CEPM AUC0-24h in Maintenance Chemotherapy Cycle A1 [ Time Frame: Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose ]
    Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.

  57. Participants With Empirical Dosage Achieving Target System Exposure of Intravenous Topotecan [ Time Frame: Pre-infusion, 5 min., 1, and 3 hours from end of infusion ]
    Number of participants who successfully achieve target systemic exposure of intravenous topotecan after an empiric dosage during consolidation phase of therapy are reported.

  58. Participants With PK-guided Dosage Adjustment Achieving Target System Exposure of Intravenous Topotecan [ Time Frame: Pre-infusion, 5 min., 1, and 3 hours from end of infusion ]
    Number of participants who successfully achieve target systemic exposure of intravenous topotecan after a pharmacokinetic-guided dosage adjustment during consolidation phase of therapy are reported.

  59. Topotecan Clearance in Consolidation Chemotherapy [ Time Frame: Pre-infusion, 5 min., 1, and 3 hours from end of infusion ]
    Topotecan plasma concentration-time data are collected on day 1 of consolidation cycle 1 after a single IV dose. Individual estimates of topotecan clearance are obtained using post hoc analysis.

  60. Topotecan Apparent Oral Clearance in Maintenance Chemotherapy [ Time Frame: Pre-dose, 0.25, 1.5 and 6 hours post-dose ]
    Topotecan plasma concentration-time data are collected on day 1 of maintenance cycle A1 after a single oral dose. Individual estimates of topotecan apparent oral clearance are obtained using post hoc analysis.

  61. Topotecan AUC0-24h in Consolidation Chemotherapy [ Time Frame: Pre-infusion, 5 min., 1, 3, and 24 hours from end of infusion ]
    Topotecan plasma concentration-time data are collected on day 1 of consolidation cycle 1 after a single IV dose. Individual estimates of topotecan AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  62. Topotecan AUC0-24h in Maintenance Chemotherapy [ Time Frame: Pre-dose, 0.25, 1.5, 6, and 24 hours post-dose ]
    Topotecan plasma concentration-time data are collected on day 1 of maintenance cycle A1 after a single oral dose. Individual estimates of topotecan AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.

  63. Erlotinib Apparent Oral Clearance [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose ]
    Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib apparent oral clearance are obtained using post hoc analysis.

  64. Erlotinib Apparent Volume of Central Compartment [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose ]
    Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib apparent volume of central compartment are obtained using post hoc analysis.

  65. Erlotinib AUC0-24h [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose ]
    Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib AUC0-24h (area under concentration curve from 0 to 24 hours post-dose) are obtained using post hoc analysis.

  66. OSI-420 AUC0-24h [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose ]
    Erlotinib metabolite OSI-420 plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of OSI-420 AUC0-24h (area under concentration curve from 0 to 24 hours post-dose) are obtained using post hoc analysis.

  67. Rate of Local Disease Progression [ Time Frame: 1 year after completion of radiation therapy for last patient ]
    Local failure was defined as the interval from end of RT to date of local failure (or combined local + distant failure). Competing events were distant failure or second malignancy. Patients without an event were censored at date of last contact. The 1-year cumulative incidence was estimated and reported with a 95% confidence interval.

  68. Rate of Distant Disease Progression [ Time Frame: 1 year after completion of radiation therapy for last patient ]
    Distant failure was defined as the interval from end of RT to date of distant failure (or combined local + distant failure). Competing events were local failure or second malignancy. Patients without an event were censored at date of last contact. The 1-year cumulative incidence was estimated and reported with a 95% confidence interval.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00602667


Locations
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United States, California
Lucile Packard Children's Hospital at Stanford University Medical Center
Palo Alto, California, United States, 94304
Rady Children's Hospital
San Diego, California, United States, 92123
United States, Minnesota
Children's Hospitals and Clinics of Minnesota - St. Paul
Saint Paul, Minnesota, United States, 55102
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75390
Australia, Queensland
Lady Cilento Children's Hospital, Brisbane
Brisbane, Queensland, Australia, 4029
Sponsors and Collaborators
St. Jude Children's Research Hospital
University of Florida
National Cancer Institute (NCI)
The Pew Charitable Trusts
Investigators
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Study Chair: Amar Gajjar, MD St. Jude Children's Research Hospital
  Study Documents (Full-Text)

Documents provided by St. Jude Children's Research Hospital:

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00602667     History of Changes
Other Study ID Numbers: SJYC07
R01CA154619 ( U.S. NIH Grant/Contract )
NCI-2011-01193 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: January 28, 2008    Key Record Dates
Results First Posted: January 30, 2019
Last Update Posted: September 11, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
untreated childhood medulloblastoma
untreated childhood supratentorial primitive neuroectodermal tumor
untreated childhood pineoblastoma
childhood atypical teratoid/rhabdoid tumor
childhood choroid plexus tumor
childhood high grade glioma
newly diagnosed childhood ependymoma
Additional relevant MeSH terms:
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Glioma
Ependymoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Cisplatin
Cyclophosphamide
Carboplatin
Methotrexate
Erlotinib Hydrochloride
Etoposide
Etoposide phosphate
Vincristine
Topotecan
Vinblastine
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents