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

Primary Purpose

Brain and Central Nervous System Tumors

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Induction Chemotherapy
Low-Risk Therapy
High-Risk Therapy
Intermediate-Risk Therapy
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring 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

Eligibility Criteria

undefined - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Lucile Packard Children's Hospital at Stanford University Medical Center
  • Rady Children's Hospital
  • Children's Hospitals and Clinics of Minnesota - St. Paul
  • St. Jude Children's Research Hospital
  • University of Texas Southwestern Medical Center at Dallas
  • Lady Cilento Children's Hospital, Brisbane

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Low-Risk Patients

High-Risk Patients

Intermediate-Risk Therapy

Arm Description

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.

Patients with CNS metastatic disease will receive induction chemotherapy and high-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.

Outcomes

Primary Outcome Measures

Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients
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.
Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients by DNA Methylation Subgroup
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.
Percent Probability of Event-free Survival (EFS) for Medulloblastoma Patients
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

Number of Participants With Chromosomal Abnormalities
Amplifications and deletions (gains and losses) for chromosomes of interest are shown in the table of measured values.
Numbers of Patients With Gene Alterations
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.
Numbers of Patients With Molecular Abnormalities by Tumor Type
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.
Number of Successful Collections for Frozen and Fixed Tumor Samples
Successful collections will be defined as the number of patients who have frozen/fixed tumor samples available.
Event-free Survival (EFS) Compared to Historical Controls
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.
Overall Survival (OS) Compared to Historical Controls
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.
Percentage of Patients With Objective Responses Rate to Induction Chemotherapy
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.
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
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.
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
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.
Percent of Patients With Sustained Objective Responses Rate After Consolidation
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.
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
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.
Change in Neurostructure, Especially White Matter Volume and Integrity
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.
Percent of PET Scans With Loss of Signal Intensity
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 quantify the decay in signal, 134 scans from 53 patients were analyzed by recording the mean activation value (MAV), the average recorded PET signal from activation, within the target volume. With each patient being given the same dose, the percent standard deviation in the MAV can serve as a quantitative representation of signal loss due to radioactive decay.
Concentration of Cerebrospinal Fluid Neurotransmitters
Concentrations of various neurotransmitters in cerebrospinal fluid were measured at 5 timepoints. The median concentration of each neurotransmitter at each time point was calculated and provided with a full range.
Change in Neurocognitive Performance
Age standardized performance on measures of global cognitive functioning, attention, processing speed and executive functions.
Number and Type of Genetic Polymorphisms
Types of genetic polymorphisms of neurotransmitters were examined. We studied 3 genetic polymorphisms; these were types of genetic polymorphisms involved in dopamine metabolism. They were as follows: rs6323, rs4680, and rs6280.
Pharmacogenetic Variation on Central Nervous System Transmitters
Frequencies of genetic polymorphisms were reported.
Change in Neuropsychological Performance
The primary interest is in global cognitive functioning. This is measured using the SB-V Routing subtests.
Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe
Change in Neurocognitive Performance in Attention, Working Memory, and Fluency
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.
Change in Quantitative MR Measures in the Right Frontal-parietal Regions
Change in Neurocognitive Performance in Visual-spatial Reasoning and Processing Speed
Processing speed will be measured using the WJIII. Visual perception and visual-motor integration will be measured using the Beery VMI.
Number of Participants With Endocrinopathy
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.
Longitudinal Change in Growth Hormone Secretion
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.
Methotrexate Clearance in Induction Cycle 1
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.
Methotrexate Clearance in Induction Cycle 2
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.
Methotrexate Clearance in Induction Cycle 3
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.
Methotrexate Clearance in Induction Cycle 4
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.
Methotrexate Volume of Central Compartment in Induction Cycle 1
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.
Methotrexate Volume of Central Compartment in Induction Cycle 2
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.
Methotrexate Volume of Central Compartment in Induction Cycle 3
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.
Methotrexate Volume of Central Compartment in Induction Cycle 4
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.
Methotrexate AUC0-66h in Induction Cycle 1
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.
Methotrexate AUC0-66h in Induction Cycle 2
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.
Methotrexate AUC0-66h in Induction Cycle 3
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.
Methotrexate AUC0-66h in Induction Cycle 4
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.
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 1
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.
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 2
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.
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 3
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.
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 4
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.
Cyclophosphamide Clearance in Induction Chemotherapy
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.
Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 1
Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.
Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 2
Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.
Cyclophosphamide Apparent Oral Clearance in Maintenance Chemotherapy Cycle A1
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.
Cyclophosphamide AUC0-24h in Induction Chemotherapy
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.
Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1
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.
Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2
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.
Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1
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.
4-OH Cyclophosphamide AUC0-24h in Induction Chemotherapy
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.
4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1
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.
4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2
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.
4-OH Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1
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.
CEPM AUC0-24h in Induction Chemotherapy
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.
CEPM AUC0-24h in Consolidation Chemotherapy Cycle 1
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.
CEPM AUC0-24h in Consolidation Chemotherapy Cycle 2
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.
CEPM AUC0-24h in Maintenance Chemotherapy Cycle A1
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.
Participants With Empirical Dosage Achieving Target System Exposure of Intravenous Topotecan
Number of participants who successfully achieve target systemic exposure of intravenous topotecan after an empiric dosage during consolidation phase of therapy are reported.
Participants With PK-guided Dosage Adjustment Achieving Target System Exposure of Intravenous Topotecan
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.
Topotecan Clearance in Consolidation Chemotherapy
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.
Topotecan Apparent Oral Clearance in Maintenance Chemotherapy
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.
Topotecan AUC0-24h in Consolidation Chemotherapy
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.
Topotecan AUC0-24h in Maintenance Chemotherapy
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.
Erlotinib Apparent Oral Clearance
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.
Erlotinib Apparent Volume of Central Compartment
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.
Erlotinib AUC0-24h
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.
OSI-420 AUC0-24h
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.
Rate of Local Disease Progression
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.
Rate of Distant Disease Progression
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.

Full Information

First Posted
January 10, 2008
Last Updated
May 5, 2023
Sponsor
St. Jude Children's Research Hospital
Collaborators
University of Florida, National Cancer Institute (NCI), The Pew Charitable Trusts
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1. Study Identification

Unique Protocol Identification Number
NCT00602667
Brief Title
Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Official Title
Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 17, 2007 (Actual)
Primary Completion Date
September 27, 2017 (Actual)
Study Completion Date
April 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
Collaborators
University of Florida, National Cancer Institute (NCI), The Pew Charitable Trusts

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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 Description
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 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 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 investigate the feasibility of using PET as an in-vivo dosimetric and distal edge verification system for patients treated with proton beam therapy (for participants enrolled at St Jude only). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
293 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low-Risk Patients
Arm Type
Experimental
Arm Description
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.
Arm Title
High-Risk Patients
Arm Type
Experimental
Arm Description
Patients with CNS metastatic disease will receive induction chemotherapy and high-risk therapy.
Arm Title
Intermediate-Risk Therapy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Induction Chemotherapy
Other Intervention Name(s)
MTX (methotrexate), Oncovin(R) (vincristine), Platinol-AQ(R) (cisplatin), Cytoxan(R) (cyclophosphamide)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Low-Risk Therapy
Other Intervention Name(s)
Cytoxan(R) (cyclophosphamide), Paraplatin(R) (carboplatin), Vepesid(R), VP-16 (etoposide), Hycamptin(R) (topotecan), Tarceva(TM) (erlotinib)
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
High-Risk Therapy
Other Intervention Name(s)
Velban(R) (vinblastine), Cytoxan(R) (cyclophosphamide), Hycamptin(R) (topotecan), Tarceva(TM) (erlotinib), Vepesid(R), VP-16 (etoposide)
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Intermediate-Risk Therapy
Other Intervention Name(s)
Cytoxan(R) (cyclophosphamide), Hycamptin(R) (topotecan), Tarceva(TM) (erlotinib), Vepesid(R), VP-16 (etoposide)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients
Description
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.
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
Title
Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients by DNA Methylation Subgroup
Description
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.
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
Title
Percent Probability of Event-free Survival (EFS) for Medulloblastoma Patients
Description
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.
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
Secondary Outcome Measure Information:
Title
Number of Participants With Chromosomal Abnormalities
Description
Amplifications and deletions (gains and losses) for chromosomes of interest are shown in the table of measured values.
Time Frame
Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Title
Numbers of Patients With Gene Alterations
Description
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.
Time Frame
Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Title
Numbers of Patients With Molecular Abnormalities by Tumor Type
Description
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.
Time Frame
Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Title
Number of Successful Collections for Frozen and Fixed Tumor Samples
Description
Successful collections will be defined as the number of patients who have frozen/fixed tumor samples available.
Time Frame
Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Title
Event-free Survival (EFS) Compared to Historical Controls
Description
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.
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
Title
Overall Survival (OS) Compared to Historical Controls
Description
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.
Time Frame
1 year after treatment initiation of last patient
Title
Percentage of Patients With Objective Responses Rate to Induction Chemotherapy
Description
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.
Time Frame
From on-study date to 2 months after completion of induction chemotherapy (up to 4 months after on-study date)
Title
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
Description
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.
Time Frame
From on-study date up to 4 months after on-study date
Title
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
Description
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.
Time Frame
At completion of consolidation therapy (up to 6 months after on-study date)
Title
Percent of Patients With Sustained Objective Responses Rate After Consolidation
Description
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.
Time Frame
8 weeks after completion of consolidation therapy (up to 8 months after on-study date)
Title
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
Description
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.
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)
Title
Change in Neurostructure, Especially White Matter Volume and Integrity
Description
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.
Time Frame
From baseline to 60 months off therapy
Title
Percent of PET Scans With Loss of Signal Intensity
Description
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 quantify the decay in signal, 134 scans from 53 patients were analyzed by recording the mean activation value (MAV), the average recorded PET signal from activation, within the target volume. With each patient being given the same dose, the percent standard deviation in the MAV can serve as a quantitative representation of signal loss due to radioactive decay.
Time Frame
Up to 3 times during RT consolidation
Title
Concentration of Cerebrospinal Fluid Neurotransmitters
Description
Concentrations of various neurotransmitters in cerebrospinal fluid were measured at 5 timepoints. The median concentration of each neurotransmitter at each time point was calculated and provided with a full range.
Time Frame
Baseline, at the completion of therapy, and every 12 months up to 36 months after off therapy date
Title
Change in Neurocognitive Performance
Description
Age standardized performance on measures of global cognitive functioning, attention, processing speed and executive functions.
Time Frame
Baseline, at the completion of therapy, and every 12 months up to 60 months off therapy
Title
Number and Type of Genetic Polymorphisms
Description
Types of genetic polymorphisms of neurotransmitters were examined. We studied 3 genetic polymorphisms; these were types of genetic polymorphisms involved in dopamine metabolism. They were as follows: rs6323, rs4680, and rs6280.
Time Frame
At study enrollment (Day 0)
Title
Pharmacogenetic Variation on Central Nervous System Transmitters
Description
Frequencies of genetic polymorphisms were reported.
Time Frame
At study enrollment (Day 0)
Title
Change in Neuropsychological Performance
Description
The primary interest is in global cognitive functioning. This is measured using the SB-V Routing subtests.
Time Frame
Baseline, 6- and 12-months from treatment initiation, and yearly after the first year (up to 5 years)
Title
Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe
Time Frame
Baseline and up to 60 months after completion of therapy.
Title
Change in Neurocognitive Performance in Attention, Working Memory, and Fluency
Description
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.
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.
Title
Change in Quantitative MR Measures in the Right Frontal-parietal Regions
Time Frame
Baseline and up to 5 years after completion of therapy
Title
Change in Neurocognitive Performance in Visual-spatial Reasoning and Processing Speed
Description
Processing speed will be measured using the WJIII. Visual perception and visual-motor integration will be measured using the Beery VMI.
Time Frame
Baseline and up to 5 years after completion of therapy.
Title
Number of Participants With Endocrinopathy
Description
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.
Time Frame
Baseline, end of therapy, and at 6- and 24-months after completion of therapy
Title
Longitudinal Change in Growth Hormone Secretion
Description
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.
Time Frame
Baseline, end of therapy, and at 6- and 24-months after completion of therapy
Title
Methotrexate Clearance in Induction Cycle 1
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of Methotrexate (MTX)
Title
Methotrexate Clearance in Induction Cycle 2
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Clearance in Induction Cycle 3
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Clearance in Induction Cycle 4
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Volume of Central Compartment in Induction Cycle 1
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Volume of Central Compartment in Induction Cycle 2
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Volume of Central Compartment in Induction Cycle 3
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Volume of Central Compartment in Induction Cycle 4
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate AUC0-66h in Induction Cycle 1
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate AUC0-66h in Induction Cycle 2
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate AUC0-66h in Induction Cycle 3
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate AUC0-66h in Induction Cycle 4
Description
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.
Time Frame
Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Title
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 1
Description
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.
Time Frame
42 hours from start of MTX
Title
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 2
Description
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.
Time Frame
42 hours from start of MTX
Title
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 3
Description
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.
Time Frame
42 hours from start of MTX
Title
Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 4
Description
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.
Time Frame
42 hours from start of MTX
Title
Cyclophosphamide Clearance in Induction Chemotherapy
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 1
Description
Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 2
Description
Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide Apparent Oral Clearance in Maintenance Chemotherapy Cycle A1
Description
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.
Time Frame
Pre-dose, 0.5, 1.75, 3 and 6 hours post-dose
Title
Cyclophosphamide AUC0-24h in Induction Chemotherapy
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1
Description
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.
Time Frame
Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Title
4-OH Cyclophosphamide AUC0-24h in Induction Chemotherapy
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
4-OH Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1
Description
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.
Time Frame
Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Title
CEPM AUC0-24h in Induction Chemotherapy
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
CEPM AUC0-24h in Consolidation Chemotherapy Cycle 1
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
CEPM AUC0-24h in Consolidation Chemotherapy Cycle 2
Description
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.
Time Frame
Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Title
CEPM AUC0-24h in Maintenance Chemotherapy Cycle A1
Description
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.
Time Frame
Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Title
Participants With Empirical Dosage Achieving Target System Exposure of Intravenous Topotecan
Description
Number of participants who successfully achieve target systemic exposure of intravenous topotecan after an empiric dosage during consolidation phase of therapy are reported.
Time Frame
Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Title
Participants With PK-guided Dosage Adjustment Achieving Target System Exposure of Intravenous Topotecan
Description
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.
Time Frame
Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Title
Topotecan Clearance in Consolidation Chemotherapy
Description
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.
Time Frame
Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Title
Topotecan Apparent Oral Clearance in Maintenance Chemotherapy
Description
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.
Time Frame
Pre-dose, 0.25, 1.5 and 6 hours post-dose
Title
Topotecan AUC0-24h in Consolidation Chemotherapy
Description
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.
Time Frame
Pre-infusion, 5 min., 1, 3, and 24 hours from end of infusion
Title
Topotecan AUC0-24h in Maintenance Chemotherapy
Description
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.
Time Frame
Pre-dose, 0.25, 1.5, 6, and 24 hours post-dose
Title
Erlotinib Apparent Oral Clearance
Description
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.
Time Frame
Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Title
Erlotinib Apparent Volume of Central Compartment
Description
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.
Time Frame
Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Title
Erlotinib AUC0-24h
Description
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.
Time Frame
Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Title
OSI-420 AUC0-24h
Description
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.
Time Frame
Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Title
Rate of Local Disease Progression
Description
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.
Time Frame
1 year after completion of radiation therapy for last patient
Title
Rate of Distant Disease Progression
Description
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.
Time Frame
1 year after completion of radiation therapy for last patient

10. Eligibility

Sex
All
Maximum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amar Gajjar, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Lucile Packard Children's Hospital at Stanford University Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Rady Children's Hospital
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
Children's Hospitals and Clinics of Minnesota - St. Paul
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55102
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
University of Texas Southwestern Medical Center at Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Lady Cilento Children's Hospital, Brisbane
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
33945291
Citation
Ali JS, Ashford JM, Swain MA, Harder LL, Carlson-Green BL, Miller JM, Wallace J, Kaner RJ, Billups CA, Onar-Thomas A, Merchant TE, Gajjar A, Conklin HM. Predictors of Cognitive Performance Among Infants Treated for Brain Tumors: Findings From a Multisite, Prospective, Longitudinal Trial. J Clin Oncol. 2021 Jul 20;39(21):2350-2358. doi: 10.1200/JCO.20.01687. Epub 2021 May 4.
Results Reference
derived
PubMed Identifier
33502920
Citation
Kumar R, Smith KS, Deng M, Terhune C, Robinson GW, Orr BA, Liu APY, Lin T, Billups CA, Chintagumpala M, Bowers DC, Hassall TE, Hansford JR, Khuong-Quang DA, Crawford JR, Bendel AE, Gururangan S, Schroeder K, Bouffet E, Bartels U, Fisher MJ, Cohn R, Partap S, Kellie SJ, McCowage G, Paulino AC, Rutkowski S, Fleischhack G, Dhall G, Klesse LJ, Leary S, Nazarian J, Kool M, Wesseling P, Ryzhova M, Zheludkova O, Golanov AV, McLendon RE, Packer RJ, Dunham C, Hukin J, Fouladi M, Faria CC, Pimentel J, Walter AW, Jabado N, Cho YJ, Perreault S, Croul SE, Zapotocky M, Hawkins C, Tabori U, Taylor MD, Pfister SM, Klimo P Jr, Boop FA, Ellison DW, Merchant TE, Onar-Thomas A, Korshunov A, Jones DTW, Gajjar A, Ramaswamy V, Northcott PA. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma. J Clin Oncol. 2021 Mar 1;39(7):807-821. doi: 10.1200/JCO.20.01359. Epub 2021 Jan 27.
Results Reference
derived
PubMed Identifier
29778738
Citation
Robinson GW, Rudneva VA, Buchhalter I, Billups CA, Waszak SM, Smith KS, Bowers DC, Bendel A, Fisher PG, Partap S, Crawford JR, Hassall T, Indelicato DJ, Boop F, Klimo P, Sabin ND, Patay Z, Merchant TE, Stewart CF, Orr BA, Korbel JO, Jones DTW, Sharma T, Lichter P, Kool M, Korshunov A, Pfister SM, Gilbertson RJ, Sanders RP, Onar-Thomas A, Ellison DW, Gajjar A, Northcott PA. Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol. 2018 Jun;19(6):768-784. doi: 10.1016/S1470-2045(18)30204-3. Epub 2018 May 16.
Results Reference
derived
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

Learn more about this trial

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

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