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

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00602667
• Collaborator: University of Florida (Other), National Cancer Institute (NCI) (NIH), The Pew Charitable Trusts (Other)
• Enrollment: 293
• Locations: 6
• Arms: 3
• Anticipated Duration (Months): 184.4
• Patients Per Site: 48.8
• Patients Per Site Per Month: 0.3

Study Details

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.

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

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.

Study Design

• Study Type: Interventional
• 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: Dec 17, 2007
• Actual Primary Completion Date: Sep 27, 2017
• Anticipated Study Completion Date: Apr 30, 2023

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 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.

14. Change in Concentration of Cerebrospinal Fluid (CSF) Neurotransmitters [Baseline, at the completion of therapy, and every 12 months up to 36 months after off therapy date]

15. Change in Neurocognitive Performance [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 [At study enrollment (Day 0)]

17. Pharmacogenetic Variation on CNS Transmitters [At study enrollment (Day 0)]

18. Change in Neuropsychological Performance [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 [Baseline and up to 60 months after completion of therapy.]

20. Change in Neurocognitive Performance in Attention, Working Memory, and Fluency [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 [Baseline and up to 5 years after completion of therapy]

22. Change in Neurocognitive Performance in Visual-spatial Reasoning and Processing Speed [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California	United States	94304
2	Rady Children's Hospital	San Diego	California	United States	92123
3	Children's Hospitals and Clinics of Minnesota - St. Paul	Saint Paul	Minnesota	United States	55102
4	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
5	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
6	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

• Study Chair: Amar Gajjar, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 24, 2018

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00602667
• Other Study ID Numbers: SJYC07; R01CA154619; NCI-2011-01193
• First Posted: Jan 28, 2008
• Last Update Posted: Dec 6, 2021
• Last Verified: Dec 1, 2021

• 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: Glioma; Ependymoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Cyclophosphamide; Cisplatin; Carboplatin; Methotrexate; Etoposide; Etoposide phosphate; Vincristine; Erlotinib Hydrochloride; Topotecan; Vinblastine

Study Results

Participant Flow

Recruitment Details	293 participants were enrolled between December 17, 2007 and April 19, 2017.
Pre-assignment Detail	Of the 293 participants enrolled, 3 were ineligible and removed from study, leaving 290 eligible patients. Eighty-one (81) of the 290 eligible patients enrolled had histologically confirmed medulloblastoma; medulloblastoma patients are the focus of the primary study objectives.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic (M0) medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-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.	Patients with central nervous system (CNS) metastatic disease will receive induction chemotherapy and high-risk therapy.
Period Title: Overall Study
STARTED	57	156	77
COMPLETED	38	75	14
NOT COMPLETED	19	81	63

Baseline Characteristics

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group	Total
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic (M0) medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-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.	Patients with central nervous system (CNS) metastatic disease will receive induction chemotherapy and high-risk therapy.	Total of all reporting groups
Overall Participants	57	156	77	290
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	17.0 (10.0)	22.9 (12.8)	19.3 (10.4)	20.8 (11.9)
Age (months) [Median (Full Range) ]
Median (Full Range) [months]	16.1	21.9	20.0	20.1
Sex: Female, Male (Count of Participants)
Female	22 38.6%	66 42.3%	43 55.8%	131 45.2%
Male	35 61.4%	90 57.7%	34 44.2%	159 54.8%
Race/Ethnicity, Customized (Count of Participants)
Mexican/Chicano	0 0%	5 3.2%	2 2.6%	7 2.4%
NOS Spanish, Hispanic, Latino	7 12.3%	16 10.3%	7 9.1%	30 10.3%
Non Spanish speaking, Non Hispanic	47 82.5%	120 76.9%	64 83.1%	231 79.7%
Puerto Rican	1 1.8%	2 1.3%	1 1.3%	4 1.4%
South or Central American	0 0%	2 1.3%	0 0%	2 0.7%
Unknown	2 3.5%	11 7.1%	3 3.9%	16 5.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian/Alaskan/White	1 1.8%	0 0%	0 0%	1 0.3%
American Indian/Alaskan Native	0 0%	1 0.6%	0 0%	1 0.3%
Asian	3 5.3%	6 3.8%	1 1.3%	10 3.4%
Asian and White	0 0%	2 1.3%	2 2.6%	4 1.4%
Black	6 10.5%	14 9%	10 13%	30 10.3%
Black and White	0 0%	1 0.6%	0 0%	1 0.3%
Multiple Race (NOS)	1 1.8%	7 4.5%	1 1.3%	9 3.1%
Other	2 3.5%	4 2.6%	1 1.3%	7 2.4%
Pacific Islander	1 1.8%	0 0%	0 0%	1 0.3%
Unknown	2 3.5%	3 1.9%	1 1.3%	6 2.1%
White	41 71.9%	118 75.6%	61 79.2%	220 75.9%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All eligible medulloblastoma patients started methotrexate and were included (n=81). PFS estimates are reported by risk group.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	Medulloblastoma patients <3 years of age, M0, and either R0 resection with any other medullo histology other than DN/MBEN (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group High Risk	Medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
Number (95% Confidence Interval) [Percent Probability]	73.9	46.9	30.8

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients with molecularly confirmed medulloblastoma (n=76) were included. PFS estimates are reported by methylation subgroup and risk group. There were no low-risk group 3 or group 4 patients.

Arm/Group Title	Low-risk SHH Patients	Intermediate-risk SHH Patients	High-risk SHH Patients	Low-risk Group 3 Patients	Intermediate-risk Group 3 Patients	High-risk Group 3 Patients	Low-risk Group 4 Patients	Intermediate-risk Group 4 Patients	High-risk Group 4 Patients
Arm/Group Description	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the low-risk group	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the intermediate-risk group	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the high-risk group	Group 3 (G3) medulloblastoma subgroup patients in the low-risk group	Group 3 medulloblastoma subgroup patients in the intermediate-risk group	Group 3 medulloblastoma subgroup patients in the high-risk group	Group 4 (G4) medulloblastoma subgroup patients in the low-risk group	Group 4 (G4) medulloblastoma subgroup patients in the intermediate-risk group	Group 4 medulloblastoma subgroup patients in the high-risk group
Measure Participants	23	8	11	0	13	11	0	8	2
Number (95% Confidence Interval) [Percent Probability]	73.9	50.0	54.5	30.8	9.1	62.5	50.0

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible medulloblastoma patients (n=81) were included. EFS estimates are reported by risk group.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	Medulloblastoma patients <3 years of age, M0, and either R0 resection with any other medullo histology other than DN/MBEN (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group High Risk	Medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
Number (95% Confidence Interval) [Percent Probability]	73.9	46.9	30.8

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible medulloblastoma patients (n=81) were included in these analyses. 23 of 23 low risk patients had data available for this objective, as did 27/32 and 24/26 intermediate and high risk patients.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	Medulloblastoma patients <3 years of age, M0, and either R0 resection with any other medullo histology other than DN/MBEN (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group High Risk	Medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
chr2p gain/amplification	5 8.8%	1 0.6%	6 7.8%
chr2p loss/deletion	0 0%	2 1.3%	0 0%
chr2q gain/amplification	5 8.8%	1 0.6%	6 7.8%
chr2q loss/deletion	0 0%	2 1.3%	0 0%
chr6p gain/amplification	1 1.8%	3 1.9%	3 3.9%
chr6p loss/deletion	0 0%	0 0%	2 2.6%
chr6q gain/amplification	1 1.8%	3 1.9%	3 3.9%
chr6q loss/deletion	0 0%	0 0%	2 2.6%
chr8p gain/amplification	1 1.8%	2 1.3%	0 0%
chr8p loss/deletion	0 0%	6 3.8%	8 10.4%
chr8q gain/amplification	1 1.8%	3 1.9%	0 0%
chr8q loss/deletion	0 0%	5 3.2%	7 9.1%
chr9p gain/amplification	4 7%	6 3.8%	3 3.9%
chr9p loss/deletion	4 7%	0 0%	3 3.9%
chr9q gain/amplification	2 3.5%	1 0.6%	1 1.3%
chr9q loss/deletion	6 10.5%	5 3.2%	5 6.5%
chr10p gain/amplification	0 0%	0 0%	0 0%
chr10p loss/deletion	0 0%	5 3.2%	7 9.1%
chr10q gain/amplification	0 0%	0 0%	0 0%
chr10q loss/deletion	3 5.3%	7 4.5%	9 11.7%
chr20p gain/amplification	0 0%	0 0%	0 0%
chr20p loss/deletion	2 3.5%	4 2.6%	5 6.5%
chr20q gain/amplification	0 0%	0 0%	0 0%
chr20q loss/deletion	1 1.8%	3 1.9%	5 6.5%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible medulloblastoma patients (n=81) were included in these analyses. Not all patients had data available for each gene.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	Medulloblastoma patients <3 years of age, M0, and either R0 resection with any other medullo histology other than DN/MBEN (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group High Risk	Medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
PTCH1 alteration	7 12.3%	4 2.6%	3 3.9%
SUFU alteration	6 10.5%	1 0.6%	1 1.3%
KMT2D alteration	5 8.8%	1 0.6%	3 3.9%
SMO alteration	2 3.5%	0 0%	1 1.3%
BCOR alteration	1 1.8%	0 0%	0 0%
PTEN alteration	1 1.8%	0 0%	0 0%
BRCA2 alteration	0 0%	0 0%	0 0%
GLI2 alteration	0 0%	0 0%	0 0%
SMARCA4 alteration	2 3.5%	1 0.6%	0 0%
TP53 alteration	0 0%	0 0%	0 0%
MYCN alteration	0 0%	1 0.6%	1 1.3%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients with molecularly confirmed medulloblastoma (n=76) were included in these analyses. Not all patients had data available for each gene.

Arm/Group Title	Low-risk SHH Patients	Intermediate-risk SHH Patients	High-risk SHH Patients	Low-risk Group 3 Patients	Intermediate-risk Group 3 Patients	High-risk Group 3 Patients	Low-risk Group 4 Patients	Intermediate-risk Group 4 Patients	High-risk Group 4 Patients
Arm/Group Description	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the low-risk group	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the intermediate-risk group	Sonic hedgehog (SHH) medulloblastoma subgroup patients in the high-risk group	Group 3 (G3) medulloblastoma subgroup patients in the low-risk group	Group 3 medulloblastoma subgroup patients in the intermediate-risk group	Group 3 medulloblastoma subgroup patients in the high-risk group	Group 4 (G4) medulloblastoma subgroup patients in the low-risk group	Group 4 (G4) medulloblastoma subgroup patients in the intermediate-risk group	Group 4 medulloblastoma subgroup patients in the high-risk group
Measure Participants	23	8	11	0	13	11	0	8	2
PTCH1 alteration	7 12.3%	4 2.6%	3 3.9%	0 0%	0 NaN	0 NaN	0 NaN
SUFU alteration	6 10.5%	1 0.6%	1 1.3%	0 0%	0 NaN	0 NaN	0 NaN
KMT2D alteration	5 8.8%	1 0.6%	3 3.9%	0 0%	0 NaN	0 NaN	0 NaN
SMO alteration	2 3.5%	0 0%	1 1.3%	0 0%	0 NaN	0 NaN	0 NaN
BCOR alteration	1 1.8%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
PTEN alteration	1 1.8%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
BRCA2 alteration	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
GLI2 alteration	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
SMARCA4 alteration	2 3.5%	0 0%	0 0%	1 0.3%	0 NaN	0 NaN	0 NaN
TP53 alteration	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
MYCN amplification	0 0%	1 0.6%	0 0%	0 0%	1 NaN	0 NaN	0 NaN
chr2p gain/amplification	5 8.8%	0 0%	4 5.2%	0 0%	1 NaN	0 NaN	0 NaN
chr2p loss/deletion	0 0%	0 0%	0 0%	1 0.3%	0 NaN	1 NaN	0 NaN
chr2q gain/amplification	5 8.8%	0 0%	4 5.2%	0 0%	1 NaN	0 NaN	0 NaN
chr2q loss/deletion	0 0%	0 0%	0 0%	1 0.3%	0 NaN	1 NaN	0 NaN
chr6p gain/amplification	1 1.8%	0 0%	0 0%	2 0.7%	3 NaN	1 NaN	0 NaN
chr6p loss/deletion	0 0%	0 0%	0 0%	0 0%	2 NaN	0 NaN	0 NaN
chr6q gain/amplification	1 1.8%	0 0%	0 0%	2 0.7%	3 NaN	1 NaN	0 NaN
chr6q loss/deletion	0 0%	0 0%	0 0%	0 0%	2 NaN	0 NaN	0 NaN
chr8p gain/amplification	1 1.8%	0 0%	0 0%	1 0.3%	0 NaN	0 NaN	0 NaN
chr8p loss/deletion	0 0%	0 0%	0 0%	2 0.7%	7 NaN	4 NaN	1 NaN
chr8q gain/amplification	1 1.8%	0 0%	0 0%	2 0.7%	0 NaN	0 NaN	0 NaN
chr8q loss/deletion	0 0%	0 0%	0 0%	1 0.3%	6 NaN	4 NaN	1 NaN
chr9p gain/amplification	4 7%	4 2.6%	3 3.9%	1 0.3%	0 NaN	1 NaN	0 NaN
chr9p loss/deletion	4 7%	0 0%	0 0%	0 0%	3 NaN	0 NaN	0 NaN
chr9q gain/amplification	2 3.5%	0 0%	1 1.3%	0 0%	0 NaN	1 NaN	0 NaN
chr9q loss/deletion	6 10.5%	5 3.2%	2 2.6%	0 0%	3 NaN	0 NaN	0 NaN
chr10p gain/amplification	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
chr10p loss/deletion	0 0%	0 0%	0 0%	5 1.7%	7 NaN	0 NaN	0 NaN
chr10q gain/amplification	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
chr10q loss/deletion	3 5.3%	2 1.3%	1 1.3%	5 1.7%	8 NaN	0 NaN	0 NaN
chr20p gain/amplification	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
chr20p loss/deletion	2 3.5%	1 0.6%	1 1.3%	3 1%	4 NaN	0 NaN	0 NaN
chr20q gain/amplification	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN
chr20q loss/deletion	1 1.8%	0 0%	1 1.3%	3 1%	4 NaN	0 NaN	0 NaN

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All eligible patients enrolled (n=290) were included in this analysis. The numbers of patients with pre-study samples were considered for these results.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-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.	Patients with central nervous system (CNS) metastatic disease will receive induction chemotherapy and high-risk therapy.
Measure Participants	57	156	77
Number with frozen tumor tissue	27 47.4%	73 46.8%	32 41.6%
Number with fixed tumor tissue	54 94.7%	153 98.1%	71 92.2%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible medulloblastoma patients who received any methotrexate were included in this analysis. Hazard ratios with 95% confidence intervals are reported and compare SJYC07 patients to historical controls in each risk group. As there were too few low-risk historical controls, no hazard ratio is included for the low-risk group.

Arm/Group Title	SJYC07 Low-risk Medulloblastoma Patients	SJYC07 Intermediate-risk Medulloblastoma Patients	SJYC07 High-risk Medulloblastoma Patients
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	SJYC07 medulloblastoma patients <3 years of age, no evidence of metastatic disease (M0), and either R0 resection with any other medullo histology other than histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN) (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group	SJYC07 medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
Number (95% Confidence Interval) [Percent probability]	73.9	46.9	30.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intermediate-Risk Group
	Comments	The historical control included 10 medulloblastoma patients treated during 1998-2006 who would have been classified as intermediate risk according to SJYC07 criteria (section 13.1.3 of protocol).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	4.99
	Confidence Interval	(2-Sided) 95%; 1.17 to 21.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High-Risk Group
	Comments	The historical control included 14 medulloblastoma patients treated during 1998-2006 who would have been classified as high risk according to SJYC07 criteria (section 13.1.3 of protocol).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible medulloblastoma patients who received any methotrexate were included in this analysis. Hazard ratios with 95% confidence intervals are reported and compare SJYC07 patients to historical controls in each risk group. As there were too few low-risk historical controls, no hazard ratio is included for the low-risk group.

Arm/Group Title	SJYC07 Low-risk Medulloblastoma Patients	SJYC07 Intermediate-risk Medulloblastoma Patients	SJYC07 High-risk Medulloblastoma Patients
Arm/Group Description	Medulloblastoma patients <3 years of age; histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN); no evidence of metastatic disease (M0); and a surgical gross total resection (GTR) or near total resection (NTR) defined as residual tumor or imaging abnormality (not definite for residual tumor) with a size of less than 1 cm^2 on post-op computed tomography (CT) or magnetic resonance imaging (MRI) [R0])	SJYC07 medulloblastoma patients <3 years of age, no evidence of metastatic disease (M0), and either R0 resection with any other medullo histology other than histological diagnosis of desmoplastic nodular (DN)/medulloblastoma with extensive nodularity (MBEN) (i.e., classic or large cell anaplastic (LCA)), or with a subtotal resection (with a residual tumor or imaging abnormality with a size of >1 cm^2 on post-op imaging (R+), and DN/MBEN). Children 3-5 years of age were also included in this group	SJYC07 medulloblastoma patients <3 years of age with evidence of metastatic disease
Measure Participants	23	32	26
Number (95% Confidence Interval) [Percent probability]	100	84.4	61.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intermediate-Risk Group
	Comments	The historical control included 10 medulloblastoma patients treated during 1998-2006 who would have been classified as intermediate risk according to SJYC07 criteria (section 13.1.3 of protocol).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.85
	Confidence Interval	(2-Sided) 95%; 0.42 to 8.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High-Risk Group
	Comments	The historical control included 14 medulloblastoma patients treated during 1998-2006 who would have been classified as high risk according to SJYC07 criteria (section 13.1.3 of protocol).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.31 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Eligible intermediate and high risk group patients who received at least 1 dose of methotrexate were included in this analysis. One of the high risk patients did not start therapy and was excluded.

Arm/Group Title	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	156	76
Number (95% Confidence Interval) [Percentage of patients]	58.3	21.1

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible high-risk group patients who started therapy were included in this analysis (n=76). 1 patient enrolled on the high-risk arm did not start therapy due to early disease progression and was excluded. Courses 2-4 of induction and the 1st consolidation course were used in this analysis. 76 patients (with 263 courses) were included.

Arm/Group Title	High-Risk Group
Arm/Group Description	Patients with central nervous system (CNS) metastatic disease
Measure Participants	76
Measure courses	263
Number (95% Confidence Interval) [Percentage of courses delayed]	3.8

12. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Eligible high-risk group patients who started therapy were included. Course 2 of consolidation and the 1st course of maintenance were used in this analysis and assessed for delays >7 days due to toxicity. Of the 76 high-risk patients that started induction therapy, 50 started consolidation (with 47 courses included in this analysis).

Arm/Group Title	High-Risk Group
Arm/Group Description	Patients with central nervous system (CNS) metastatic disease
Measure Participants	50
Measure courses	47
Number (95% Confidence Interval) [Percentage of courses delayed]	2.6

13. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Of the 50 high-risk patients that started consolidation chemotherapy, 38 had measurable residual disease after induction and were included in this result.

Arm/Group Title	High-Risk Group
Arm/Group Description	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38
Number (95% Confidence Interval) [percentage of participants]	13.2 23.2%

14. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Eligible patients less than 3 years of age (n=273) constituted the study population for this analysis; 167 of these patients started the first course of maintenance and were included in this analysis (50 low-risk, 87 intermediate-risk, and 30 high-risk patients).

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients <3 years of age with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-risk therapy.	Patients <3 years of age 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.	Patients <3 years of age with central nervous system (CNS) metastatic disease will receive induction chemotherapy and high-risk therapy
Measure Participants	50	87	30
Mean (Standard Deviation) [Percentage of scheduled doses received]	96 (8)	91 (23)	98 (4)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intermediate risk patients treated at St. Jude were eligible to receive proton beam therapy through referral to the University of Florida Proton Therapy Institute. Patients electing to receive PBT and post-treatment PET scans after the delivery of one treatment beam were included in the analysis.

Arm/Group Title	Intermediate Risk Group
Arm/Group Description	Patients with M0 medulloblastoma or nodular desmoplastic histology with less than a GTR, other histologic diagnoses with no metastatic disease
Measure Participants	53
Measure Scans	134
Mean (Standard Deviation) [mean activation value (MAV)]	60 (27)

17. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	Number and Type of Genetic Polymorphisms
Time Frame	At study enrollment (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Secondary Outcome

Title	Pharmacogenetic Variation on CNS Transmitters
Time Frame	At study enrollment (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Secondary Outcome

Title	Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe
Time Frame	Baseline and up to 60 months after completion of therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

24. Secondary Outcome

Title	Change in Quantitative MR Measures in the Right Frontal-parietal Regions
Time Frame	Baseline and up to 5 years after completion of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

25. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

26. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

27. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

28. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 1 and had samples collected for PK analysis

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	37	94	44
Median (Full Range) [L/h/m^2]	5.69	6.06	5.65

29. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	93	41
Median (Full Range) [L/h/m^2]	5.47	5.70	5.70

30. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 3 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	35	82	36
Median (Full Range) [L/h/m^2]	5.68	5.78	5.81

31. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 4 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	34	80	34
Median (Full Range) [L/h/m^2]	5.75	5.89	5.79

32. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	37	94	44
Median (Full Range) [L/m^2]	11.63	13.70	13.25

33. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	93	41
Median (Full Range) [L/m^2]	13.77	13.73	13.62

34. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 3 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	35	82	36
Median (Full Range) [L/m^2]	12.70	13.55	13.87

35. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 4 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	34	80	34
Median (Full Range) [L/m^2]	12.64	13.31	13.68

36. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	37	94	44
Median (Full Range) [µmol·h/L]	1797	1813	1821

37. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	93	41
Median (Full Range) [µmol·h/L]	1900	1902	1879

38. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 3 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	35	82	36
Median (Full Range) [µmol·h/L]	1872	1879	1831

39. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 4 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	34	80	34
Median (Full Range) [µmol·h/L]	1804	1841	1886

40. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	37	93	44
Median (Full Range) [µmol/L]	0.49	0.57	0.61

41. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	93	41
Median (Full Range) [µmol/L]	0.75	0.72	0.69

42. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 3 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	35	82	36
Median (Full Range) [µmol/L]	0.65	0.70	0.58

43. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received methotrexate during induction cycle 4 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	34	80	34
Median (Full Range) [µmol/L]	0.64	0.64	0.55

44. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during a cycle of induction therapy and had samples collected for PK analysis..

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	91	42
Median (Full Range) [L/h/m^2]	2.40	2.23	2.25

45. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	20	4	28
Median (Full Range) [L/h/m^2]	2.39	2.08	2.43

46. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	3	29
Median (Full Range) [L/h/m^2]	2.48	2.55	2.37

47. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during maintenance cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	26	42	14
Median (Full Range) [L/h/m^2]	2.95	2.83	2.74

48. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during a cycle of induction therapy and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	91	42
Median (Full Range) [µmol·h/L]	2070	2150	2105

49. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	20	4	28
Median (Full Range) [µmol·h/L]	1968	1504	868

50. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	3	29
Median (Full Range) [µmol·h/L]	1966	799	899

51. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during maintenance cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	26	42	14
Median (Full Range) [µmol·h/L]	39.9	38.7	42.2

52. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during a cycle of induction therapy and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	91	42
Median (Full Range) [µmol·h/L]	116.4	111.3	109.1

53. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	20	4	28
Median (Full Range) [µmol·h/L]	96.8	48.7	39.8

54. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	3	29
Median (Full Range) [µmol·h/L]	95.9	49.5	43.5

55. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during maintenance cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	26	42	14
Median (Full Range) [µmol·h/L]	1.98	1.96	1.82

56. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during a cycle of induction therapy and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	38	91	42
Median (Full Range) [µmol·h/L]	140.2	137.8	135.3

57. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	20	4	28
Median (Full Range) [µmol·h/L]	128.9	62.2	51.8

58. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during consolidation cycle 2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	3	29
Median (Full Range) [µmol·h/L]	132.7	46.8	44.0

59. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received cyclophosphamide during maintenance cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	26	42	14
Median (Full Range) [µmol·h/L]	1.59	1.65	1.41

60. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received topotecan with empirical dosage during consolidation therapy were included in this analysis. Per protocol, low-risk and intermediate-risk patients did not receive topotecan during consolidation unless they experienced disease progression during induction. One such intermediate-risk patient was included.

Arm/Group Title	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	1	27
Number [participants]	0 0%	8 5.1%

61. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received topotecan with PK-guided dosage adjustment during consolidation therapy were included in this analysis. Per protocol, low-risk and intermediate-risk patients did not receive topotecan during consolidation unless they experienced disease progression during induction. One such intermediate-risk patient was included.

Arm/Group Title	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	1	27
Number [participants]	1 1.8%	20 12.8%

62. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received intravenous topotecan during consolidation cycle 1 and had PK samples collected were included in this analysis. Per protocol, low- and intermediate-risk patients did not receive topotecan during consolidation unless they experienced disease progression during induction. One such intermediate-risk patient was included.

Arm/Group Title	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	1	27
Median (Full Range) [L/h/m^2]	30.3	26.40

63. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral topotecan during maintenance therapy cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	33	10
Median (Full Range) [L/h]	41.4	41.0	44.6

64. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received intravenous topotecan during consolidation cycle 1 and had PK samples collected were included in this analysis. Per protocol, low- and intermediate-risk patients did not receive topotecan during consolidation unless they experienced disease progression during induction. One such intermediate-risk patient was included.

Arm/Group Title	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	1	27
Median (Full Range) [µg·h/L]	117	116

65. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral topotecan during maintenance therapy cycle A1 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	18	33	10
Median (Full Range) [µg·h/L]	10.90	11.60	10.33

66. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral erlotinib during maintenance therapy cycle B2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	10	11	3
Median (Full Range) [L/h/m^2]	6.53	7.79	8.40

67. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral erlotinib during maintenance therapy cycle B2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	10	11	3
Median (Full Range) [L/m^2]	72.9	61.7	104.8

68. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral erlotinib during maintenance therapy cycle B2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	10	11	3
Median (Full Range) [µmol·h/L]	31.0	23.5	22.0

69. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients who received oral erlotinib during maintenance therapy cycle B2 and had samples collected for PK analysis.

Arm/Group Title	Low-Risk Group	Intermediate-Risk Group	High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic histology, or high grade glioma	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a gross total resection (GTR), other histologic diagnoses with no metastatic disease	Patients with central nervous system (CNS) metastatic disease
Measure Participants	10	11	3
Median (Full Range) [µmol·h/L]	2.17	1.81	1.62

70. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible intermediate-risk patients who received focal radiation were included in this analysis. Of the 156 intermediate risk patients, 121 started radiation.

Arm/Group Title	Intermediate-risk Patients Who Received Focal Radiation
Arm/Group Description	Patients with no evidence of metastatic disease (M0) medulloblastoma or nodular desmoplastic histology with less than a surgical gross total resection (GTR), other histologic diagnoses with no metastatic disease who received induction chemotherapy and intermediate-risk therapy that included focal radiation.
Measure Participants	121
Number (95% Confidence Interval) [Percentage of participants]	13.2 23.2%

71. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible intermediate-risk patients who received focal radiation were included in this analysis. Of the 156 intermediate risk patients, 121 started radiation.

Arm/Group Title	Intermediate-risk Patients Who Received Focal Radiation
Arm/Group Description	Patients with M0 medulloblastoma or nodular desmoplastic histology with less than a GTR, other histologic diagnoses with no metastatic disease who received induction chemotherapy and intermediate-risk therapy that included focal radiation.
Measure Participants	121
Number (95% Confidence Interval) [percentage of participants]	25.6 44.9%

Adverse Events

Time Frame	All adverse events grades 3, 4, and 5 which occur during treatment and for 30 days after the end of treatment, and events which occur later than 30 days after the end of treatment which are felt to be at least possibly related to treatment, to the time of off study, were collected with some exceptions noted in the additional description section.
Adverse Event Reporting Description	Per protocol, some grade 3 and 4 hematologic toxicities, grade 3 elevation in serum ALT or AST, grade 3 and 4 electrolyte abnormalities, and total parenteral nutrition or intravenous fluids administered to prevent significant weight loss/malnutrition were not collected, especially if they occurred from the beginning of induction chemotherapy. The one patient in the high-risk group who did not start therapy due to early disease progression was excluded from adverse event results.
Arm/Group Title	Low-Risk Group		Intermediate-Risk Group		High-Risk Group
Arm/Group Description	Patients with gross total resection (GTR)/no evidence of metastatic disease (M0) medulloblastoma, nodular desmoplastic or high grade glioma histology will receive induction chemotherapy and low-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.		Patients with central nervous system (CNS) metastatic disease will receive induction chemotherapy and high-risk therapy.
All Cause Mortality
	Low-Risk Group		Intermediate-Risk Group		High-Risk Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/57 (17.5%)		58/156 (37.2%)		49/77 (63.6%)
Serious Adverse Events
	Low-Risk Group		Intermediate-Risk Group		High-Risk Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/57 (5.3%)		7/156 (4.5%)		5/76 (6.6%)
Blood and lymphatic system disorders
Hemoglobin	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	0/57 (0%)	0	0/156 (0%)	0	1/76 (1.3%)	1
Platelets	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Cardiac disorders
Hypotension	0/57 (0%)	0	2/156 (1.3%)	2	0/76 (0%)	0
Ear and labyrinth disorders
Hearing: patients with/without baseline audiogram and enrolled in a monitoring program	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Gastrointestinal disorders
Anorexia	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Colitis	0/57 (0%)	0	0/156 (0%)	0	1/76 (1.3%)	1
Dehydration	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Diarrhea	0/57 (0%)	0	0/156 (0%)	0	1/76 (1.3%)	1
Mucositis/stomatitis (clinical exam), Oral cavity	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Perforation, GI, Duodenum	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Vomiting	1/57 (1.8%)	1	2/156 (1.3%)	2	1/76 (1.3%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	1/57 (1.8%)	1	0/156 (0%)	0	1/76 (1.3%)	1
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/57 (1.8%)	1	3/156 (1.9%)	3	0/76 (0%)	0
Weight loss	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Infections and infestations
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L), Pharynx	0/57 (0%)	0	0/156 (0%)	0	1/76 (1.3%)	1
Infection, Upper airway NOS	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Infection - Other	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, Blood	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, Catheter-related	1/57 (1.8%)	1	1/156 (0.6%)	1	1/76 (1.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils, Eye NOS	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, Wound	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory)	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Musculoskeletal and connective tissue disorders
Fracture	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Nervous system disorders
Hydrocephalus	1/57 (1.8%)	1	0/156 (0%)	0	1/76 (1.3%)	1
Irritability (children <3 years of age)	1/57 (1.8%)	1	0/156 (0%)	0	0/76 (0%)	0
Neurology - Other	1/57 (1.8%)	1	0/156 (0%)	0	0/76 (0%)	0
Neuropathy: motor	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Seizure	1/57 (1.8%)	1	1/156 (0.6%)	1	1/76 (1.3%)	1
Somnolence/depressed level of consciousness	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Speech impairment (e.g., dysphasia or aphasia)	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Hypoxia	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Pneumonitis/pulmonary infiltrates	0/57 (0%)	0	1/156 (0.6%)	1	0/76 (0%)	0
Pulmonary/Upper Respiratory - Other	0/57 (0%)	0	0/156 (0%)	0	2/76 (2.6%)	2
Vascular disorders
Hemorrhage/Bleeding - Other	1/57 (1.8%)	1	0/156 (0%)	0	0/76 (0%)	0
Other (Not Including Serious) Adverse Events
	Low-Risk Group		Intermediate-Risk Group		High-Risk Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/57 (96.5%)		145/156 (92.9%)		70/76 (92.1%)
Blood and lymphatic system disorders
Febrile neutropenia	36/57 (63.2%)	83	92/156 (59%)	169	48/76 (63.2%)	120
Neutrophils/granulocytes (ANC/AGC)	32/57 (56.1%)	60	57/156 (36.5%)	124	10/76 (13.2%)	20
Leukocytes (total WBC)	24/57 (42.1%)	38	45/156 (28.8%)	83	6/76 (7.9%)	11
Hemoglobin	13/57 (22.8%)	15	9/156 (5.8%)	20	3/76 (3.9%)	3
Platelets	7/57 (12.3%)	19	8/156 (5.1%)	9	4/76 (5.3%)	4
Lymphopenia	2/57 (3.5%)	6	8/156 (5.1%)	8	0/76 (0%)	0
Ear and labyrinth disorders
Hearing: patients with/without baseline audiogram and enrolled in a monitoring program	3/57 (5.3%)	3	1/156 (0.6%)	1	1/76 (1.3%)	1
Gastrointestinal disorders
Vomiting	10/57 (17.5%)	11	25/156 (16%)	32	22/76 (28.9%)	29
Anorexia	6/57 (10.5%)	7	15/156 (9.6%)	16	12/76 (15.8%)	13
Diarrhea	6/57 (10.5%)	7	13/156 (8.3%)	14	8/76 (10.5%)	11
Mucositis/stomatitis (functional/symptomatic), Oral cavity	4/57 (7%)	4	7/156 (4.5%)	8	7/76 (9.2%)	7
Nausea	1/57 (1.8%)	1	6/156 (3.8%)	6	6/76 (7.9%)	6
Mucositis/stomatitis (clinical exam), Oral cavity	1/57 (1.8%)	1	11/156 (7.1%)	12	4/76 (5.3%)	5
Dehydration	3/57 (5.3%)	4	8/156 (5.1%)	9	3/76 (3.9%)	3
General disorders
Weight loss	1/57 (1.8%)	1	0/156 (0%)	0	6/76 (7.9%)	6
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	0/57 (0%)	0	8/156 (5.1%)	8	3/76 (3.9%)	3
Infections and infestations
Infection, Catheter-related	11/57 (19.3%)	14	17/156 (10.9%)	19	8/76 (10.5%)	9
Infection with normal ANC or Grade 1 or 2 neutrophils, Catheter-related	8/57 (14%)	8	19/156 (12.2%)	26	5/76 (6.6%)	7
Colitis, infectious (e.g., Clostridium difficile)	3/57 (5.3%)	3	8/156 (5.1%)	12	7/76 (9.2%)	10
Infection, Skin (cellulitis)	0/57 (0%)	0	7/156 (4.5%)	9	7/76 (9.2%)	7
Infection, Blood	5/57 (8.8%)	5	5/156 (3.2%)	6	5/76 (6.6%)	5
Infection - Other	4/57 (7%)	4	8/156 (5.1%)	11	4/76 (5.3%)	5
Infection with normal ANC or Grade 1 or 2 neutrophils, Blood	2/57 (3.5%)	3	9/156 (5.8%)	9	4/76 (5.3%)	4
Infection, Upper airway NOS	1/57 (1.8%)	1	4/156 (2.6%)	4	4/76 (5.3%)	4
Infection, Urinary tract NOS	1/57 (1.8%)	1	2/156 (1.3%)	3	4/76 (5.3%)	4
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	1/57 (1.8%)	1	8/156 (5.1%)	9	3/76 (3.9%)	3
Nervous system disorders
Seizure	1/57 (1.8%)	1	4/156 (2.6%)	5	7/76 (9.2%)	7
Hydrocephalus	2/57 (3.5%)	2	8/156 (5.1%)	9	5/76 (6.6%)	5
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/57 (1.8%)	1	8/156 (5.1%)	10	9/76 (11.8%)	13
Skin and subcutaneous tissue disorders
Rash/desquamation	6/57 (10.5%)	7	8/156 (5.1%)	8	2/76 (2.6%)	2

Limitations/Caveats

Results for the some of the secondary objectives are not available yet. These results will be posted as they become available.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.