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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00602667
• Other study ID #: SJYC07
• Secondary ID: R01CA154619NCI-2
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 17, 2007
• Est. completion date: April 2026

Study information

• Verified date: March 2024
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 293
• Est. completion date: April 2026
• Est. primary completion date: September 27, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 5 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Ependymoma
• Glioma
• Nervous System Neoplasms

Intervention

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.
• 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).
• 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).
• 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.

Locations

Country	Name	City	State
Australia	Lady Cilento Children's Hospital, Brisbane	Brisbane	Queensland
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California
United States	Children's Hospitals and Clinics of Minnesota - St. Paul	Saint Paul	Minnesota
United States	Rady Children's Hospital	San Diego	California

Sponsors (4)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	National Cancer Institute (NCI), The Pew Charitable Trusts, University of Florida

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients	Progression was defined as 25% increase in the size of any measurable lesion; the appearance of a new lesion; or the conversion of negative cerebrospinal fluid (CSF) cytology to positive. Defined as the time interval from date on treatment until the date of first progression, medulloblastoma-related death or date of last contact for patients who have not experienced an event. All eligible medulloblastoma patients who received any methotrexate are included in this analysis.	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
Primary	Percent Probability of Progression-free Survival (PFS) for Medulloblastoma Patients by DNA Methylation Subgroup	Defined as the time interval from date on treatment until the date of first progression, medulloblastoma-related death or date of last contact for patients who have not experienced an event. Eligible medulloblastoma patients who received any methotrexate and had molecularly confirmed medulloblastoma are included in this analysis. Five patients were excluded as 3 had no archival tissue available and 2 were found to not be medulloblastoma by methylation profile.	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
Primary	Percent Probability of Event-free Survival (EFS) for Medulloblastoma Patients	Defined as the time interval from date on treatment until the date of first progression, second malignancy or death due to any cause; or date of last contact for patients who have not experienced an event. All eligible medulloblastoma patients who received any methotrexate are included in this analysis.	From date on treatment to date of first progression, relapse, second malignancy or death from any cause or to date of last contact, estimated at 1 year after
Secondary	Number of Participants With Chromosomal Abnormalities	Amplifications and deletions (gains and losses) for chromosomes of interest are shown in the table of measured values.	Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Secondary	Numbers of Patients With Gene Alterations	Gene alterations, which include single nucleotide variants (SNPs), amplifications, deletions, translocations, indels, and germline alterations are shown for specific genes of interest in the results table.	Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Secondary	Numbers of Patients With Molecular Abnormalities by Tumor Type	Alterations included single nucleotide variants (SNPs), amplifications, deletions, translocations, indels, and germline alterations. Cytogenetic information shows gains and losses as specified in the table of measured values.	Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Secondary	Number of Successful Collections for Frozen and Fixed Tumor Samples	Successful collections will be defined as the number of patients who have frozen/fixed tumor samples available.	Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment
Secondary	Event-free Survival (EFS) Compared to Historical Controls	EFS was measured from the date of initial treatment to the earliest date of disease progression, second malignancy or death for patients who fail; and to the date of last contact for patients who remain at risk for failure. 1-year EFS estimates are reported by risk group. EFS was compared to St. Jude historical cohorts by risk group using hazard ratios with 95% confidence intervals.	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
Secondary	Overall Survival (OS) Compared to Historical Controls	OS was measured from the date of initial treatment to date of death or to date of last contact for survivors. 1-year OS estimates were reported by risk group. OS was compared to St. Jude historical cohorts by risk group using hazard ratios with 95% confidence intervals.	1 year after treatment initiation of last patient
Secondary	Percentage of Patients With Objective Responses Rate to Induction Chemotherapy	For patients treated in the intermediate and high risk strata with residual or metastatic disease we will estimate the stratum-specific objective response rate (complete response (CR) or partial response [ PR]). All patients who receive at least 1 -dose of methotrexate are evaluable for response. Objective responses must be sustained for at least eight weeks.	From on-study date to 2 months after completion of induction chemotherapy (up to 4 months after on-study date)
Secondary	Feasibility and Toxicity of Administering Vinblastine With Induction Chemotherapy for Patients With Metastatic Disease as Measured by the Percentage of Courses Delayed for More Than 7 Days Due to Toxicity	For the subset of patients with metastatic disease (high-risk group patients), during induction, the proportion percentage of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity will be calculated. Patients were to receive 4 courses of induction and then consolidation chemotherapy.	From on-study date up to 4 months after on-study date
Secondary	Feasibility and Toxicity of Administering Consolidation Therapy Including Cyclophosphamide and Pharmacokinetically Targeted Topotecan to Patients With Metastatic Disease Based on the Percentage of Courses Delayed for More Than 7 Days Due to Toxicity	For the subset of patients with metastatic disease (high-risk group patients), during consolidation, we will calculate the number and proportion of courses during which subsequent chemotherapy administration was delayed for more than 7 days due to toxicity. Patients were to received 2 courses of consolidation chemotherapy and then maintenance therapy.	At completion of consolidation therapy (up to 6 months after on-study date)
Secondary	Percent of Patients With Sustained Objective Responses Rate After Consolidation	For patients enrolled on the high-risk arm with measurable residual disease after induction treated with consolidation therapy, we will estimate the objective response (complete response (CR)/partial response (PR)) rate after consolidation therapy with a 95% confidence interval. Objective responses must be sustained for at least eight weeks. All patients who receive at least 1 dose of cyclophosphamide or topotecan during consolidation are evaluable for response.	8 weeks after completion of consolidation therapy (up to 8 months after on-study date)
Secondary	Feasibility and Toxicity of Administering Oral Maintenance Therapy in Children <3 Years of Age as Measured by the Percentage of Total Scheduled Maintenance Doses Received	These data are based on patient diaries. For children <3 years of age, we will calculate the percentage of total scheduled doses each patient received per course for each of the oral maintenance courses and report the overall average number percentage of doses received per course across patients. If patients received all planned doses, their percentage would be 100%. If the average percentage was less than 75%, then feasibility would be in question.	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)
Secondary	Change in Neurostructure, Especially White Matter Volume and Integrity	Quantitative MRI measures of change in neurostructure (especially white matter volume and integrity) over time will be assessed using a random effects model incorporating various covariates. Covariates to be considered include age at diagnosis, time since diagnosis and risk-arm. Differences in quantitative MRI measures of neurostructure volume and integrity between patient groups will be evaluated as a metric of structural neurotoxicity of therapy.	From baseline to 60 months off therapy
Secondary	Percent of PET Scans With Loss of Signal Intensity	Measures will be analyzed for intermediate risk participants who receive proton beam therapy (PBT) and who consent. This objective aims to assess the feasibility of using post-proton beam therapy (PBT) positron emission tomography (PET) as an in-vivo dosimetric and distal edge verification system in this patient population. To quantify the decay in signal, 134 scans from 53 patients were analyzed by recording the mean activation value (MAV), the average recorded PET signal from activation, within the target volume. With each patient being given the same dose, the percent standard deviation in the MAV can serve as a quantitative representation of signal loss due to radioactive decay.	Up to 3 times during RT consolidation
Secondary	Concentration of Cerebrospinal Fluid Neurotransmitters	Concentrations of various neurotransmitters in cerebrospinal fluid were measured at 5 timepoints. The median concentration of each neurotransmitter at each time point was calculated and provided with a full range.	Baseline, at the completion of therapy, and every 12 months up to 36 months after off therapy date
Secondary	Number and Type of Genetic Polymorphisms	Types of genetic polymorphisms of neurotransmitters were examined. We studied 3 genetic polymorphisms; these were types of genetic polymorphisms involved in dopamine metabolism. They were as follows: rs6323, rs4680, and rs6280.	At study enrollment (Day 0)
Secondary	Pharmacogenetic Variation on Central Nervous System Transmitters	Frequencies of genetic polymorphisms were reported.	At study enrollment (Day 0)
Secondary	Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe		Baseline and up to 60 months after completion of therapy.
Secondary	Change in Quantitative MR Measures in the Right Frontal-parietal Regions		Baseline and up to 5 years after completion of therapy
Secondary	Number of Participants With Endocrinopathy	Serial GH testing (at baseline, the end of therapy, and at 6 and 24 months after completion of therapy) will be performed on consenting patients in order to estimate longitudinal change in GH secretion as measured by mean peak GH values, with the intent to explore associations with radiation dose to the hypothalamus. Since determination of proton- or photon-based radiotherapy is not based on randomization, it will not be possible to compare the endocrine outcome between the patients with and without PBT. However, the differences between these two clinical cohorts with respect to clinical and demographic variables of interest will be summarized via descriptive statistics.	Baseline, end of therapy, and at 6- and 24-months after completion of therapy
Secondary	Longitudinal Change in Growth Hormone Secretion	The intent of this objective is to estimate the longitudinal change in abnormal GH secretion as measured by mean peak GH values via a mixed effects model for the patients who receive PBT.	Baseline, end of therapy, and at 6- and 24-months after completion of therapy
Secondary	Methotrexate Clearance in Induction Cycle 1	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of Methotrexate (MTX)
Secondary	Methotrexate Clearance in Induction Cycle 2	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Clearance in Induction Cycle 3	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Clearance in Induction Cycle 4	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate clearance are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Volume of Central Compartment in Induction Cycle 1	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Volume of Central Compartment in Induction Cycle 2	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Volume of Central Compartment in Induction Cycle 3	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate AUC0-66h in Induction Cycle 1	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate AUC0-66h in Induction Cycle 2	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Volume of Central Compartment in Induction Cycle 4	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate volume of central compartment are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate AUC0-66h in Induction Cycle 3	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate AUC0-66h in Induction Cycle 4	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate AUC0-66h (area under concentration curve from time 0 to 66 hours post-dose) are obtained using post hoc analysis.	Pre-infusion and 6, 23, 42, 66 hours from start of MTX
Secondary	Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 1	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 1. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.	42 hours from start of MTX
Secondary	Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 2	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 2. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.	42 hours from start of MTX
Secondary	Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 3	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 3. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.	42 hours from start of MTX
Secondary	Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 4	Methotrexate plasma concentration-time data are collected after the start of methotrexate infusion in induction cycle 4. Population parameters and inter-subject variability are estimated. Individual estimates of methotrexate concentration at 42 hours post-dose are obtained using post hoc analysis.	42 hours from start of MTX
Secondary	Cyclophosphamide Clearance in Induction Chemotherapy	Cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 1	Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 2	Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide clearance are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide Apparent Oral Clearance in Maintenance Chemotherapy Cycle A1	Cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of cyclophosphamide apparent oral clearance are obtained using post hoc analysis.	Pre-dose, 0.5, 1.75, 3 and 6 hours post-dose
Secondary	Cyclophosphamide AUC0-24h in Induction Chemotherapy	Cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1	Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 1	4-OH cyclophosphamide plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2	Cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1	Cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of cyclophosphamide AUC0-24h are obtained using post hoc analysis.	Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Secondary	4-OH Cyclophosphamide AUC0-24h in Induction Chemotherapy	4-OH cyclophosphamide plasma concentration-time data are collected on day 9 in one cycle of induction chemotherapy. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	4-OH Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2	4-OH cyclophosphamide plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	4-OH Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1	4-OH cyclophosphamide plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of 4-OH cyclophosphamide AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Secondary	CEPM AUC0-24h in Induction Chemotherapy	Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected on day 9 in one induction cycle. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	CEPM AUC0-24h in Consolidation Chemotherapy Cycle 1	Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected in consolidation cycle 1. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	CEPM AUC0-24h in Consolidation Chemotherapy Cycle 2	Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected in consolidation cycle 2. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion
Secondary	CEPM AUC0-24h in Maintenance Chemotherapy Cycle A1	Carboxyethylphosphoramide mustard (CEPM) plasma concentration-time data are collected on day 1 of maintenance cycle A1. Individual estimates of CEPM AUC0-24h (area under concentration curve from time 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose
Secondary	Participants With Empirical Dosage Achieving Target System Exposure of Intravenous Topotecan	Number of participants who successfully achieve target systemic exposure of intravenous topotecan after an empiric dosage during consolidation phase of therapy are reported.	Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Secondary	Participants With PK-guided Dosage Adjustment Achieving Target System Exposure of Intravenous Topotecan	Number of participants who successfully achieve target systemic exposure of intravenous topotecan after a pharmacokinetic-guided dosage adjustment during consolidation phase of therapy are reported.	Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Secondary	Topotecan Clearance in Consolidation Chemotherapy	Topotecan plasma concentration-time data are collected on day 1 of consolidation cycle 1 after a single IV dose. Individual estimates of topotecan clearance are obtained using post hoc analysis.	Pre-infusion, 5 min., 1, and 3 hours from end of infusion
Secondary	Topotecan Apparent Oral Clearance in Maintenance Chemotherapy	Topotecan plasma concentration-time data are collected on day 1 of maintenance cycle A1 after a single oral dose. Individual estimates of topotecan apparent oral clearance are obtained using post hoc analysis.	Pre-dose, 0.25, 1.5 and 6 hours post-dose
Secondary	Topotecan AUC0-24h in Consolidation Chemotherapy	Topotecan plasma concentration-time data are collected on day 1 of consolidation cycle 1 after a single IV dose. Individual estimates of topotecan AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-infusion, 5 min., 1, 3, and 24 hours from end of infusion
Secondary	Topotecan AUC0-24h in Maintenance Chemotherapy	Topotecan plasma concentration-time data are collected on day 1 of maintenance cycle A1 after a single oral dose. Individual estimates of topotecan AUC0-24h (area under concentration curve from time 0 to 24 hours post- dose) are obtained using post hoc analysis.	Pre-dose, 0.25, 1.5, 6, and 24 hours post-dose
Secondary	Erlotinib Apparent Oral Clearance	Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib apparent oral clearance are obtained using post hoc analysis.	Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Secondary	Erlotinib Apparent Volume of Central Compartment	Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib apparent volume of central compartment are obtained using post hoc analysis.	Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Secondary	Erlotinib AUC0-24h	Erlotinib plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of erlotinib AUC0-24h (area under concentration curve from 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Secondary	OSI-420 AUC0-24h	Erlotinib metabolite OSI-420 plasma concentration-time data are collected on day 1 of maintenance cycle B2. Individual estimates of OSI-420 AUC0-24h (area under concentration curve from 0 to 24 hours post-dose) are obtained using post hoc analysis.	Pre-dose, 1, 2, 4, 8, and 24 hours post-dose
Secondary	Rate of Local Disease Progression	Local failure was defined as the interval from end of RT to date of local failure (or combined local + distant failure). Competing events were distant failure or second malignancy. Patients without an event were censored at date of last contact. The 1-year cumulative incidence was estimated and reported with a 95% confidence interval.	1 year after completion of radiation therapy for last patient
Secondary	Rate of Distant Disease Progression	Distant failure was defined as the interval from end of RT to date of distant failure (or combined local + distant failure). Competing events were local failure or second malignancy. Patients without an event were censored at date of last contact. The 1-year cumulative incidence was estimated and reported with a 95% confidence interval.	1 year after completion of radiation therapy for last patient
Secondary	Neurocognitive Performance Related to Global Cognitive Functioning as Measured by Cognitive Composite Scores and Estimated IQ Scores	Global cognitive functioning was measured based on Cognitive Composite Scores from the Bayley III instrument for subjects <3 years of age and on estimated IQ scores from the Stanford Binet V instrument for subjects =3 years of age. Higher scores indicate better performance. The normative mean is 100 with a standard deviation of 15.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Attention as Measured by Attention Problems T-scores	Scores measuring attention were obtained from the Attention Problems T-score on the BASC-2 instrument which is a parent report. Higher scores indicate more attention problems. The normative mean is 50 with a standard deviation of 10.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Processing Speed as Measured by Visual Matching Standard Scores	Scores measuring processing speed were obtained based on the visual matching standard score from the Woodcock Johnson III instrument. Higher scores indicate better performance. The normative mean is 100 with a standard deviation of 15.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Executive Functioning as Measured by Global Executive Composite T-scores	Scores measuring executive functioning were obtained from Global Executive Composite (GEC) T-scores, which were obtained from the Behavior Rating Inventory of Executive Function (BRIEF) instrument which is a parent report. Higher scores indicate more problems. The normative mean is 50 with a standard deviation of 10.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Working Memory as Measured by Working Memory T-scores	Scores measuring working memory were obtained from Working Memory T-scores, which were obtained from the Behavior Rating Inventory of Executive Function (BRIEF) instrument which is a parent report. Higher scores indicate more problems. The normative mean is 50 with a standard deviation of 10.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Verbal Fluency as Measured by Retrieval Fluency Standard Scores	Scores measuring verbal fluency were obtained from Retrieval Fluency standard scores on the Woodcock Johnson III instrument. Higher scores indicate better performance. The normative mean is 100 with a standard deviation of 15.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Visual-spatial Reasoning as Measured by Visual Perception T-scores	Scores measuring visual-spatial reasoning were obtained from Visual Perception T-scores on the Beery Visual Motor Integration (VMI) instrument. Higher scores indicate better performance. The normative mean is 50 with a standard deviation of 10.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy
Secondary	Neurocognitive Performance Related to Visual-spatial Reasoning as Measured by Visual Motor Integration (VMI) T-scores	Scores measuring visual-spatial reasoning were obtained from VMI T-scores on the Beery VMI instrument. Higher scores indicate better performance. The normative mean is 50 with standard deviation of 10.	Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy

External Links

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