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

简要总结

详细描述

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.

主要结局

次要结局

• Number of Participants With Chromosomal Abnormalities(Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment)
• Overall Survival (OS) Compared to Historical Controls(1 year after treatment initiation of last patient)
• 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))
• Numbers of Patients With Gene Alterations(Based on samples obtained at the time of initial surgery or repeat surgery prior to treatment)
• 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)
• 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))
• 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)
• 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)
• 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)
• Pharmacogenetic Variation on Central Nervous System Transmitters(At study enrollment (Day 0))
• Methotrexate Volume of Central Compartment in Induction Cycle 2(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• 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))
• 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))
• Percent of PET Scans With Loss of Signal Intensity(Up to 3 times during RT consolidation)
• Methotrexate Clearance in Induction Cycle 2(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Concentration of Cerebrospinal Fluid Neurotransmitters(Baseline, at the completion of therapy, and every 12 months up to 36 months after off therapy date)
• Number and Type of Genetic Polymorphisms(At study enrollment (Day 0))
• Number of Participants With Endocrinopathy(End of induction therapy (approximately 16 weeks from start of treatment), end of therapy (approximately 48 weeks from start of treatment), and 6, 12, 24, 36, 48, and 60 months off therapy)
• Growth Hormone Secretion(End of induction therapy (approximately 16 weeks from start of treatment), end of therapy (approximately 48 weeks from start of treatment), and 6, 12, 24, 36, 48, and 60 months off therapy)
• Methotrexate Clearance in Induction Cycle 1(Pre-infusion and 6, 23, 42, 66 hours from start of Methotrexate (MTX))
• Methotrexate Clearance in Induction Cycle 3(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate Clearance in Induction Cycle 4(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate Volume of Central Compartment in Induction Cycle 1(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate Volume of Central Compartment in Induction Cycle 3(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate AUC0-66h in Induction Cycle 1(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate Volume of Central Compartment in Induction Cycle 4(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate AUC0-66h in Induction Cycle 2(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate AUC0-66h in Induction Cycle 3(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate AUC0-66h in Induction Cycle 4(Pre-infusion and 6, 23, 42, 66 hours from start of MTX)
• Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 1(42 hours from start of MTX)
• Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 2(42 hours from start of MTX)
• Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 4(42 hours from start of MTX)
• Methotrexate Concentration at 42 Hours Post-dose in Induction Cycle 3(42 hours from start of MTX)
• Cyclophosphamide Clearance in Induction Chemotherapy(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 2(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide AUC0-24h in Induction Chemotherapy(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide Clearance in Consolidation Chemotherapy Cycle 1(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide Apparent Oral Clearance in Maintenance Chemotherapy Cycle A1(Pre-dose, 0.5, 1.75, 3 and 6 hours post-dose)
• 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 AUC0-24h in Consolidation Chemotherapy Cycle 1(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide AUC0-24h in Consolidation Chemotherapy Cycle 2(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• Cyclophosphamide AUC0-24h in Maintenance Chemotherapy Cycle A1(Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose)
• 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 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 AUC0-24h in Maintenance Chemotherapy Cycle A1(Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose)
• CEPM AUC0-24h in Consolidation Chemotherapy Cycle 1(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• CEPM AUC0-24h in Induction Chemotherapy(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• CEPM AUC0-24h in Consolidation Chemotherapy Cycle 2(Pre-infusion, end of infusion, 3, 6, and 24 hours from end of cyclophosphamide infusion)
• 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)
• CEPM AUC0-24h in Maintenance Chemotherapy Cycle A1(Pre-dose, 0.5, 1.75, 3, 6, and 24 hours post-dose)
• Participants With Empirical Dosage Achieving Target System Exposure of Intravenous Topotecan(Pre-infusion, 5 min., 1, and 3 hours from end of infusion)
• Topotecan Clearance in Consolidation Chemotherapy(Pre-infusion, 5 min., 1, and 3 hours from end of infusion)
• Topotecan Apparent Oral Clearance in Maintenance Chemotherapy(Pre-dose, 0.25, 1.5 and 6 hours post-dose)
• Topotecan AUC0-24h in Consolidation Chemotherapy(Pre-infusion, 5 min., 1, 3, and 24 hours from end of infusion)
• Topotecan AUC0-24h in Maintenance Chemotherapy(Pre-dose, 0.25, 1.5, 6, and 24 hours post-dose)
• Erlotinib Apparent Oral Clearance(Pre-dose, 1, 2, 4, 8, and 24 hours post-dose)
• Erlotinib Apparent Volume of Central Compartment(Pre-dose, 1, 2, 4, 8, and 24 hours post-dose)
• Erlotinib AUC0-24h(Pre-dose, 1, 2, 4, 8, and 24 hours post-dose)
• OSI-420 AUC0-24h(Pre-dose, 1, 2, 4, 8, and 24 hours post-dose)
• Rate of Distant Disease Progression(1 year after completion of radiation therapy for last patient)
• Rate of Local Disease Progression(1 year after completion of radiation therapy for last patient)
• Neurocognitive Performance Related to Attention as Measured by Attention Problems T-scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Global Cognitive Functioning as Measured by Cognitive Composite Scores and Estimated IQ Scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Processing Speed as Measured by Visual Matching Standard Scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Executive Functioning as Measured by Global Executive Composite T-scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Working Memory as Measured by Working Memory T-scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Verbal Fluency as Measured by Retrieval Fluency Standard Scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Visual-spatial Reasoning as Measured by Visual Motor Integration (VMI) T-scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Neurocognitive Performance Related to Visual-spatial Reasoning as Measured by Visual Perception T-scores(Baseline, prior to maintenance therapy, completion of therapy, and 12 months, 24 months, 36 months, 48 months, and 60 months off therapy)
• Change in Neurostructure, Especially White Matter Volume and Integrity(From baseline (month 0) to 60 months (therapy duration lasted approximately 48 weeks or 11 months))
• Change in Quantitative Magnetic Resonance (MR) Measures in the Frontal Lobe(From baseline (month 0) to 60 months (therapy duration lasted approximately 48 weeks or 11 months))
• Change in Quantitative MR Measures in the Right Frontal-parietal Regions(From baseline (month 0) to 60 months (therapy duration lasted approximately 48 weeks or 11 months))