This phase I/II trial tests the safety, side effects best dose and how well giving fluorouracil and tretinoin along with standard of care radiation therapy works for the treatment of high risk posterior fossa ependymoma that has not spread to other parts of the body (localized). Fluorouracil is a type medication called an antimetabolite. It works by stopping cells from making DNA and it may kill tumor cells. Tretinoin, also called all-trans retinoic acid (ATRA), retinoic acid, and vitamin A acid is in a class of medications called retinoids. It is made in the body from vitamin A and helps cells to grow and develop, especially in the embryo. Laboratory made form of tretinoin works by slowing or stopping the growth of tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Giving fluorouracil and tretinoin along with standard of care radiation therapy may be safe, tolerable and/or effective in treating patients with localized high risk posterior fossa ependymoma.
PRE-ENROLLMENT: Patients must be > 12 months and < 21 years of age at the time of enrollment
PRE-ENROLLMENT: Patient has newly diagnosed posterior fossa ependymoma based on institutional pathologic diagnosis
PRE-ENROLLMENT: The patient and/or their parents or legal guardians must have signed informed consent for APEC14B1 Part A - Eligibility Screening
PRE-ENROLLMENT: If relying on APEC14B1-MCI for molecular characterization, required specimens for molecular characterization should be submitted as soon as possible, preferably within 5 calendar days of definitive surgery
Patients with metastatic disease by either MRI evaluation or lumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
Hypersensitivity to fluorouracil, tretinoin, other retinoids, or any component of the formulation
Personal history of Torsades de pointes, atrial fibrillation, supraventricular tachycardia (SVT), or heart failure; personal history of prolonged QT Syndrome; other uncontrolled arrhythmia in the past 6 months prior to study enrollment
Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
Single group
Biospecimen Collection
Procedure/SurgeryUndergo blood and CSF sample collection
Echocardiography Test
Procedure/SurgeryUndergo echocardiography
Fluorouracil
DrugGiven IV
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA scan
Radiation Therapy
RadiationUndergo standard of care radiation therapy
Tretinoin
DrugGiven PO
Occurrence of dose limiting toxicity chemoradiotherapy (DLT) (phase 1)
Will report the sample proportion of analysis patients experiencing DLTs with binominal exact 95% confidence intervals by dose level. Other toxicity data will also be described as appropriate for supportive analyses.
Occurrence of DLT for maintenance therapy (phase 1)
Will report the sample proportion of analysis patients experiencing DLTs with binominal exact 95% confidence intervals by dose level. Other toxicity data will also be described as appropriate for supportive analyses. A planned supportive analysis will descriptively assess any interaction between increasing chemoradiotherapy dose and maintenance therapy tolerability.
Event free survival (EFS)
Will test whether the EFS in the prospective patients is superior to the historical control using a stratified log-rank test adjusting for resection status (subtotal resection \[STR\] or gross total resection/near total resection GTR/NTR\]) with a one-sided type-1 error rate of 0.10. The primary analysis will also report the Kaplan-Meier estimates of the prospective and historical control patients. Planned supportive analyses will assess whether EFS differs by resection status within the prospective patients, and conduct separate resection status-specific comparisons between the prospective and corresponding historical control patients. These analyses will use unadjusted log-rank tests.
Overall response
STR patients will be analyzed separately from GTR/NTR patients, as GTR/NTR patients are only evaluable for experiencing progressive disease. Analyses will also be reported separately by dose level. We will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals.
Overall survival
Will be summarized by the Kaplan Meyer method with similar considerations for the analysis population and intercurrent events as for EFS.
Correlate presence of tumor cell free deoxyribonucleic acid (DNA) with methylation profiling and clinical outcome
Will explore the associations between tumor cell free DNA and EFS using Cox models. Initial analyses will use univariable models, and suitable multivariable models will be considered, subject to data constraints (e.g., number of events).Cox models incorporating these covariates as baseline covariates will be used for covariates available at the time of enrollment, and landmark analyses or time-varying covariates will be used for analyses with post-enrollment covariates.
Correlate histopathologic grade with clinical outcome
Will explore the associations between histopathologic grade and EFS using Cox models. Initial analyses will use univariable models, and suitable multivariable models will be considered, subject to data constraints (e.g., number of events).Cox models incorporating these covariates as baseline covariates will be used for covariates available at the time of enrollment, and landmark analyses or time-varying covariates will be used for analyses with post-enrollment covariates.
Correlate gene expression profiles with clinical outcome
Will explore the associations between gene expression profiles and EFS using Cox models. Initial analyses will use univariable models, and suitable multivariable models will be considered, subject to data constraints (e.g., number of events).Cox models incorporating these covariates as baseline covariates will be used for covariates available at the time of enrollment, and landmark analyses or time-varying covariates will be used for analyses with post-enrollment covariates.
Correlate epigenetic profiles with clinical outcome
Will explore the associations between epigenetic profiles and EFS using Cox models. Initial analyses will use univariable models, and suitable multivariable models will be considered, subject to data constraints (e.g., number of events).Cox models incorporating these covariates as baseline covariates will be used for covariates available at the time of enrollment, and landmark analyses or time-varying covariates will be used for analyses with post-enrollment covariates.
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