This is a multi-site study of the pharmacodynamic effects and efficacy of metformin in children and young adults with recurrent or progressive Posterior Fossa Group A (PFA) ependymoma.
Participants must have recurrent or progressive posterior fossa A (PFA) ependymoma following surgery AND radiation treatment (RT).
Participants must have a diagnosis of PFA ependymoma. Any number of previous recurrences are permissible provided the participant meets other enrollment criteria.
Participants must have adequate tumor tissue available from initial diagnosis or from pre- trial enrollment. Formalin-fixed paraffin-embedded (FFPE) material (1 full block) should be provided. If FFPE material is not available, 10 unstained slides with an accompanying hematoxylin and eosin (H&E) report should be provided.
Participant must have measurable disease; this will be defined as lesions that can be accurately measured in two dimensions (longest diameter to be recorded) The size threshold is met if both in-plane diameters are ≥10 mm or both in-plane diameters are at least two times the MRI slice thickness, plus the interslice gap with a minimum size of no less than double the slice thickness on MRI.
Participants with a history of diabetes mellitus or those meeting criteria for pre-diabetes are excluded. Pre-diabetes is defined per American Diabetes Association criteria as any of the following: fasting plasma glucose (FPG) 100-125 mg/dL (5.6-6.9 mmol/L); 2-hour plasma glucose (OGTT) 140-199 mg/dL (7.8-11.0 mmol/L); or hemoglobin A1c (HbA1c) 5.7%-6.4% (39-47 mmol/mol).
Participants without any measurable disease.
Participants who have had chemotherapy or have received radiotherapy to the non-target lesion within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
Participants must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants should also be discussed with study chairs.
Sequential
Metformin
DrugGiven orally (PO)
Planned Surgical Resection
Procedure/SurgeryUndergo planned surgery as part of regular care
Magnetic Resonance Imaging (MRI)
Procedure/SurgeryUndergo MRI imaging
Specimen Collection
Procedure/SurgeryTumor Tissue, blood, and cerebral spinal fluid (CSF) may be collected for correlative analysis.
MR spectroscopy (MRS)
Procedure/SurgeryUndergo MRS imaging
Proportion of participants with changes in biomarkers between the pre-and post-metformin treated samples (Target Validation Phase)
Proportion of participants with a 10% reduction in Enhancer of Zeste Inhibitory Protein (EZHIP) and/or a 10% increase in the epigenetic modification to the DNA packaging protein histone H3, with tri-methylation of lysine 27 on histone H3 (H3K27me3) between the pre- and post-metformin treated samples by Immunohistochemistry (IHC).
Disease Stabilization Rate (Efficacy Phase)
The primary endpoint of the efficacy phase is the disease stabilization rate by RAPNO criteria (complete (CR), partial (PR); response \>50% reduction in size \< CR, and stable (SD) which is a \< 50% reduction in size and not meeting the definition for progressive disease) tumor responses), CR+PR+SD.
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University of California, San Francisco
Lead sponsor
The Lilabean Foundation, Inc.
Collaborator
Pediatric Neuro-Oncology Consortium
Collaborator
