This phase Ib trial tests the safety and side effects of ERAS-801 in treating patients with isocitrate dehydrogenase (IDH) wildtype, epidermal growth factor receptor (EGFR) amplified or mutated grade IV glioblastoma or astrocytoma that can be removed by surgery (resectable) and that is growing, spreading, or getting worse (progressive) or that has come back after a period of improvement (recurrent). Glioblastoma is the most common brain cancer in adults and survival rates remain poor despite treatment including surgery, radiation and chemotherapy. EGFR is a protein found on the surface of some cells, to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of tumor cells, so these cells may divide excessively in the presence of epidermal growth factor. ERAS-801, an EGFR inhibitor that can penetrate the central nervous system, binds to the tumor cells that express EGFR and may help shrink or slow the growth of the tumor cells.
Patients must be 18 years of age or older on the day of signing informed consent
Patients must have histologically proven surgically accessible World Health Organization (WHO) grade IV glioblastoma/astrocytoma, which is progressive or recurrent following radiation therapy +/- chemotherapy
Patient tumor sample must have wild type IDH with evidence of EGFR mutation/amplification by Clinical Laboratory Improvement Act (CLIA)-certified laboratory assay
Patients may have had no more than two prior recurrences
Participants may not be receiving any other investigational agents
Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ERAS-801 are ineligible
Participants with prior therapy with EGFR inhibitors are ineligible because treatment with EGFR kinase inhibitors or other EGFR-targeted agents has the potential to deplete the tumor of EGFR-amplified or EGFR mutant cell populations and confound the evaluation of ERAS-801 effects on participants
Participants on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs. Patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of ERAS-801
Single group
Biospecimen Collection
Procedure/SurgeryUndergo urine, blood, and CSF sample collection
Echocardiography Test
Procedure/SurgeryUndergo ECHO
EGFR Inhibitor ERAS-801
DrugGiven PO
Fludeoxyglucose F-18
Other interventionGiven FDG
Magnetic Resonance Imaging
Procedure/SurgeryUndergo brain MRI
Positron Emission Tomography
Procedure/SurgeryUndergo FDG PET
Surgical Procedure
Procedure/SurgeryUndergo surgical resection
Incidence of adverse events
Adverse events will be described by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Will be presented using a 95% confidence interval and 2-sided p-value, combined with Bayesian posterior means and High Posterior Density intervals. Descriptive summaries and data visualization will be used
Fludeoxyglucose F-18 (FDG) tumor uptake
FDG positron emission tomography (PET), as measured by median normalized FDG standardized uptake value (SUV) within the contrast enhancing tumor, will be compared to estimate the change in FDG uptake in the tumor. A formal test for the mean difference will be based on a paired T-test. 95% confidence intervals will be used to quantify uncertainty in estimation
Change in glycolytic index (GI)
The GI measurement will be measured by the product of FDG PET SUV and potential of hydrogen (pH)-weighted chemical exchange saturation transfer (CEST)-spin-and-gradient echo (SAGE)- echoplanar imaging (EPI) and will be compared to estimate the change in GI in the tumor area as a surrogate for changes in glycolytic flux.
pH-weighted CEST-SAGE-EPI
Amine proton CEST-SAGE-EPI will be evaluated for change in acidity in the tumor. Continued monitoring for tumor acidity will occur throughout the study treatment cycles.
Level of ERAS-801
Blood, cerebrospinal fluid (CSF) and frozen tumor tissue will be collected to investigate the level of ERAS-801. Serial blood samples for determination of study drug and its metabolites in plasma will be taken at pre-dose on Day 1 of pre-surgery study treatment, on Day 8 of Pre-surgery study treatment, at the time of surgery and then at the beginning of each post-surgery treatment cycle (every 28 days). CSF will be collected at the time of surgery. Frozen tumor samples from the protocol on-study surgery will be collected at the time of the protocol surgery. Blood samples will be used to determine the drug concentration in the plasma. Any residual back-up samples may be used for additional exploratory biomarker research.
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Jonsson Comprehensive Cancer Center
Lead sponsor
National Institutes of Health (NIH)
Collaborator
United States Department of Defense
Collaborator
