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 gliosarcoma that can be removed by surgery (resectable) and that is growing, spreading, or getting worse (progressive), that has come back after a period of improvement (recurrent) or that is newly diagnosed in an elderly patient. 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/gliosarcoma, 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 with EGFR mutations in T790M or exon 20 will be excluded
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 such as EGFR kinase inhibitors or other EGFR-targeted agents that have the potential to deplete the tumor of EGFR-amplified or EGFR mutant cell populations and confound the evaluation of ERAS-801 effects on participants are ineligible. If a participant had received previous treatment with EGFR-targeted agents but tumor resection after completing this treatment still shows EGFR amplification, patient might still be eligible and should be discussed with the principal investigator (PI)
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
Parallel
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
Fludeoxyglucose F-18 (FDG) tumor uptake (Cohort A)
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. Analyses will be descriptive, summarizing changes with confidence intervals and exploring correlations; no formal hypothesis testing is planned.
Pharmacokinetics (PK) dose modification (Cohort B)
Will evaluate the effect of 120 mg twice daily dosing on corrected QT interval (QTc) relative to maximum concentration compared with historical 240 mg once-daily data. PK data and triplicate electrocardiograms will be summarized descriptively, with QTc analyzed as a continuous change.
6 month progression free survival (Cohort C)
Will be summarized as a proportion with corresponding 95% exact confidence intervals. Nominal exact two-sided p-values will be presented, testing EGFR inhibitor ERAS-801 against a fixed 5% null rate. Simon's minimax two-stage design will be used for conducting the trial.
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
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.
PK profile
PK concentration data will be summarized using appropriate summary statistics and further details will be provided.
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Jonsson Comprehensive Cancer Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
