ERAS-801 for the Treatment of Resectable and Progressive or Recurrent or Elderly Newly Diagnosed IDH Wildtype Grade IV Glioblastoma or Gliosarcoma With an EGFR Amplification or Mutation, ERAS801-SARG Trial

Inclusion Criteria: * COHORT A: Patients must be 18 years of age or older on the day of signing informed consent * COHORT A: Patients must have histologically proven surgically accessible World Health Organization (WHO) grade IV glioblastoma/gliosarcoma, which is progressive or recurrent following radiation therapy +/- chemotherapy * COHORT A: 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 * COHORT A: Patients may have had no more than two prior recurrences * COHORT A: Patient must be able to tolerate MRIs. Pre-study enrollment MRIs must be available for central review, including at least the immediate pre-progression scan and the scan demonstrating progression. Patients must have measurable, by RANO, supratentorial contrast-enhancing progressive or recurrent high-grade glioma by MRI imaging within 28 days prior to enrollment * COHORT A: Patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible: * 12 weeks from the completion of radiation * 6 weeks from a nitrosourea chemotherapy * 3 weeks from a non-nitrosourea chemotherapy * 4 weeks from any investigational (not Food and Drug Administration \[FDA\]-approved) agents * 4 weeks from the last treatment with bevacizumab * 2 weeks from administration of a non-cytotoxic, FDA-approved agent other than bevacizumab (e.g., hydroxychloroquine, etc.) * 1 week from the tumor treating fields * COHORT A: Patients must be undergoing surgery that is clinically indicated as determined by their care providers. Patients must be eligible for surgical resection according to the following criteria: * Expectation that the surgeon can resect at least 500 mg of tumor from enhancing tumor and 100 mg from non-enhancing tumor (if available) with low risk of inducing neurological injury * COHORT A: Paraffin embedded tissue must be available from initial surgical resection at diagnosis (prior to any treatment). The following amount of tissue is requested: 1 formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 30 FFPE unstained slides (5µm thick) * COHORT A: Patients must have a Karnofsky performance status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others) * COHORT A: Absolute neutrophil count (ANC) ≥ 1000/uL * COHORT A: Platelets ≥ 100,000/uL * COHORT A: Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks * COHORT A: Creatinine ≤ 1 x upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 30 mL/min for participant with creatinine levels \> 1 x institutional ULN (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) * Creatinine clearance (CrCl) should be calculated per institutional standard * COHORT A: Total bilirubin ≤ 1.5 x ULN unless with Gilbert's syndrome * COHORT A: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x ULN * COHORT A: International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * COHORT A: Patients must have left ventricular ejection fraction (LVEF) within normal institutional limits within 21 days of starting treatment * COHORT A: Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment start with Fridericia's formula-corrected QT interval (QTcF) =\< 450 msec * COHORT A: Patients must be able to provide written informed consent * COHORT A: Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the first dose * COHORT A: Women of childbearing potential and men must agree to use adequate method of contraception for the duration of study participation and for at least 6 months after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after the last dose of study drug * COHORT A: Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, prostate, bladder or melanoma in situ. Patients with prior malignancies must be disease-free for \> three years * COHORT A: Patients must be able to swallow medication by mouth * COHORT B: Patients must be 18 years of age or older on the day of signing informed consent * COHORT B: Patients must have histologically proven WHO grade 4 glioblastoma/gliosarcoma, which is progressive or recurrent following radiation therapy +/- chemotherapy * COHORT B: Patient initial tumor sample must have wild type IDH with evidence of EGFR mutation/amplification by CLIA-certified laboratory assay. Patients with EGFR mutations in T790M or exon 20 will be excluded * COHORT B: Patients may have had no more than two prior recurrences * COHORT B: Patient must be able to tolerate MRIs. Pre-study enrollment MRIs must be available for central review, including at least the immediate pre-progression scan and the scan demonstrating progression. Patients must have measurable, by RANO, supratentorial contrast-enhancing progressive or recurrent high-grade glioma by MRI imaging within 14 days prior to enrollment * COHORT B: Patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible: * 12 weeks from the completion of radiation * 6 weeks from a nitrosourea chemotherapy * 3 weeks from a non-nitrosourea chemotherapy * 4 weeks from any investigational (not FDA-approved) agents * 4 weeks from the last treatment with bevacizumab * 2 weeks from administration of an anti-cancer, non-cytotoxic, FDA-approved agent other than bevacizumab (e.g., hydroxychloroquine, etc.) * 1 week from the tumor treating fields device(s) * COHORT B: Paraffin embedded tissue must be available from initial surgical resection at diagnosis. The following amount of tissue is requested: 1 formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 30 FFPE unstained slides (5um thick). * COHORT B: Patients must have a Karnofsky performance status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others) * COHORT B: Absolute neutrophil count (ANC) ≥ 1000/uL * COHORT B: Platelets ≥ 100000/uL * COHORT B: Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks * COHORT B: Creatinine \< 1.5 times ULN or measured or calculated creatinine clearance \> 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN (GFR can also be used in place of creatinine or CrCl) * Creatinine clearance (CrCl) should be calculated per institutional standard. * COHORT B: Total bilirubin ≤ 1.5 x ULN unless with Gilbert's syndrome * COHORT B: AST (SGOT) and ALT (SGPT) ≤ 3 x ULN * COHORT B: International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * COHORT B: Patients must have left ventricular ejection fraction (LVEF) within normal institutional limits within 21 days of starting treatment * COHORT B: Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment start with QTcF ≤ 450 msec * COHORT B: Patients must be able to provide written informed consent * COHORT B: Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the first dose * COHORT B: Women of childbearing potential and men must agree to use adequate method of contraception for the duration of study participation and for at least 6 months after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after the last dose of study drug * COHORT B: Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, prostate, bladder or melanoma in situ. Patients with prior malignancies must be disease-free for \> three years * COHORT B: Patients must be able to swallow medication by mouth * COHORT C: Patients must be ≥ 70 years of age at the time of informed consent, with a life expectancy \> 8 weeks * COHORT C: Patients must have histologically proven newly diagnosed WHO grade 4 glioblastoma/gliosarcoma * COHORT C: Patient initial tumor sample must have wild type IDH with evidence of EGFR mutation/amplification by CLIA-certified laboratory assay. Patients with EGFR mutations in T790M or exon 20 will be excluded * COHORT C: Patient must be able to tolerate MRIs. Pre-study enrollment MRIs must be available for central review, including the pre-surgery MRI and the immediate post-diagnostic surgery MRI. The immediate postoperative MRI is preferred but not required to occur within 96 hours of surgery. The patient must also have a baseline MRI within 14 days prior to enrollment. Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis. Enrollment is at least 2-4 weeks from prior surgery (if time is needed to be extended, PI approval needed) * COHORT C: Patients must have a Karnofsky performance status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others) * COHORT C: Absolute neutrophil count (ANC) ≥ 1000/uL * COHORT C: Platelets ≥ 100000/uL * COHORT C: Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks * COHORT C: Creatinine \< 1.5 times ULN OR measured or calculated creatinine clearance \> 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN (GFR can also be used in place of creatinine or CrCl) * Creatinine clearance (CrCl) should be calculated per institutional standard * COHORT C: Total bilirubin ≤ 1.5 x ULN unless with Gilbert's syndrome * COHORT C: AST (SGOT) and ALT (SGPT) ≤ 3 x ULN * COHORT C: International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * COHORT C: Paraffin embedded tissue must be available from initial surgical resection at diagnosis. The following amount of tissue is requested: 1 formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 30 FFPE unstained slides (5um thick) * COHORT C: Patients must have left ventricular ejection fraction (LVEF) within normal institutional limits within 21 days of starting treatment * COHORT C: Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment start with QTcF ≤ 450 msec * COHORT C: Patients must be able to provide written informed consent * COHORT C: Men treated or enrolled on this protocol who has a partner with reproductive potential must agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after the last dose of study drug * COHORT C: Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, prostate, bladder or melanoma in situ. Patients with prior malignancies must be disease-free for \> three years * COHORT C: Patients must be able to swallow medication by mouth Exclusion Criteria: * COHORT A: Participants may not be receiving any other investigational agents * COHORT A: Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ERAS-801 are ineligible * COHORT A: 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) * COHORT A: 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 * COHORT A: Participants must not have evidence of significant hematologic, renal, or hepatic dysfunction * COHORT A: Participants must not have evidence of significant intracranial hemorrhage * COHORT A: Participants with clinically significant cardiovascular disease including, but not limited to: * Myocardial infarction or unstable angina within the 6 months prior to the first dose of study drug * Clinically significant cardiac arrhythmia * Prolonged QTcF \> 450 ms * Uncontrolled (persistent) hypertension: systolic blood pressure \> 180 mmHg; diastolic blood pressure \> 100 mmHg * Congestive heart failure (New York Heart Association class III-IV) * Use of pacemaker * Pulmonary embolism \< 30 days * COHORT A: Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible * COHORT A: Pregnant women are excluded from this study because ERAS-801 has unknown potential for teratogenic or abortifacients effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ERAS-801, breastfeeding should be discontinued if the mother is treated with ERAS-801 * COHORT A: Participants currently using or anticipating need to use drugs, food, or herbal supplements known to be strong or moderate inducers or inhibitors of CYP3A4, CYP2C8, and/or CYP2D6 and P-glycoprotein (P-gp) substrates may be enrolled if they have been off the substrates for at least 10 days or 5 half-lives prior to the first dose of ERAS 801, whichever is shorter * COHORT A: Participants who have acute or currently active/requiring anti-viral therapy hepatic or biliary disease are ineligible (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, or stable chronic liver disease per investigator assessment) * COHORT A: Patients with gastrointestinal conditions that may affect reliable administration/absorption of medications including difficulty swallowing/unable to swallow pills; malabsorption syndrome; refractory nausea and vomiting, chronic gastrointestinal (GI) disease or previous significant bowel resection with clinically significant sequelae are ineligible * COHORT A: Participants receiving P-gp inhibitors are ineligible * COHORT A: Patients who have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial are ineligible * COHORT B: Participants may not be receiving any other investigational agents * COHORT B: Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ERAS-801 are ineligible * COHORT B: 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 PI * COHORT B: 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 * COHORT B: Participants must not have evidence of significant hematologic, renal, or hepatic dysfunction * COHORT B: Participants must not have evidence of significant intracranial hemorrhage * COHORT B: Participants with clinically significant cardiovascular disease including, but not limited to: * Myocardial infarction or unstable angina within the 6 months prior to the first dose of study drug * Clinically significant cardiac arrhythmia * Prolonged QTcF\> 450 ms * Uncontrolled (persistent) hypertension: systolic blood pressure \> 180 mmHg; diastolic blood pressure \> 100 mmHg * Congestive heart failure (New York Heart Association class III-IV) * Use of pacemaker * Pulmonary embolism \< 30 days * COHORT B: Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible * COHORT B: Pregnant women are excluded from this study because ERAS-801 has unknown potential for teratogenic or abortifacients effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ERAS-801, breastfeeding should be discontinued if the mother is treated with ERAS-801 * COHORT B: Participants currently using or anticipating need to use drugs, food, or herbal supplements known to be strong or moderate inducers or inhibitors of CYP3A4, CYP2C8, and/or CYP2D6 and P-gp substrates may be enrolled if they have been off the substrates for at least 10 days or 5 half-lives prior to the first dose of ERAS 801, whichever is shorter * COHORT B: Participants who have acute or currently active/requiring anti-viral therapy hepatic or biliary disease are ineligible (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, or stable chronic liver disease per investigator assessment) * COHORT B: Patients with gastrointestinal conditions that may affect reliable administration/absorption of medications including difficulty swallowing/unable to swallow pills; malabsorption syndrome; refractory nausea and vomiting, chronic gastrointestinal (G