This phase 1b trial studies the side effects and best dose of telaglenastat in combination with radiation therapy and temozolomide in treating patients with IDH-mutated diffuse or anaplastic astrocytoma. Telaglenastat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving telaglenastat with radiation therapy and temozolomide may work better than surgery, radiation therapy, and temozolomide in treating patients with IDH-mutated diffuse astrocytoma or anaplastic astrocytoma.

PRIMARY OBJECTIVE:

I. Determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of telaglenastat (CB-839) hydrochloride (HCl) when combined with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed IDH-mutated diffuse astrocytoma (DA) and anaplastic astrocytoma (AA).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Determine the safety and tolerability of RT/TMZ/telaglenastat (CB-839) HCl in patients based on physician reported adverse event (AE) data.

III. Estimate the 2-year progression-free survival (PFS2) of RT/TMZ/telaglenastat (CB-839) HCl in patients with IDH-mutated glioma based on the Response Assessment in Neuro-Oncology (RANO) criteria.

IV. Estimate the 2-year overall survival (OS2) of RT/TMZ/telaglenastat (CB-839) HCl in patients with IDH-mutated glioma based on RANO criteria.

CORRELATIVE OBJECTIVES:

I. Determine the minor response rate (MRR) and clinical benefit rate (CBR) for the combination of telaglenastat (CB-839) HCl and RT/TMZ in IDH-mutated glioma based on RANO criteria.

II. Determine the patient-reported tolerability of RT/TMZ/telaglenastat (CB-839) HCl using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) instrument to measure self-reported symptom severity and interference with daily activities.

II. Determine the neurocognitive impact of telaglenastat (CB-839) HCl when used in combination with RT/TMZ.

III. Determine the effect of telaglenastat (CB-839) HCl/RT/TMZ on plasma oncometabolite levels of glutamine, glutamate, aspartate, asparagine, and 2-hydroxyglutarate (2-HG) in patients with IDH-mutated glioma and associate the changes with disease response.

IV. Determine the effect of telaglenastat (CB-839) HCl/RT/TMZ on tumor glutamine and glutamate MRS signals in patients with IDH-mutated glioma and associate the signal with disease response.

V. Determine the pharmacokinetics (PK) of telaglenastat (CB-839) HCl when used alone and in combination with TMZ.

VI. To perform molecular profiling assays on archived tumor tissue and peripheral blood, including, but not limited to, low-pass whole genome sequencing (WGS), whole exome sequencing (WES), and messenger ribonucleic acid (RNA) sequencing (RNA-Seq) in order to VIa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned.

VIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.

VII. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

VIII. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

OUTLINE: This is a dose escalation study of telaglenastat.

Patients receive telaglenastat orally (PO) twice daily (BID) 7 days a week, temozolomide PO once daily (QD) 7 days a week, and undergo RT 5 days a week for up to 5.5 weeks (diffuse astrocytoma) or 6.5 weeks (anaplastic astrocytoma) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Inclusion Criteria:

• Patients must have histopathologic or molecular confirmation of either IDH-mutant DA or IDH-mutant AA. Acceptable IDH mutations for study eligibility include any IDH1 mutation at codon 132 or any IDH2 mutation at codon 172.
• Age >= 16 years. The intended neurocognitive tests have not been validated in children below the age of 16.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%).
• Hemoglobin > 9.0 g/dL (within 14 days prior to registration)
• Leukocytes >= 3.0 x 10^9/L (within 14 days prior to registration)
• Absolute neutrophil count >= 1.5 x 10^9/L (within 14 days prior to registration)
• Platelets >= 100 x 10^9/L (within 14 days prior to registration)
• International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)
• Partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) =< 1.5 x ULN (within 14 days prior to registration)
• Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the investigator's discretion.
• Total bilirubin =< 1.5 x institutional ULN and < 3 mg/dL for patients with Gilbert's disease (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) & alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (within 14 days prior to registration)
• Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 60 mL/minute
• If there is history of human immunodeficiency virus (HIV) infection, patients must be on effective antiretroviral therapy and HIV viral load must be undetectable within 6 months of study enrollment.
• If there is history of chronic hepatitis B virus (HBV) infection, patients must have either been treated or are on suppressive therapy (as indicated), and HBV viral load must be undetectable.
• If there is history of hepatitis C virus (HCV) infection, patients must have been treated and HCV viral load must be undetectable.
• Patient must have measurable disease by RANO criteria (dose expansion cohort only).
• Patient must be at least 7 days beyond stereotactic biopsy and/or at least 14 days beyond open craniotomy at the time of registration.
• Patients must have been on a stable or decreasing dose of corticosteroids over the last 7 days at the time of registration.
• Patients must have been on a stable or decreasing dose of antiepileptic therapy over the last 14 days at the time of registration.
• Females of childbearing potential must have a negative pregnancy test (=< 14 days) prior to start of trial treatment. The effects of telaglenastat (CB-839) HCl on the developing human fetus are unknown. For this reason and because alkylating agents as well as TMZ are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is 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 4 months after completion of telaglenastat (CB-839) HCl administration.
• Ability to understand and the willingness to sign a written informed consent document.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better.
• Availability of archival FFPE tumor tissue collected within 12 months prior to registration.

Exclusion Criteria:

• Patients must not have received prior chemotherapy to treat the glioma.
• Patients who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to telaglenastat (CB-839) HCl or TMZ.
• Patient must not have received prior radiation therapy to the brain. Prior radiation therapy to the head and neck is also excluded if radiation fields overlap.
• No prior use of Gliadel wafers.
• Patient must have no evidence of either infratentorial or spinal involvement with tumor.
• Patients who are unable to swallow tablets.
• Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection.
• Patients with uncontrolled intercurrent illness.
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than 3 years.
• Pregnant women are excluded from this study because telaglenastat (CB-839) HCl is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with telaglenastat (CB-839) HCl, breastfeeding should be discontinued if the mother is treated with telaglenastat (CB-839) HCl. These potential risks may also apply to TMZ.
• Adolescent patients who require sedation for magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS).
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• The primary language of communication for the patient must be English (dose expansion cohort only). The intended neurocognitive tests have not been validated in patients who do not primarily speak English.