CB-839 With Radiation Therapy and Temozolomide in Treating Participants With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of
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/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/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/CB-839 HCl in patients with
IDH-mutated glioma based on RANO criteria.

CORRELATIVE OBJECTIVES:

I. Determine the patient-reported tolerability of RT/TMZ/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 CB-839 HCl when used in combination with RT/TMZ.

III. Determine the effect of 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 CB-839 HCl/RT/TMZ on tumor 2-HG, glutamine, and glutamate MRS
signals in patients with IDH-mutated glioma and associate the signal with disease response.

V. Determine the pharmacokinetics (PK) of 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 RNA sequencing (RNA-Seq) in order to identify potential predictive and
prognostic biomarkers beyond any genomic alteration by which treatment may be assigned, and
identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and ribonucleic
acid (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 CB-839.

Participants receive CB-839 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, participants 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

- Leukocytes >= 3.0 x 10^9/L

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN)

- Partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) =<
1.5 x ULN

- 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

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) &
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
institutional ULN

- 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.

- Patients must have been on a stable or decreasing dose of corticosteroids over the
last 7 days.

- Patients must have been on a stable or decreasing dose of antiepileptic therapy over
the last 14 days.

- Females of childbearing potential must have a negative pregnancy test (=<14 days)
prior to start of trial treatment. The effects of 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 CB-839 HCl
administration.

- Ability to understand and the willingness to sign a written informed consent document.

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 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.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- 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 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
CB-839 HCl, breastfeeding should be discontinued if the mother is treated with CB-839
HCl. These potential risks may also apply to TMZ.