CB-839 With Radiation Therapy and Temozolomide in Treating Patients With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma
CB-839 With Radiation Therapy and Temozolomide in Treating Patients With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma
This phase 1b trial studies the side effects and best dose of glutaminase inhibitor CB-839
 hydrochloride (CB-839) in combination with radiation therapy and temozolomide in treating
 patients with IDH-mutated diffuse or anaplastic astrocytoma. CB-839 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 CB-839 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
 CB-839 hydrochloride (HCl) (telaglenastat) 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 (telaglenastat) 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
 (telaglenastat) 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 (telaglenastat) 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 CB-839 HCl (telaglenastat) and RT/TMZ in IDH-mutated glioma based on RANO
 criteria.

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

 III. Determine the effect of CB-839 HCl (telaglenastat)/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 (telaglenastat)/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 CB-839 HCl (telaglenastat) 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 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
 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.

 Patients receive CB-839 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

 -  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 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 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
 (telaglenastat) 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 CB-839 HCl (telaglenastat) 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 CB-839 HCl (telaglenastat) 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 (telaglenastat), breastfeeding should be discontinued if the
 mother is treated with CB-839 HCl (telaglenastat). 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.