Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer

Inclusion Criteria:

• Patients must have stage IV or recurrent/metastatic NSCLC and have progressed on orafter platinum-based chemotherapy and/or PD-(L)1 immune checkpoint inhibitor.Patients with autoimmune or other conditions where PD-(L)1 checkpoint inhibitors arecontraindicated are eligible with progression on or after platinum-basedchemotherapy or immunotherapy

• Dose escalation: patients with NSCLC known to harbor EGFR, ALK, ROS1, BRAF V600E/Kactivating mutations must have also progressed on appropriate Food and DrugAdministration (FDA)-approved targeted therapies to be eligible for dose escalation

• Dose expansion: patients must have stage IV or recurrent/metastatic NSCLC harboring

1. NFE2L2 mutations (LSCC); 2) KEAP1 mutations (LSCC); KRAS/KEAP1 or KRAS/NFE2L2co-mutations (non-squamous NSCLC); or 3) LSCC WT for NFE2L2 or KEAP1 who haveprogressed on or after platinum-based chemotherapy and/or PD (L)1 immune checkpointinhibitors or immunotherapy. Acceptable molecular testing includes Foundation ACTcirculating tumor deoxyribonucleic acid (ctDNA) or Guardant 360 ctDNA in plasma orFoundation One or Memorial Sloan Kettering Cancer Center (MSK)-Integrated MutationProfiling of Actionable Cancer Targets (IMPACT) in tumor tissue. Patients withautoimmune or other conditions where PD-(L)1 checkpoint inhibitors arecontraindicated are eligible with progression on or after platinum-basedchemotherapy or immunotherapy

• Eastern Cooperative Oncology Group (ECOG) - American College of Radiology ImagingNetwork (ACRIN) performance status 0-2

• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Fasting blood glucose (FBS) =< 130 and hemoglobin A1C (HGBA1C) =< 8.0% and fastingtriglycerides =< 300 mg/dL

• Tissue accessible for fine needle and/or core needle biopsy for molecular testing (for expansion cohorts only)

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN if liver metastases are present)

• Creatinine =< 1.3 mg/dL OR

• Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2

• Hemoglobin >= 9 g/dL (without transfusion within 1 week preceding study drugadministration)

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Because no dosing or adverse event data are currently available on the use of CB-839HCl (telaglenastat) in combination with MLN0128 (sapanisertib) in patients < 18years of age, children are excluded from this study, but will be eligible for futurepediatric trials

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with stable, treated, asymptomatic brain metastases (active brainmetastases) or leptomeningeal disease are eligible if the treating physiciandetermines that immediate CNS specific treatment is not required and is unlikely tobe required during the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Females of childbearing potential must have a negative pregnancy test (=< 14 days)prior to start of trial treatment

• Females who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 1 effectivemethod of contraception and 1 additional effective (barrier) method, atthe same time, from the time of signing the informed consent through 90days (or longer as mandated by local labeling [e.g. USPI, SmPC, etc])after the last dose of study drug, OR

• Agree to practice true abstinence, when this is in line with the preferredand usual lifestyle of the patient (Periodic abstinence [e.g. calendar,ovulation, symptothermal postovulation methods], withdrawal, spermicidesonly, and lactational amenorrhea are not acceptable methods ofcontraception. Female and male condoms should not be used together)

• Agree not to donate egg(s) during the course of this study or within 90days after receiving their last dose of study drug

• Male patients, even if surgically sterilized (i.e. status post vasectomy), mustagree to the following contraceptive requirements:

• Agree to practice highly effective barrier contraception during the entirestudy treatment period and through 120 days after the last dose of studydrug, OR

• Agree to practice true abstinence, when this is in line with the preferredand usual lifestyle of the patient (Periodic abstinence [e.g. calendar,ovulation, symptothermal postovulation methods], withdrawal, spermicidesonly, and lactational amenorrhea are not acceptable methods ofcontraception. Female and male condoms should not be used together)

• Agree not to donate sperm during the course of this study or within 120days after receiving their last dose of study drug

• The effects of CB-839 HCl (telaglenastat) and MLN0128 (sapanisertib)on the developing human fetus are unknown. For this reason, women ofchild-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control;abstinence) prior to study entry and for the duration of studyparticipation. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of studyparticipation, and 4 months after completion of CB-839 HCl (telaglenastat) administration

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who have had chemotherapy within 3 weeks or radiotherapy within 2 weeks (6weeks for nitrosoureas or mitomycin C) prior to entering the study

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to CB-839 HCl (telaglenastat) and MLN0128 (sapanisertib)

• CB-839 HCl (telaglenastat) is a weak in vitro inhibitor of CYP2C9. Therefore,patients receiving any medications or substances that are substrates of CYP2C9 areeligible, but should use caution with substrates that have a narrow therapeuticindex. Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference. As part of theenrollment/informed consent procedures, the patient will be counseled on the risk ofinteractions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because CB-839 HCl (telaglenastat) is anagent with the potential for teratogenic or abortifacient effects. Because there isan unknown but potential risk for adverse events (AEs) in nursing infants secondaryto treatment of the mother with CB-839 HCl (telaglenastat), breastfeeding should bediscontinued if the mother is treated with CB-839 HCl (telaglenastat). Thesepotential risks may also apply to MLN0128 (sapanisertib)

• Patients who are unable to swallow tablets

• Human immunodeficiency virus (HIV)-infected patients

• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GIdisease, or for an unknown reason that may alter the absorption of MLN0128 (sapanisertib). In addition, patients with enteric stomata are also excluded

• Significant active cardiovascular or pulmonary disease including:

• Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolicblood pressure > 95 mm Hg). Use of anti-hypertensive agents to controlhypertension before cycle 1 day 1 is allowed

• Pulmonary hypertension

• Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gasanalysis or pulse oximetry on room air

• Significant valvular disease; severe regurgitation or stenosis by imagingindependent of symptom control with medical intervention, or history of valvereplacement

• Medically significant (symptomatic) bradycardia

• History of arrhythmia requiring an implantable cardiac defibrillator

• Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeateddemonstration of QTc interval > 480 milliseconds, or history of congenital longQT syndrome, or torsades de pointes)

• Patients receiving systemic corticosteroids (either IV or oral steroids, excludinginhalers or low-dose hormone replacement therapy) within 1 week beforeadministration of the first dose of study drugs

• Patients who are taking proton pump inhibitors (PPIs) within 7 days of the firstdose of study drug or who require treatment with PPIs throughout the trial or thosewho are taking H2 receptor antagonists within 24 hours of the first dose of studydrug

• Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors orTORC1 inhibitors

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better