| Eligibility |
Inclusion Criteria:
- Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease
- Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in
combination with other EGFR mutations) as per local assessment of a tissue
biopsy/cytology specimen. The tissue biopsy must have been obtained since the time of
disease progression on most recent targeted therapy. "Liquid" biopsies (i.e. blood
based) biopsies cannot be used for eligibility determination
- Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib,
erlotinib, afatinib, or osimertinib). There is no limit to lines of prior tyrosine
kinase inhibitor (TKI) therapy. Prior osimertinib (AZD9291) therapy is permitted
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam
- Age > 18 years. NSCLC is exceedingly rare in patients < 18 years of age. Because no
dosing or adverse event (AE) data are currently available on the use of telaglenastat
(CB-839) HCl in combination with osimertinib (AZD9291) in patients < 18 years of age,
children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Must be able to swallow pills
- Life expectancy > 3 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 90 g/L
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) and up to 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])
=< 2.5 x institutional ULN and =< 5 x institutional ULN for patients with liver
metastases
- Creatinine within 1.5 x ULN OR
- Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (measured or calculated by
Cockcroft and Gault equation) - confirmation of creatinine clearance is only required
for patients with creatinine levels above institutional upper limit of normal
- Should participants with hepatitis B virus (HBV) infection be included, patients are
only eligible if they meet all the following criteria:
- Demonstrated absence of hepatitis C virus (HCV) co-infection or history of HCV
co-infection
- Demonstrated absence of human immunodeficiency virus (HIV) infection
- Participants with active HBV infection are eligible if they are:
- Receiving anti-viral treatment for at least 6 weeks prior to study
treatment, HBV DNA is suppressed to <100 IU/mL and transaminase levels are
below ULN. Participants with a resolved or chronic infection HBV are
eligible if they are:
- Negative for hepatitis B surface antigen (HBsAg) and positive for
hepatitis B core antibody [anti-HBc IgG]. In addition, patients must be
receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment
and 6-12 months (To be determined [TBD] by hepatologist) post treatment
OR
- Positive for HBsAg, but for > 6 months have had transaminases levels
below ULN and HBV DNA levels below <100 IU/mL (i.e., are in an inactive
carrier state). In addition, patients must be receiving anti-viral
prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD
by hepatologist) post treatment
- If history of hepatitis C virus (HCV) infection, must be treated and have an
undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS) - directed therapy shows no evidence of progression
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required and is unlikely to be required during
the first cycle of therapy. Patients on corticosteroids for the treatment of brain
metastases will be permitted as long as the dose is =< 10 mg of prednisone-equivalent
and has not been increased within 2 weeks of screening
- 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
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
- EXPANSION COHORT: Patients must have had progressive disease on prior first line EGFR
inhibitor therapy with osimertinib
Exclusion Criteria:
- Patients who have not recovered from AEs due to prior systemic anti-cancer therapy
(i.e., have residual toxicities > grade 1), with the exception of alopecia. Note:
Subjects with irreversible toxicity that in the opinion of the treating physician is
not reasonably expected to be exacerbated by the investigational treatment may be
included (e.g., hearing loss, hormone deficiency requiring replacement therapy)
- Previous enrollment in the present study
- Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis requiring steroid treatment, or any evidence of
clinically active interstitial lung disease
- Patients who are receiving any other investigational agent within five half-lives of
the compound or 3 months, whichever is greater. Patients who have received prior
immunotherapy may be included only if time from last immunotherapy is at least 3
months (i.e. 90 days)
- Spinal cord compression, symptomatic and unstable brain metastases except for those
patients who have completed definitive therapy, and have had a stable neurological
status for at least 2 weeks after completion of definitive therapy. Patients may be on
corticosteroids (=< 10 mg of prednisone-equivalent) to control brain metastases if
they have been on a stable dose for 2 weeks (14 days) prior to the start of study
treatment and are clinically asymptomatic
- Patients with an uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to telaglenastat (CB-839) HCl, osimertinib (AZD9291), or other agents used
in study. Patients with hypersensitivity to to any of the inactive excipients thereof
should also be excluded
- Currently receiving (or unable to stop use prior to receiving the first dose of study
treatment) medications or herbal supplements known to be potent inducers of CYP3A4
(wash-out periods vary). All patients must try to avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known inducer effects
on CYP3A4
- Pregnant women are excluded from this study because telaglenastat (CB-839) HCl is a
glutaminase inhibitor 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 and osimertinib (AZD9291),
breastfeeding should be discontinued if the mother is treated with telaglenastat
(CB-839) HCl and osimertinib (AZD9291). Breastfeeding patients will be excluded. These
potential risks may also apply to other agents used in this study
- Patients with a significant history of cardiovascular disease (e.g., myocardial
infarction [MI], thrombotic or thromboembolic event in the last 6 months)
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470
msec (Fridericia's Criteria for Corrected QT interval [QTc] Calculation:
Fridericia's formula QTcF = (QT/RR 0.33). RR is the time from the interval of 1
QRS complex to the next measured in seconds and is commonly calculated as (60/HR)
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third
degree heart block, second degree heart block)
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, electrolyte abnormalities (including: Serum/plasma
potassium < lower limit of normal (LLN); serum/plasma magnesium < LLN;
serum/plasma calcium < LLN , congenital long QT syndrome, family history of long
QT syndrome or unexplained sudden death under 40 years of age in first degree
relatives, or any concomitant medication known to prolong the QT interval and
cause Torsades de Pointes
- Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) as
assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO)
- Patients with active malignancies other than NSCLC or patients with prior curatively
treated malignancy at high risk of relapse during the study period with the exception
of localized squamous or basal cell skin cancers, ductal carcinoma in-situ (DCIS), or
indolent cancer currently on observation (i.e. chronic lymphocytic leukemia [CLL] or
low-risk prostate cancer)
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the patient to participate in the trial or which would jeopardize
compliance with the protocol, or active infection with human immunodeficiency virus
(HIV). Screening for chronic conditions is not required
- Patients with symptomatic CNS metastases who are neurologically unstable
- Patients who are at risk for impaired absorption of oral medication including, but not
limited to, refractory nausea and vomiting, chronic gastrointestinal diseases,
inability to swallow the formulated product or previous significant bowel resection
that would preclude adequate absorption of telaglenastat (CB-839) HCl and osimertinib
(AZD9291)
- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirements
- Involvement in the planning and/or conduct of the study (applies to both investigator
staff and/or staff at the study site)
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