Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: Glutaminase Inhibitor CB-839 Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer

Summary: This phase I/II trial studies the side effects and best dose of glutaminase inhibitor CB-839 hydrochloride, and to see how well it works when given together with osimertinib in treating patients with stage IV non-small cell lung cancer and a mutation in the EGFR gene. Glutaminase inhibitor CB-839 hydrochloride and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVES:
  I. To assess the safety and tolerability of osimertinib (AZD9291) and glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) and determine the recommended phase II dose (RP2D) in patients with metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC). (Phase I) II. To determine the efficacy of AZD9291 and CB-839 HCl in patients with metastatic, EGFR activating mutation-positive, T790M mutation-negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy, as defined by response rate (RR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. (Phase II)
  SECONDARY OBJECTIVES:
  I. To determine toxicity profile of the combination of AZD9291 and CB-839 HCl in patients with metastatic EGFR activating mutation positive NSCLC. (Phase I) II. To assess the pharmacokinetics (PK) of CB-839 HCl and AZD9291 in patients with metastatic EGFR activating mutation positive. (Phase I) III. To determine the progression free survival (PFS) of AZD9291 and CB-839 HCl in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy. (Phase II) IV. To determine the overall survival (OS) of AZD9291 and CB-839 HCl in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed PD on front-line EGFR inhibitor therapy. (Phase II)
  EXPLORATORY/CORRELATIVE OBJECTIVES:
  I. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with response to treatment as well as disease progression (EGFR sensitizing mutations, T790M resistance mutation, recognized bypass mechanisms). (Phase II) II. To assess circulating levels of glutamine, glutamate, aspartate and asparagine, and measure changes with response to treatment as well as disease progression. (Phase II) III. To assess 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) parameters at baseline and after treatment to evaluate changes with response to treatment as well as emergence of disease resistance or progression. (Phase II - select patients) IV. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing (RNAseq), in order to identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned.
  V. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and RNA sequencing (RNAseq), in order to identify resistance mechanisms using genomic DNA- and RNA-based assessment platforms.
  OUTLINE: This is a phase I, dose-escalation study of glutaminase inhibitor CB-839 hydrochloride followed by a phase II study.
  Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) twice daily (BID) and osimertinib PO once daily (QD) (starting cycle 1 day 16 of phase I). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up at 30 days.

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 specimen. The tissue biopsy must have been obtained since the time of disease progression on prior therapy. Liquid biopsies cannot be used for eligibility determination
  -  Must be T790M mutation negative as determined by local Clinical Laboratory Improvement Amendments (CLIA)-certified assessment of a tissue biopsy obtained after progression on front-line therapy
  -  Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib, erlotinib, afatinib). There is no limit to lines of prior tyrosine kinase inhibitor (TKI) therapy. Prior AZD9291 (osimertinib) therapy is not 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
  -  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 CB-839 HCl in combination with 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
  -  If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
  -  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
  Exclusion Criteria:
  -  Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia
  -  Previous enrollment in the present study or previous treatment with AZD9291
  -  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 should also be excluded
  -  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 CB-839 HCl, AZD9291, or other agents used in study. Patients with hypersensitivity 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 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 CB-839 HCl and AZD9291, breastfeeding should be discontinued if the mother is treated with CB-839 HCl and 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, hypokalemia, 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
  -  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 CB-839 HCl and 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)
  -  PHASE 2:
  -  Prior chemotherapy for NSCLC is not permitted

Relevance to patient case: not relevant