Clinical Trials /

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

NCT03831932

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Glutaminase Inhibitor CB-839 Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer
  • Official Title: A Phase I/II Study of AZD9291 (Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00572
  • SECONDARY ID: NCI-2019-00572
  • SECONDARY ID: 10216
  • SECONDARY ID: 10216
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT03831932

Conditions

  • Advanced Lung Carcinoma
  • EGFR Activating Mutation
  • EGFR Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.L858R
  • EGFR T790M Mutation Negative
  • Lung Non-Small Cell Carcinoma
  • Metastatic Lung Carcinoma
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
Glutaminase Inhibitor CB-839CB-839Treatment (CB-839 HCl, osimertinib)
Glutaminase Inhibitor CB-839 HydrochlorideCB-839 HClTreatment (CB-839 HCl, osimertinib)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (CB-839 HCl, osimertinib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CB-839 HCl, osimertinib)ExperimentalPatients receive glutaminase inhibitor CB-839 hydrochloride PO BID and osimertinib PO QD (starting cycle 1 day 16 of phase I). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Glutaminase Inhibitor CB-839
  • Glutaminase Inhibitor CB-839 Hydrochloride
  • Osimertinib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose (RP2D) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).

Secondary Outcome Measures

Measure:Dose limiting toxicities (DLT) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Progression-free survival (PFS) (Phase II)
Time Frame:From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy
Safety Issue:
Description:Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Measure:Overall survival (OS) (Phase II)
Time Frame:From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy
Safety Issue:
Description:Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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