Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03831932
Recruitment Status : Recruiting
First Posted : February 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
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 Drug: Glutaminase Inhibitor CB-839 Drug: Glutaminase Inhibitor CB-839 Hydrochloride Drug: Osimertinib Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of osimertinib (AZD9291) and glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) (telaglenastat) 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 (telaglenastat) 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 (telaglenastat) in patients with metastatic EGFR activating mutation positive NSCLC. (Phase I) II. To assess the pharmacokinetics (PK) of CB-839 HCl (telaglenastat) 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 (telaglenastat) 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 (telaglenastat) 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:

IVa. To identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned.

IVb. 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of AZD9291(Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer
Actual Study Start Date : May 2, 2019
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Treatment (CB-839 HCl, osimertinib)
Patients 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.
Drug: Glutaminase Inhibitor CB-839
Given PO
Other Name: CB-839

Drug: Glutaminase Inhibitor CB-839 Hydrochloride
Given PO
Other Name: CB-839 HCl

Drug: Osimertinib
Given PO
Other Names:
  • AZD-9291
  • AZD9291
  • Mereletinib
  • Tagrisso




Primary Outcome Measures :
  1. Recommended phase II dose (RP2D) (Phase I) [ Time Frame: Up to 28 days ]
  2. Objective response rate (ORR) (Phase II) [ Time Frame: Up to 30 days after completion of therapy ]
    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 :
  1. Dose limiting toxicities (DLT) (Phase I) [ Time Frame: Up to 28 days ]
    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.

  2. 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 ]
    Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

  3. 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 ]
    Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.


Other Outcome Measures:
  1. Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl) (Phase I) [ Time Frame: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle ]
    Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

  2. Post-AZD9291 PK (Phase I) [ Time Frame: Day 2 of cycle 2 and day 1 of each subsequent cycle ]
    Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

  3. Change in EGFR mutational status (Phase II) [ Time Frame: Baseline up to disease progression, assessed up to 30 days after completion of therapy ]
    Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

  4. Change in circulating levels of glutamine, glutamate, aspartate, and asparagine (Phase II) [ Time Frame: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy ]
    Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

  5. Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging (Phase II) [ Time Frame: Baseline up to 2 cycles of treatment ]
    Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (telaglenastat) 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. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

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 (telaglenastat), 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 (telaglenastat) 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 (telaglenastat) and AZD9291, breastfeeding should be discontinued if the mother is treated with CB-839 HCl (telaglenastat) 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 (telaglenastat) 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03831932


Locations
Layout table for location information
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Dwight H. Owen         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Dwight H Owen Ohio State University Comprehensive Cancer Center LAO

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03831932     History of Changes
Other Study ID Numbers: NCI-2019-00572
NCI-2019-00572 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10216 ( Other Identifier: Ohio State University Comprehensive Cancer Center LAO )
10216 ( Other Identifier: CTEP )
UM1CA186712 ( U.S. NIH Grant/Contract )
First Posted: February 6, 2019    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action