Clinical Trials /

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

NCT04250545

Description:

This phase I/Ib trial studies the side effects and best dose of CB-839 HCl when given together with sapanisertib in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced). CB-839 HCl and sapanisertib 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

Trial Eligibility

Document

Title

  • Brief Title: Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer
  • Official Title: A Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Advanced NSCLC Patients

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-00478
  • SECONDARY ID: NCI-2020-00478
  • SECONDARY ID: PHI-113
  • SECONDARY ID: 10327
  • SECONDARY ID: 10327
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT04250545

Conditions

  • Leptomeningeal Neoplasm
  • Metastatic Lung Non-Small Cell Carcinoma
  • Metastatic Malignant Neoplasm in the Brain
  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (CB-839 HCl, sapanisertib)
Telaglenastat HydrochlorideCB-839 HCl, Glutaminase Inhibitor CB-839 HydrochlorideTreatment (CB-839 HCl, sapanisertib)

Purpose

This phase I/Ib trial studies the side effects and best dose of CB-839 HCl when given together with sapanisertib in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced). CB-839 HCl and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the safety and tolerability of glutaminase inhibitor CB-839 hydrochloride
      (CB-839 HCl) (telaglenastat) in combination with MLN0128 (sapanisertib) and determine the
      recommended phase 2 dose (RP2D) of the combination.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To examine preliminary efficacy of CB-839
      HCl (telaglenastat) and MLN0128 (sapanisertib) in squamous cell lung cancers (LSCC) and in
      select, molecularly-defined non-small cell lung cancer (NSCLC) cohorts.

      IIa. To evaluate the objective response rate (ORR), progression-free survival (PFS), and
      disease control rate (DCR) of patients treated with CB-839 HCl (telaglenastat) and MLN0128
      (sapanisertib).

      EXPLORATORY OBJECTIVES:

      I. To correlate genomic and metabolomic signatures with response. II. To evaluate metabolic
      response (18Glutamine [GLN]-positron emission tomography [PET]/computed tomography [CT];
      18Fluorodeoxyglucose [FDG]-PET/CT) in NSCLC tumors treated with CB-839 HCl (telaglenastat)
      and MLN0128 (sapanisertib) in the dose expansion.

      OUTLINE: This is a dose-escalation study of glutaminase inhibitor CB-839 hydrochloride.

      Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) twice daily (BID) and
      sapanisertib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up quarterly.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CB-839 HCl, sapanisertib)ExperimentalPatients receive glutaminase inhibitor CB-839 hydrochloride PO BID and sapanisertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sapanisertib
  • Telaglenastat Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

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

          -  Dose escalation: patients with NSCLC known to harbor EGFR, ALK, ROS1, BRAF V600E/K
             activating mutations must have also progressed on appropriate Food and Drug
             Administration (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/NFE2L2
             co-mutations (non-squamous NSCLC); or 3) LSCC WT for NFE2L2 or KEAP1 who have
             progressed on or after platinum-based chemotherapy and/or PD (L)1 immune checkpoint
             inhibitors or immunotherapy. Acceptable molecular testing includes Foundation ACT
             circulating tumor deoxyribonucleic acid (ctDNA) or Guardant 360 ctDNA in plasma or
             Foundation One or Memorial Sloan Kettering Cancer Center (MSK)-Integrated Mutation
             Profiling of Actionable Cancer Targets (IMPACT) in tumor tissue. Patients with
             autoimmune or other conditions where PD-(L)1 checkpoint inhibitors are contraindicated
             are eligible with progression on or after platinum-based chemotherapy or immunotherapy

          -  Eastern Cooperative Oncology Group (ECOG) - American College of Radiology Imaging
             Network (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 fasting
             triglycerides =< 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 drug
             administration)

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

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

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

          -  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 stable, treated, asymptomatic 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 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

          -  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 effective method
                       of contraception and 1 additional effective (barrier) method, at the same
                       time, from the time of signing the informed consent through 90 days (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 preferred
                       and usual lifestyle of the patient (Periodic abstinence [e.g. calendar,
                       ovulation, symptothermal postovulation methods], withdrawal, spermicides
                       only, and lactational amenorrhea are not acceptable methods of
                       contraception. Female and male condoms should not be used together)

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

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

                    -  Agree to practice highly effective barrier contraception during the entire
                       study treatment period and through 120 days after the last dose of study
                       drug, OR

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

                    -  Agree not to donate sperm during the course of this study or within 120 days
                       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 of
                            child-bearing potential and men must agree to use adequate
                            contraception (hormonal or barrier method of birth control; abstinence)
                            prior to study entry and for the duration of study participation.
                            Should a woman become pregnant or suspect she is pregnant while she or
                            her partner is participating in this study, she should inform her
                            treating physician immediately. Men treated or enrolled on this
                            protocol must also agree to use adequate contraception prior to the
                            study, for the duration of study participation, and 4 months after
                            completion of CB-839 HCl (telaglenastat) administration

          -  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 had chemotherapy within 3 weeks or radiotherapy within 2 weeks (6
             weeks 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 or biologic
             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 are eligible,
             but should use caution with substrates that have a narrow therapeutic index. Because
             the lists of these agents are constantly changing, it is important to regularly
             consult a frequently-updated medical reference. As part of the enrollment/informed
             consent procedures, the patient will be counseled on the risk of interactions with
             other agents, and what to do if new medications need to be prescribed or if the
             patient is considering a new over-the-counter medicine or herbal product

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because CB-839 HCl (telaglenastat) is an
             agent with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk for adverse events (AEs) in nursing infants secondary to
             treatment of the mother with CB-839 HCl (telaglenastat), breastfeeding should be
             discontinued if the mother is treated with CB-839 HCl (telaglenastat). These potential
             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, GI
             disease, 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, diastolic
                  blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control
                  hypertension before cycle 1 day 1 is allowed

               -  Pulmonary hypertension

               -  Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas
                  analysis or pulse oximetry on room air

               -  Significant valvular disease; severe regurgitation or stenosis by imaging
                  independent of symptom control with medical intervention, or history of valve
                  replacement

               -  Medically significant (symptomatic) bradycardia

               -  History of arrhythmia requiring an implantable cardiac defibrillator

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

          -  Patients receiving systemic corticosteroids (either IV or oral steroids, excluding
             inhalers or low-dose hormone replacement therapy) within 1 week before administration
             of the first dose of study drugs

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

          -  Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or
             TORC1 inhibitors

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

Primary Outcome Measures

Measure:Maximum tolerated dose/recommended phase II dose of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in combination (dose-escalation)
Time Frame:Up to 28 days
Safety Issue:
Description:Will be evaluated according to dose-limiting toxicities during cycle 1 graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 27 months
Safety Issue:
Description:ORR will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Measure:PFS
Time Frame:Up to 27 months
Safety Issue:
Description:Will be evaluated by Kaplan-Meier estimates.
Measure:Disease control rate (DCR)
Time Frame:Up to 27 months
Safety Issue:
Description:DCR will be assessed by RECIST 1.1 criteria.
Measure:Metabolic response (18Glutamine [GLN]-positron emission tomography [PET]/computed tomography [CT]; 18Fluorodeoxyglucose [FDG]-PET/CT)
Time Frame:Up to 27 months
Safety Issue:
Description:Change in tumor uptake of radio-labelled glutamine on PET from baseline to cycle 1 day 8 will be quantified by the standardized uptake value maximum (SUVmax) (a standard PET parameter) in the largest measurable lesion. The before and after 18F-Gln PET values will be compared using log(after/before) as a measure of relative change.

Details

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

Last Updated

August 27, 2020