<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03798678</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2019-00111</org_study_id>
    <secondary_id>NCI-2019-00111</secondary_id>
    <secondary_id>10219</secondary_id>
    <secondary_id>10219</secondary_id>
    <secondary_id>UM1CA186686</secondary_id>
    <nct_id>NCT03798678</nct_id>
  </id_info>
  <brief_title>CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma</brief_title>
  <official_title>Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination With Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib&#xD;
      and dexamethasone in treating patients with multiple myeloma that has come back or does not&#xD;
      respond to previous treatment. CB-839 HCl and carfilzomib may stop the growth of cancer cells&#xD;
      by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as&#xD;
      dexamethasone work in different ways to stop the growth of cancer cells, either by killing&#xD;
      the cells, by stopping them from dividing, or by stopping them from spreading. Giving CB-839&#xD;
      HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple&#xD;
      myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of&#xD;
      glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) in combination with carfilzomib and&#xD;
      dexamethasone.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the safety and tolerability of CB-839 HCl in combination with carfilzomib and&#xD;
      dexamethasone.&#xD;
&#xD;
      II. To determine the overall response rate (ORR) associated with the combination of CB-839&#xD;
      HCl with carfilzomib and dexamethasone.&#xD;
&#xD;
      CORRELATIVE RESEARCH OBJECTIVES:&#xD;
&#xD;
      I. Evaluate plasma pharmacokinetic (PK) profiles of CB-839 HCl and carfilzomib when used in&#xD;
      combination.&#xD;
&#xD;
      II. To perform molecular profiling assays on malignant and normal tissues, including, but not&#xD;
      limited to, whole exome sequencing (WES), messenger ribonucleic acid (RNA) sequencing&#xD;
      (RNAseq), circulating cell free (cf) deoxyribonucleic acid (DNA) analysis, flow cytometry&#xD;
      assessments, immunohistochemical (IHC) staining, and metabolomics-based assessments in order&#xD;
      to identify potential predictive and prognostic biomarkers, and identify resistance&#xD;
      mechanisms using genomic DNA, RNA, flow cytometry, IHC, and metabolomics-based assessment&#xD;
      platforms.&#xD;
&#xD;
      III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data&#xD;
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current&#xD;
      and future research.&#xD;
&#xD;
      IV. To bank CD138+ multiple myeloma (MM) cells from the bone marrow, and blood (for cfDNA&#xD;
      analysis) obtained from patients at the Experimental Therapeutics Clinical Trials Network&#xD;
      (ETCTN) Biorepository at Nationwide Children's Hospital.&#xD;
&#xD;
      OUTLINE: This is a dose escalation study of glutaminase inhibitor CB-839 hydrochloride.&#xD;
&#xD;
      Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) every 12 hours on&#xD;
      days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib intravenously&#xD;
      (IV) over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the&#xD;
      absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days and then&#xD;
      periodically for up to 1 year.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 26, 2018</start_date>
  <completion_date type="Anticipated">January 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 30, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose (MTD) and recommended phase II dose (RP2D)</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>MTD will be determined by dose limiting toxicity (DLT). MTD is defined as the dose level below the lowest dose that induces DLT in at least 2 patients (out of 6). The highest dose is defined as the RP2D. A standard cohort 3+3 design will be used.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 30 days after study treatment</time_frame>
    <description>Incidence of adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0. The number and severity of all AEs (overall and by dose-level) will be tabulated and summarized in this patient population. These data will be summarized with and without regard to the relationship to the treatment (i.e., ignoring the relationship data and after sub-setting the data to only events that are at least possibly related to study drug).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR)</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>The ORR will be defined as the percentage of patients that achieve at least a partial response (as their best response). Properties of the binomial distribution will be used in order to construct an exact 95% confidence interval around this proportion.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Pharmacokinetic (PK) profiles and pharmacodynamic effect</measure>
    <time_frame>Days 1 and 15 of cycle 1</time_frame>
    <description>PK and pharmacodynamic data will be examined in an exploratory manner.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Recurrent Multiple Myeloma</condition>
  <condition>Refractory Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Treatment (CB-839 HCI, dexamethasone, carfilzomib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive glutaminase inhibitor CB-839 Patients receive glutaminase inhibitor CB-839 hydrochloride PO every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (CB-839 HCI, dexamethasone, carfilzomib)</arm_group_label>
    <other_name>Carfilnat</other_name>
    <other_name>CFZ</other_name>
    <other_name>Kyprolis</other_name>
    <other_name>PR-171</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (CB-839 HCI, dexamethasone, carfilzomib)</arm_group_label>
    <other_name>Aacidexam</other_name>
    <other_name>Adexone</other_name>
    <other_name>Aknichthol Dexa</other_name>
    <other_name>Alba-Dex</other_name>
    <other_name>Alin</other_name>
    <other_name>Alin Depot</other_name>
    <other_name>Alin Oftalmico</other_name>
    <other_name>Amplidermis</other_name>
    <other_name>Anemul mono</other_name>
    <other_name>Auricularum</other_name>
    <other_name>Auxiloson</other_name>
    <other_name>Baycadron</other_name>
    <other_name>Baycuten</other_name>
    <other_name>Baycuten N</other_name>
    <other_name>Cortidexason</other_name>
    <other_name>Cortisumman</other_name>
    <other_name>Decacort</other_name>
    <other_name>Decadrol</other_name>
    <other_name>Decadron</other_name>
    <other_name>Decadron DP</other_name>
    <other_name>Decalix</other_name>
    <other_name>Decameth</other_name>
    <other_name>Decasone R.p.</other_name>
    <other_name>Dectancyl</other_name>
    <other_name>Dekacort</other_name>
    <other_name>Deltafluorene</other_name>
    <other_name>Deronil</other_name>
    <other_name>Desamethasone</other_name>
    <other_name>Desameton</other_name>
    <other_name>Dexa-Mamallet</other_name>
    <other_name>Dexa-Rhinosan</other_name>
    <other_name>Dexa-Scheroson</other_name>
    <other_name>Dexa-sine</other_name>
    <other_name>Dexacortal</other_name>
    <other_name>Dexacortin</other_name>
    <other_name>Dexafarma</other_name>
    <other_name>Dexafluorene</other_name>
    <other_name>Dexalocal</other_name>
    <other_name>Dexamecortin</other_name>
    <other_name>Dexameth</other_name>
    <other_name>Dexamethasone Intensol</other_name>
    <other_name>Dexamethasonum</other_name>
    <other_name>Dexamonozon</other_name>
    <other_name>Dexapos</other_name>
    <other_name>Dexinoral</other_name>
    <other_name>Dexone</other_name>
    <other_name>Dinormon</other_name>
    <other_name>Dxevo</other_name>
    <other_name>Fluorodelta</other_name>
    <other_name>Fortecortin</other_name>
    <other_name>Gammacorten</other_name>
    <other_name>Hemady</other_name>
    <other_name>Hexadecadrol</other_name>
    <other_name>Hexadrol</other_name>
    <other_name>Lokalison-F</other_name>
    <other_name>Loverine</other_name>
    <other_name>Methylfluorprednisolone</other_name>
    <other_name>Millicorten</other_name>
    <other_name>Mymethasone</other_name>
    <other_name>Orgadrone</other_name>
    <other_name>Spersadex</other_name>
    <other_name>TaperDex</other_name>
    <other_name>Visumetazone</other_name>
    <other_name>ZoDex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Telaglenastat Hydrochloride</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (CB-839 HCI, dexamethasone, carfilzomib)</arm_group_label>
    <other_name>CB-839 HCl</other_name>
    <other_name>Glutaminase Inhibitor CB-839 Hydrochloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have relapsed and/or refractory myeloma and be experiencing disease&#xD;
             relapse&#xD;
&#xD;
          -  Patients must have measurable disease by International Myeloma Working Group (IMWG)&#xD;
             criteria (any of the following):&#xD;
&#xD;
               -  Serum M-protein &gt;= 0.5 g/dL or for IgA myeloma, an elevated IgA level by&#xD;
                  quantitative IgA nephelometry&#xD;
&#xD;
               -  Urine M-protein &gt;= 200 mg in a 24-hour collection&#xD;
&#xD;
               -  Serum free light chain level &gt;= 10 mg/dL with an abnormal free light chain ratio&#xD;
&#xD;
               -  Measurable plasmacytoma by cross sectional imaging (computed tomography [CT],&#xD;
                  magnetic resonance imaging [MRI] or [18F]-fluorodeoxyglucose positron emission&#xD;
                  tomography with CT [FDG PET/CT])&#xD;
&#xD;
               -  20% or more light chain restricted, clonal plasma cells in the bone marrow&#xD;
&#xD;
          -  At least two prior lines of therapy and all patients should have at least been exposed&#xD;
             to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38&#xD;
             antibody&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,000 cells/mm3 without growth factors (within 14 days of&#xD;
             enrollment)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL (within 14 days of enrollment)&#xD;
&#xD;
          -  Platelets &gt;= 50,000 cells/mm3 (&gt;= 30,000 cells/mm3 if bone marrow plasma cells &gt;= 50%&#xD;
             at enrollment)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3 x institutional ULN&#xD;
&#xD;
          -  Creatinine =&lt; institutional ULN OR glomerular filtration rate (GFR) &gt;= 40 mL/min/1.73&#xD;
             m^2 for patients with creatinine levels above institutional normal&#xD;
&#xD;
          -  Willingness to undergo interim bone marrow biopsy/aspiration for clinical purposes&#xD;
&#xD;
          -  Negative pregnancy test done =&lt; 7 days prior to registration, for women of&#xD;
             childbearing potential only&#xD;
&#xD;
               -  The effects of CB-839 HCl on the developing human fetus are unknown. For this&#xD;
                  reason and because carfilzomib caused embryo-fetal toxicity in pregnant rabbits&#xD;
                  at doses lower than the recommended dose, women of child-bearing potential and&#xD;
                  men must agree to use two effective methods of contraception (hormonal or barrier&#xD;
                  method of birth control; abstinence) prior to study entry, for the duration of&#xD;
                  study participation, and 4 months after completion of CB-839 HCl, carfilzomib,&#xD;
                  and dexamethasone administration. Should a woman become pregnant or suspect she&#xD;
                  is pregnant while she or her partner is participating in this study, she should&#xD;
                  inform her treating physician immediately. Men treated or enrolled on this&#xD;
                  protocol must also agree to use adequate contraception prior to the study, for&#xD;
                  the duration of study participation, and 4 months after completion of CB-839 HCl,&#xD;
                  carfilzomib, and dexamethasone administration&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are refractory or intolerant to carfilzomib (prior carfilzomib exposure&#xD;
             accepted)&#xD;
&#xD;
          -  Patients who have received recent prior chemotherapy with:&#xD;
&#xD;
               -  Alkylators (e.g., melphalan, cyclophosphamide) and anthracyclines =&lt; 14 days&#xD;
                  prior to registration,&#xD;
&#xD;
               -  High dose corticosteroids and immunomodulatory drugs (thalidomide or&#xD;
                  lenalidomide) =&lt; 7 days prior to registration, or&#xD;
&#xD;
               -  Monoclonal antibodies =&lt; 14 days prior to registration&#xD;
&#xD;
          -  Patients who have not recovered from adverse events (AEs) due to prior anti-cancer&#xD;
             therapy (i.e., have residual toxicities &gt; grade 1 except peripheral neuropathy)&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to CB-839 HCl, carfilzomib, or dexamethasone&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness&#xD;
&#xD;
          -  Any of the following:&#xD;
&#xD;
               -  Pregnant women or women of reproductive ability who are unwilling to use two&#xD;
                  effective methods of contraception from the time of signing the informed consent&#xD;
                  form through 4 months after the last dose of study drug&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
               -  And men who are unwilling to use birth control while taking the drug and for 4&#xD;
                  months after stopping treatment&#xD;
&#xD;
                    -  Pregnant women are excluded from this study because carfilzomib is a PI with&#xD;
                       the potential for abortifacient effects. Because there is an unknown but&#xD;
                       potential risk for AEs in nursing infants secondary to treatment of the&#xD;
                       mother with CB-839 HCl, carfilzomib, and dexamethasone, breastfeeding should&#xD;
                       be discontinued if the mother is treated with this drug combination&#xD;
&#xD;
          -  Adverse cardiac history (unstable angina, myocardial infarction less than 4 months,&#xD;
             New York Heart Association [NYHA] class III or IV congestive heart failure [CHF],&#xD;
             ejection fraction [EF] &lt; 40%, uncontrolled arrhythmias)&#xD;
&#xD;
          -  Concomitant high dose corticosteroids other than what is part of treatment protocol&#xD;
             (concurrent use of corticosteroids). EXCEPTION: Patients may be on chronic steroids&#xD;
             (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders&#xD;
             other than myeloma, e.g., adrenal insufficiency, rheumatoid arthritis, etc&#xD;
&#xD;
          -  Central nervous system (CNS) involvement&#xD;
&#xD;
               -  Patients with known brain metastases should be excluded from this clinical trial&#xD;
                  because of their poor prognosis and because they often develop progressive&#xD;
                  neurologic dysfunction that would confound the evaluation of neurologic and other&#xD;
                  AEs&#xD;
&#xD;
          -  Concurrent amyloid light-chain (AL) amyloidosis&#xD;
&#xD;
          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or&#xD;
             previously diagnosed with another malignancy and have any evidence of residual&#xD;
             disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are&#xD;
             not excluded if they have undergone complete resection&#xD;
&#xD;
          -  Patient has &gt;= grade 3 peripheral neuropathy or grade 2 with pain on clinical&#xD;
             examination during the screening period&#xD;
&#xD;
          -  Major surgery within 14 days before study registration&#xD;
&#xD;
          -  On concurrent treatment with an HIV protease inhibitor&#xD;
&#xD;
               -  Human immunodeficiency virus (HIV) protease inhibitors can affect the unfolded&#xD;
                  protein response in myeloma cells as well as the activity of PIs&#xD;
&#xD;
          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,&#xD;
             potentially interfere with the completion of treatment according to this protocol&#xD;
&#xD;
          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral&#xD;
             absorption or tolerance of CB-839 HCl including difficulty swallowing, refractory&#xD;
             vomiting, gastric resection or bypass, or duodenal/jejunal resection&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wilson I Gonsalves</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Ichthammol</mesh_term>
    <mesh_term>BB 1101</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03798678
org study id: NCI-2019-00111
secondary id: NCI-2019-00111
secondary id: 10219
secondary id: 10219
secondary id: UM1CA186686
nct id: NCT03798678
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib
      and dexamethasone in treating patients with multiple myeloma that has come back or does not
      respond to previous treatment. CB-839 HCl and carfilzomib may stop the growth of cancer cells
      by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
      dexamethasone work in different ways to stop the growth of cancer cells, either by killing
      the cells, by stopping them from dividing, or by stopping them from spreading. Giving CB-839
      HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple
      myeloma.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
      glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) in combination with carfilzomib and
      dexamethasone.

      SECONDARY OBJECTIVES:

      I. Evaluate the safety and tolerability of CB-839 HCl in combination with carfilzomib and
      dexamethasone.

      II. To determine the overall response rate (ORR) associated with the combination of CB-839
      HCl with carfilzomib and dexamethasone.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. Evaluate plasma pharmacokinetic (PK) profiles of CB-839 HCl and carfilzomib when used in
      combination.

      II. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES), messenger ribonucleic acid (RNA) sequencing
      (RNAseq), circulating cell free (cf) deoxyribonucleic acid (DNA) analysis, flow cytometry
      assessments, immunohistochemical (IHC) staining, and metabolomics-based assessments in order
      to identify potential predictive and prognostic biomarkers, and identify resistance
      mechanisms using genomic DNA, RNA, flow cytometry, IHC, and metabolomics-based assessment
      platforms.

      III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research.

      IV. To bank CD138+ multiple myeloma (MM) cells from the bone marrow, and blood (for cfDNA
      analysis) obtained from patients at the Experimental Therapeutics Clinical Trials Network
      (ETCTN) Biorepository at Nationwide Children's Hospital.

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

      Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) every 12 hours on
      days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib intravenously
      (IV) over 10 minutes on days 1, 2, 8, 9, 15, and 16. 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 and then
      periodically for up to 1 year.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD) and recommended phase II dose (RP2D)
time frame: Up to 28 days
description: MTD will be determined by dose limiting toxicity (DLT). MTD is defined as the dose level below the lowest dose that induces DLT in at least 2 patients (out of 6). The highest dose is defined as the RP2D. A standard cohort 3+3 design will be used.
measure: Incidence of adverse events
time frame: Up to 30 days after study treatment
description: Incidence of adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0. The number and severity of all AEs (overall and by dose-level) will be tabulated and summarized in this patient population. These data will be summarized with and without regard to the relationship to the treatment (i.e., ignoring the relationship data and after sub-setting the data to only events that are at least possibly related to study drug).
measure: Overall response rate (ORR)
time frame: Up to 1 year
description: The ORR will be defined as the percentage of patients that achieve at least a partial response (as their best response). Properties of the binomial distribution will be used in order to construct an exact 95% confidence interval around this proportion.
measure: Pharmacokinetic (PK) profiles and pharmacodynamic effect
time frame: Days 1 and 15 of cycle 1
description: PK and pharmacodynamic data will be examined in an exploratory manner.
arm group label: Treatment (CB-839 HCI, dexamethasone, carfilzomib)
arm group type: Experimental
description: Patients receive glutaminase inhibitor CB-839 Patients receive glutaminase inhibitor CB-839 hydrochloride PO every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity
intervention type: Drug
intervention name: Carfilzomib
description: Given IV
arm group label: Treatment (CB-839 HCI, dexamethasone, carfilzomib)
other name: Carfilnat
other name: CFZ
other name: Kyprolis
other name: PR-171
intervention type: Drug
intervention name: Dexamethasone
description: Given PO
arm group label: Treatment (CB-839 HCI, dexamethasone, carfilzomib)
other name: Aacidexam
other name: Adexone
other name: Aknichthol Dexa
other name: Alba-Dex
other name: Alin
other name: Alin Depot
other name: Alin Oftalmico
other name: Amplidermis
other name: Anemul mono
other name: Auricularum
other name: Auxiloson
other name: Baycadron
other name: Baycuten
other name: Baycuten N
other name: Cortidexason
other name: Cortisumman
other name: Decacort
other name: Decadrol
other name: Decadron
other name: Decadron DP
other name: Decalix
other name: Decameth
other name: Decasone R.p.
other name: Dectancyl
other name: Dekacort
other name: Deltafluorene
other name: Deronil
other name: Desamethasone
other name: Desameton
other name: Dexa-Mamallet
other name: Dexa-Rhinosan
other name: Dexa-Scheroson
other name: Dexa-sine
other name: Dexacortal
other name: Dexacortin
other name: Dexafarma
other name: Dexafluorene
other name: Dexalocal
other name: Dexamecortin
other name: Dexameth
other name: Dexamethasone Intensol
other name: Dexamethasonum
other name: Dexamonozon
other name: Dexapos
other name: Dexinoral
other name: Dexone
other name: Dinormon
other name: Dxevo
other name: Fluorodelta
other name: Fortecortin
other name: Gammacorten
other name: Hemady
other name: Hexadecadrol
other name: Hexadrol
other name: Lokalison-F
other name: Loverine
other name: Methylfluorprednisolone
other name: Millicorten
other name: Mymethasone
other name: Orgadrone
other name: Spersadex
other name: TaperDex
other name: Visumetazone
other name: ZoDex
intervention type: Drug
intervention name: Telaglenastat Hydrochloride
description: Given PO
arm group label: Treatment (CB-839 HCI, dexamethasone, carfilzomib)
other name: CB-839 HCl
other name: Glutaminase Inhibitor CB-839 Hydrochloride
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wilson I Gonsalves
role: Principal Investigator
affiliation: Mayo Clinic Cancer Center LAO
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Ichthammol
mesh term: BB 1101