<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/NCT03829020</url>
  </required_header>
  <id_info>
    <org_study_id>MC1811</org_study_id>
    <secondary_id>NCI-2019-00466</secondary_id>
    <secondary_id>MC1811</secondary_id>
    <nct_id>NCT03829020</nct_id>
  </id_info>
  <brief_title>Metformin, Nelfinavir, and Bortezomib in Treating Patients With Relapsed and/or Refractory Multiple Myeloma</brief_title>
  <official_title>An Open-Label Phase 1 Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and/or Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of metformin and nelfinavir in&#xD;
      combination with bortezomib in treating patients with multiple myeloma that has come back or&#xD;
      does not respond to treatment. Metformin may stop the growth of tumor cells by disrupting the&#xD;
      energy source within multiple myeloma cells. Nelfinavir and bortezomib may stop the growth of&#xD;
      tumor cells by blocking some of the enzymes needed for cell growth. Giving metformin,&#xD;
      nelfinavir, and bortezomib may work better in treating patients with multiple myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To assess the maximum tolerated dose (MTD) of administering metformin hydrochloride&#xD;
      (metformin) and nelfinavir mesylate (nelfinavir) in combination with bortezomib in patients&#xD;
      with relapsed/refractory multiple myeloma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To describe the safety and tolerability of metformin and nelfinavir in combination with&#xD;
      bortezomib in patients with relapsed/refractory multiple myeloma.&#xD;
&#xD;
      II. To assess the best hematological response of the combination of metformin, nelfinavir and&#xD;
      bortezomib within 6 cycles of initiating therapy.&#xD;
&#xD;
      EXPLORATORY OBJECTIVE:&#xD;
&#xD;
      I. Assess clinical biomarkers predictive of response to the combination of metformin,&#xD;
      nelfinavir and bortezomib such as bioenergetic profiles of the myeloma cells, GLUT4&#xD;
      expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based&#xD;
      profiling.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of metformin hydrochloride and nelfinavir mesylate.&#xD;
&#xD;
      Patients receive metformin hydrochloride orally (PO) on days 1-14, nelfinavir mesylate PO&#xD;
      twice daily (BID) on days 1-14, and bortezomib subcutaneously (SC) on days 1, 8, and 15.&#xD;
      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 17, 2019</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Actual">September 21, 2022</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 of the combination of metformin, nelfinavir, and bortezomib</measure>
    <time_frame>42 days</time_frame>
    <description>Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 2.5 years</time_frame>
    <description>The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hematologic response rate</measure>
    <time_frame>Up to 2.5 years</time_frame>
    <description>Defined to be a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) noted as the objective status on two consecutive evaluations. Exact binomial 95% confidence intervals for the true hematologic response rate will be calculated.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Clinical biomarker analysis</measure>
    <time_frame>Up to 2.5 years</time_frame>
    <description>Will be explored and correlated with response to the combination of metformin, nelfinavir, and bortezomib using Fisher's exact and Wilcoxon rank sum tests. Clinical biomarkers examined may include bioenergetic profiles of the myeloma cells, GLUT4 expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based profiling.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Recurrent Plasma Cell Myeloma</condition>
  <condition>Refractory Plasma Cell Myeloma</condition>
  <arm_group>
    <arm_group_label>Treatment (metformin, nelfinavir)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive metformin hydrochloride PO on days 1-14, nelfinavir mesylate PO BID on days 1-14, and bortezomib SC on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bortezomib</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (metformin, nelfinavir)</arm_group_label>
    <other_name>[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid</other_name>
    <other_name>LDP 341</other_name>
    <other_name>MLN341</other_name>
    <other_name>PS-341</other_name>
    <other_name>PS341</other_name>
    <other_name>Velcade</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin Hydrochloride</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (metformin, nelfinavir)</arm_group_label>
    <other_name>APO-Metformin</other_name>
    <other_name>Cidophage</other_name>
    <other_name>Dimefor</other_name>
    <other_name>Glifage</other_name>
    <other_name>Glucoformin</other_name>
    <other_name>Glucophage</other_name>
    <other_name>Glucophage ER</other_name>
    <other_name>Metformin HCl</other_name>
    <other_name>Riomet</other_name>
    <other_name>Siofor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nelfinavir Mesylate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (metformin, nelfinavir)</arm_group_label>
    <other_name>AG1343</other_name>
    <other_name>Viracept</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Actively relapsing multiple myeloma&#xD;
&#xD;
          -  Measurable disease of multiple myeloma as defined by at least ONE of the following:&#xD;
&#xD;
               -  Serum monoclonal protein &gt;= 0.5 g/dL&#xD;
&#xD;
                    -  If immunoglobulin A (IgA) isotype, then IgA quantification &gt; upper limit of&#xD;
                       normal&#xD;
&#xD;
               -  &gt;= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis&#xD;
&#xD;
               -  Serum immunoglobulin free light chain &gt;= 10 mg/dL AND abnormal serum&#xD;
                  immunoglobulin kappa to lambda free light chain ratio&#xD;
&#xD;
               -  Monoclonal bone marrow plasmacytosis &gt;= 10% (evaluable disease)&#xD;
&#xD;
          -  Patients must have received at least 2 prior regimens and patients should have been&#xD;
             exposed to a proteasome inhibitor (PI), an immunomodulatory drugs (IMiD) and an&#xD;
             anti-CD38 antibody. NOTE: Induction therapy followed by an autologous stem cell&#xD;
             transplant (ASCT) and maintenance therapy without any relapse counts as 1 regimen&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 g/dL (No red cell transfusion should have been administered within 4&#xD;
             days of registration) (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1000/mm^3 (obtained =&lt; 14 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Platelet count &gt;= 50,000/mm^3 or &gt;= 30,000/mm^3 if bone marrow plasma cells percentage&#xD;
             &gt;= 50% by morphology (No platelet transfusion should have been administered within 7&#xD;
             days of registration) (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN) (obtained =&lt; 14 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) =&lt; 3 x ULN (=&lt; 5 x ULN&#xD;
             for patients with liver involvement) (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Calculated creatinine clearance &gt;= 45 ml/min using the Cockcroft-Gault formula&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Negative pregnancy test done =&lt; 7 days prior to registration, for persons of&#xD;
             childbearing potential only. NOTE: If the urine test is positive or cannot be&#xD;
             confirmed as negative, a serum pregnancy test will be required&#xD;
&#xD;
          -  Provide written informed consent&#xD;
&#xD;
          -  Able to swallow metformin and nelfinavir tablets&#xD;
&#xD;
          -  Willingness to provide mandatory blood sample and bone marrow aspirate for research&#xD;
             purposes&#xD;
&#xD;
          -  Willingness to return to Mayo Clinic for follow-up (during the active monitoring phase&#xD;
             of the study)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The following populations should be excluded from study:&#xD;
&#xD;
               -  Pregnant persons&#xD;
&#xD;
               -  Nursing persons&#xD;
&#xD;
               -  Persons of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception&#xD;
&#xD;
          -  Major surgery =&lt; 14 days before study registration&#xD;
&#xD;
          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment&#xD;
             of the investigator, would make the patient inappropriate for entry into this study or&#xD;
             interfere significantly with the proper assessment of safety and toxicity of the&#xD;
             prescribed regimens&#xD;
&#xD;
          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)&#xD;
             positive and currently receiving antiretroviral therapy&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Receiving any other investigational agent which would be considered as a treatment for&#xD;
             the primary neoplasm&#xD;
&#xD;
          -  Another active malignancy requiring therapy such as radiation, chemotherapy, or&#xD;
             immunotherapy. NOTE: Patients on hormonal therapy for treated breast or prostate&#xD;
             cancer are permitted if they meet other eligibility criteria&#xD;
&#xD;
          -  History of myocardial infarction =&lt; 6 months prior to registration, or congestive&#xD;
             heart failure requiring use of ongoing maintenance therapy for life-threatening&#xD;
             ventricular arrhythmias&#xD;
&#xD;
          -  Known allergy to any of the study medications, their analogues or excipients in the&#xD;
             various formulations&#xD;
&#xD;
          -  Subjects must not have conditions associated with increased risk of metformin&#xD;
             associated lactic acidosis, including New York Heart Association class III or IV&#xD;
             congestive heart failure, history of acidosis of any type, alcoholic liver disease, or&#xD;
             habitual intake of 3 or more alcoholic beverages per day&#xD;
&#xD;
          -  Clinical history of type I or type II diabetes&#xD;
&#xD;
          -  Currently on either metformin or a HIV-PI or both&#xD;
&#xD;
          -  Elevated baseline lactate level &gt; ULN (2.3 mmol/L)&#xD;
&#xD;
          -  Any of the following recent prior anti-myeloma therapy:&#xD;
&#xD;
               -  Alkylators (e.g. melphalan, cyclophosphamide) and anthracyclines =&lt; 14 days prior&#xD;
                  to registration&#xD;
&#xD;
               -  High dose corticosteroids (equivalent to &gt; 10 mg of prednisone/day) and&#xD;
                  immunomodulatory drugs (thalidomide or lenalidomide) =&lt; 7 days prior to&#xD;
                  registration&#xD;
&#xD;
               -  Monoclonal antibodies =&lt; 14 days prior to registration&#xD;
&#xD;
          -  Currently receiving sensitive/moderate sensitive substrates of CYP3A4, strong CYP3A4&#xD;
             inhibitors, or strong CYP3A4 inducers that cannot be discontinued 7 days prior to&#xD;
             starting study and throughout study therapy&#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 in Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</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_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.mayo.edu/research/clinical-trials</url>
    <description>Mayo Clinic Clinical Trials</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>February 1, 2019</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 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>Metformin</mesh_term>
    <mesh_term>Nelfinavir</mesh_term>
    <mesh_term>Bortezomib</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/NCT03829020
org study id: MC1811
secondary id: NCI-2019-00466
secondary id: MC1811
nct id: NCT03829020
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase I trial studies the side effects and best dose of metformin and nelfinavir in
      combination with bortezomib in treating patients with multiple myeloma that has come back or
      does not respond to treatment. Metformin may stop the growth of tumor cells by disrupting the
      energy source within multiple myeloma cells. Nelfinavir and bortezomib may stop the growth of
      tumor cells by blocking some of the enzymes needed for cell growth. Giving metformin,
      nelfinavir, and bortezomib may work better in treating patients with multiple myeloma.
PRIMARY OBJECTIVE:

      I. To assess the maximum tolerated dose (MTD) of administering metformin hydrochloride
      (metformin) and nelfinavir mesylate (nelfinavir) in combination with bortezomib in patients
      with relapsed/refractory multiple myeloma.

      SECONDARY OBJECTIVES:

      I. To describe the safety and tolerability of metformin and nelfinavir in combination with
      bortezomib in patients with relapsed/refractory multiple myeloma.

      II. To assess the best hematological response of the combination of metformin, nelfinavir and
      bortezomib within 6 cycles of initiating therapy.

      EXPLORATORY OBJECTIVE:

      I. Assess clinical biomarkers predictive of response to the combination of metformin,
      nelfinavir and bortezomib such as bioenergetic profiles of the myeloma cells, GLUT4
      expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based
      profiling.

      OUTLINE: This is a dose-escalation study of metformin hydrochloride and nelfinavir mesylate.

      Patients receive metformin hydrochloride orally (PO) on days 1-14, nelfinavir mesylate PO
      twice daily (BID) on days 1-14, and bortezomib subcutaneously (SC) on days 1, 8, and 15.
      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of the combination of metformin, nelfinavir, and bortezomib
time frame: 42 days
description: Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients).
measure: Incidence of adverse events
time frame: Up to 2.5 years
description: The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
measure: Hematologic response rate
time frame: Up to 2.5 years
description: Defined to be a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) noted as the objective status on two consecutive evaluations. Exact binomial 95% confidence intervals for the true hematologic response rate will be calculated.
measure: Clinical biomarker analysis
time frame: Up to 2.5 years
description: Will be explored and correlated with response to the combination of metformin, nelfinavir, and bortezomib using Fisher's exact and Wilcoxon rank sum tests. Clinical biomarkers examined may include bioenergetic profiles of the myeloma cells, GLUT4 expression on myeloma cells, PI3K/AKT/mTOR and MAPK signaling pathways and metabolomics-based profiling.
arm group label: Treatment (metformin, nelfinavir)
arm group type: Experimental
description: Patients receive metformin hydrochloride PO on days 1-14, nelfinavir mesylate PO BID on days 1-14, and bortezomib SC on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Bortezomib
description: Given SC
arm group label: Treatment (metformin, nelfinavir)
other name: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
other name: LDP 341
other name: MLN341
other name: PS-341
other name: PS341
other name: Velcade
intervention type: Drug
intervention name: Metformin Hydrochloride
description: Given PO
arm group label: Treatment (metformin, nelfinavir)
other name: APO-Metformin
other name: Cidophage
other name: Dimefor
other name: Glifage
other name: Glucoformin
other name: Glucophage
other name: Glucophage ER
other name: Metformin HCl
other name: Riomet
other name: Siofor
intervention type: Drug
intervention name: Nelfinavir Mesylate
description: Given PO
arm group label: Treatment (metformin, nelfinavir)
other name: AG1343
other name: Viracept
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 in Rochester
facility: 
facility: 
country: United States
url: https://www.mayo.edu/research/clinical-trials
description: Mayo Clinic Clinical Trials
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Metformin
mesh term: Nelfinavir
mesh term: Bortezomib