Clinical Trials /

Metformin and Nelfinavir in Treating Patients With Relapsed and/or Refractory Multiple Myeloma

NCT03829020

Description:

This phase I trial studies the side effects and best dose of metformin and nelfinavir 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 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving metformin and nelfinavir may work better in treating patients with multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Metformin and Nelfinavir in Treating Patients With Relapsed and/or Refractory Multiple Myeloma
  • Official Title: An Open-Label Phase 1 Study of Metformin in Combination With Nelfinavir in Patients With Relapsed and/or Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: MC1811
  • SECONDARY ID: NCI-2019-00466
  • SECONDARY ID: MC1811
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03829020

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Bortezomib[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, VelcadeTreatment (metformin, nelfinavir)
Metformin HydrochlorideAPO-Metformin, Cidophage, Dimefor, Glifage, Glucoformin, Glucophage, Glucophage ER, Metformin HCl, Riomet, SioforTreatment (metformin, nelfinavir)
Nelfinavir MesylateAG1343, ViraceptTreatment (metformin, nelfinavir)

Purpose

This phase I trial studies the side effects and best dose of metformin and nelfinavir 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 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving metformin and nelfinavir may work better in treating patients with multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

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

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

      EXPLORATORY OBJECTIVES:

      I. To describe the safety and tolerability of adding bortezomib to the combination of
      metformin and nelfinavir.

      II. To describe any depth of hematological response obtained after adding bortezomib to the
      combination of metformin and nelfinavir.

      III. Assess clinical biomarkers predictive of response to the combination of metformin and
      nelfinavir with or without the addition of 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.

      Patients receive metformin hydrochloride orally (PO) on days 1-21 of cycle 1 and days 1-14 of
      cycles 2-6. Patients also receive nelfinavir mesylate PO on days 1-14. Treatment repeats
      every 21 days for up to 6 cycles in the absence of disease progression or unacceptable
      toxicity. Patients with progressive disease (PD) at any time within 5 cycles or no minimal
      response (unconfirmed [u]MR or MR) after 2 cycles or no partial response (uPR or PR) after 4
      cycles also receive bortezomib subcutaneously (SC) once weekly every 21 days in the absence
      of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (metformin, nelfinavir)ExperimentalPatients receive metformin hydrochloride PO on days 1-21 of cycle 1 and days 1-14 of cycles 2-6. Patients also receive nelfinavir mesylate PO on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with PD at any time within 5 cycles or no uMR or MR after 2 cycles or no uPR or PR after 4 cycles also receive bortezomib SC once weekly every 21 days in the absence of disease progression or unacceptable toxicity.
  • Bortezomib
  • Metformin Hydrochloride
  • Nelfinavir Mesylate

Eligibility Criteria

        Inclusion Criteria:

          -  Actively relapsing multiple myeloma

          -  Measurable disease of multiple myeloma as defined by at least ONE of the following:

               -  Serum monoclonal protein >= 0.5 g/dL

                    -  If immunoglobulin A (IgA) isotype, then IgA quantification > upper limit of
                       normal.

               -  >= 200 mg of monoclonal protein in the urine on 24-hour electrophoresis

               -  Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
                  immunoglobulin kappa to lambda free light chain ratio

               -  Monoclonal bone marrow plasmacytosis >= 10% (evaluable disease)

          -  Patients must have received at least 2 prior regimens and patients should have been
             exposed to a proteasome inhibitor (PI), an immunomodulatory drugs (IMiD) and an
             anti-CD38 antibody. NOTE: Induction therapy followed by an autologous stem cell
             transplant (ASCT) and maintenance therapy without any relapse counts as 1 regimen

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
             registration)

          -  Platelet count >= 50,000/mm^3 or >= 30,000/mm^3 if bone marrow plasma cells percentage
             >= 50% by morphology (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to
             registration)

          -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN
             for patients with liver involvement) (obtained =< 14 days prior to registration)

          -  Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula
             (obtained =< 14 days prior to registration)

          -  Negative pregnancy test done =< 7 days prior to registration, for persons of
             childbearing potential only. NOTE: If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required

          -  Provide written informed consent

          -  Able to swallow metformin and nelfinavir tablets

          -  Willingness to provide mandatory blood sample and bone marrow aspirate for research
             purposes

          -  Willingness to return to Mayo Clinic for follow-up (during the active monitoring phase
             of the study)

        Exclusion Criteria:

          -  The following populations should be excluded from study:

               -  Pregnant persons

               -  Nursing persons

               -  Persons of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Major surgery =< 14 days before study registration

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive and currently receiving antiretroviral therapy

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Another active malignancy requiring therapy such as radiation, chemotherapy, or
             immunotherapy. NOTE: Patients on hormonal therapy for treated breast or prostate
             cancer are permitted if they meet other eligibility criteria

          -  History of myocardial infarction =< 6 months prior to registration, or congestive
             heart failure requiring use of ongoing maintenance therapy for life-threatening
             ventricular arrhythmias

          -  Known allergy to any of the study medications, their analogues or excipients in the
             various formulations

          -  Subjects must not have conditions associated with increased risk of metformin
             associated lactic acidosis, including New York Heart Association class III or IV
             congestive heart failure, history of acidosis of any type, alcoholic liver disease, or
             habitual intake of 3 or more alcoholic beverages per day

          -  Clinical history of type I or type II diabetes

          -  Currently on either metformin or a HIV-PI or both

          -  Elevated baseline lactate level > ULN (2.3 mmol/L)

          -  Any of the following recent prior anti-myeloma therapy:

               -  Alkylators (e.g. melphalan, cyclophosphamide) and anthracyclines =< 14 days prior
                  to registration

               -  High dose corticosteroids (equivalent to > 10 mg of prednisone/day) and
                  immunomodulatory drugs (thalidomide or lenalidomide) =< 7 days prior to
                  registration

               -  Monoclonal antibodies =< 14 days prior to registration

          -  Currently receiving any of the medications that cannot be discontinued 7 days prior to
             starting study and throughout study therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of the combination of metformin and nelfinavir
Time Frame:42 days
Safety Issue:
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).

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2.5 years
Safety Issue:
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
Safety Issue:
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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

April 22, 2019