Multiple Myeloma Clinical Trial
Metformin, Nelfinavir, and Bortezomib in Treating Patients With Relapsed and/or Refractory Multiple Myeloma
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.
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.
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.
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.
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 (No red cell transfusion should have been administered within 4 days of registration) (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 (No platelet transfusion should have been administered within 7 days of registration) (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)
The following populations should be excluded from study:
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 sensitive/moderate sensitive substrates of CYP3A4, strong CYP3A4 inhibitors, or strong CYP3A4 inducers that cannot be discontinued 7 days prior to starting study and throughout study therapy
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There are 2 Locations for this study
Jacksonville Florida, 32224, United States
Rochester Minnesota, 55905, United States
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