Phase II Study to Evaluate Fenofibrate Therapy in Patients With Smoldering or Symptomatic Multiple Myeloma

Multiple myeloma cells are dependent on calcium (Ca2+) for their function. Specifically, Ca2+ is required for the function of the endoplasmic reticulum in which proteins, including immunoglobulins, are folded prior to their release from the cell. Multiple myeloma cells secrete large concentrations of immunoglobulins continuously and as result depend on mitochondria activity to replenish the Ca2+ levels in the endoplasmic reticulum as was shown in vitro in our lab. Fenofibrate has been shown to inhibit mitochondrial function resulting in inhibition of protein folding in the endoplasmic reticulum of multiple myeloma (MM) cells that leads to the induction of a stress signal known as the unfolded protein response and subsequently apoptosis. The effective anti-myeloma concentrations for fenofibrate are attainable in the clinical setting as they are in the same range as the effective concentrations for anti-hyperlipidemic effect. The investigators propose to evaluate fenofibrate therapy in multiple myeloma patients.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Fenofibrate

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient must have histologically or cytologically confirmed multiple myeloma (smoldering myeloma and symptomatic multiple myeloma).

2. Patients must have measurable disease and therefore must have at least one of the following:

   • Serum M-protein ≥ 1 gm/dL (≥ 10 gm/L)
   • Urine M-protein ≥ 200 mg/24 hr
   • Serum free light chain (FLC) assay: involved FLC ≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is abnormal.
3. Male or female ≥ 18 years of age.
4. Life expectancy of ≥ 6 months.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

6. Normal organ and marrow function as defined below:

   • Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3
   • Platelets ≥75,000/mm^3
   • Hemoglobin ≥ 8 g/dL
   • Calculated serum creatinine (calculated by Cockcroft-Gault method) ≥ 30 mL/min
   • Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT)/ Alanine transaminase (ALT)/serum glutamate-pyruvate transaminase (SGPT) ≤ 2.5 X upper limit of normal (ULN)
   • Total bilirubin ≤ 1.5 X ULN
7. Patient must be at least 2 weeks from prior chemotherapy, radiation therapy, biological therapy, immunotherapy, major surgery and any other investigational anti-cancer therapy prior to the first dose of study drug.
8. Patient has recovered from toxicities (≤ Grade 2) and/or complications from prior therapy.
9. Patient is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis.
10. Female patients of childbearing potential must be willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual intercourse for at least 1 month before dosing, and while women are on study and for up to 12 weeks after last dose of study drug. Adequate contraceptive methods include intrauterine device, diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
11. Male patients agree to have female partners of childbearing potential use 2 adequate barrier methods of contraception as described in Section 3.1.10.
12. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study drug.
13. Patient is available for periodic blood sampling, study related assessments and management at the treating institution for the duration of the study.
14. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who only present with isolated plasmacytomas
2. Inability to swallow oral medication.
3. Prior allogeneic stem cell transplant (subject with prior autologous transplant is eligible).
4. Patient has plans to undergo any type of stem cell transplantation (allogeneic or autologous) within 4 weeks of initiation of study therapy.
5. Concurrent therapy with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) Reductase Inhibitors.
6. Patient with gallbladder disease or cholelithiasis.
7. Patient has active liver disease, including biliary cirrhosis and unexplained liver function abnormalities.
8. Patients receiving renal dialysis.
9. History of hypersensitivity to fenofibrate or fenofibric acid, including sever skin rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
10. Patients who would be receiving any other investigational agents while on study.
11. Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
12. 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.
13. Patient has systemic infection requiring treatment.
14. Patient has acute diffuse infiltrative pulmonary disease or pericardial disease.
15. Subject is receiving corticosteroid therapy (> 10 mg of prednisone or equivalent).
16. Subject is a regular user or has a recent history (within the last year) of any illicit drugs, or substance abuse.
17. Subject is pregnant or breast feeding, or expecting to conceive or father children within the projected duration of the study.
18. Subject is known to be HIV positive.
19. Subject has clinically active Hepatitis B or C
20. History of prior malignancy except for cervical carcinoma in situ, non-melanoma skin cancer, adequately treated localized prostate cancer with prostate-specific antigen (PSA) < 0.1, or has undergone potentially curative therapy with no evidence of disease for five years, or who is deemed at low risk for recurrence by his/her treating physician.
21. Patient with central nervous system (CNS) metastases and/or carcinomatous meningitis.
22. History of gastrointestinal disease that could potentially impact the ability of the patient to swallow and/or absorb study drug (i.e., gastrointestinal surgery, malabsorption syndrome, subjects requiring the use of feeding tube)
23. History of gastrointestinal surgery or other procedures that might in the opinion of the investigator interfere with swallowing and/or absorption of the study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Fenofibrate Therapy; Fenofibrate orally daily for each 28 day cycle, per study protocol.

Drug: Fenofibrate; Upon screening, registration and enrollment, all subjects will receive Fenofibrate 160 mg orally daily for at least 2 months and may continue receiving study medication for as long as in the opinion of the investigator there is clinical benefit in doing so. Patients with calculated creatinine clearance < 50 mL/min will receive a reduced dose of 54 mg orally daily.; Other Names: Fenofibric acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Response in Participants Receiving Fenofibrate Therapy	To determine response rate (Strict Complete Response (sCR), Complete response (CR), Very Good Partial Response (VgPR), and Partial Response (PR)) in multiple myeloma patients receiving oral fenofibrate therapy. Response will be measured by serum and urine protein electrophoresis and immunofixation, as well as by percentage of plasma cells present on bone marrow biopsy.	After two cycles, about 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Experiencing Adverse Events	To evaluate safety and tolerability of fenofibrate therapy in patients with multiple myeloma.	Up to 8 months
Proportion of Participants Achieving Progression-Free Survival	Proportion of participants achieving progression-free survival. Measured from date of initiation of treatment (Day 1) to the earliest occurrence of any of the following events: documented disease progression, or death from any cause. Patients who are alive and progression-free will be censored at the date of last documented progression-free status.	6 months, 12 months

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Denise Pereria, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 19, 2012
• Primary Completion (ACTUAL): March 21, 2016
• Study Completion (ACTUAL): July 1, 2016

Study Registration Dates

• First Submitted: October 15, 2013
• First Submitted That Met QC Criteria: October 15, 2013
• First Posted (ESTIMATE): October 18, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Fenofibrate
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Fenofibric acid; Fenofibrate
• Other Study ID Numbers: 20110069

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No