Combination Study of Pomalidomide, Marizomib, and Low-Dose Dexamethasone in Relapsed and Refractory Multiple Myeloma
Combination Study of Pomalidomide, Marizomib, and Low-Dose Dexamethasone in Relapsed and Refractory Multiple Myeloma
This is a Phase 1 clinical trial to evaluate a new combination of drugs for the treatment of
 relapsed or refractory (drug-resistant) multiple myeloma. The drugs being studied are:

 -  Pomalidomide (POMALYST®) is a drug that affects the immune system (an immunomodulatory
 drug) that has been approved by the United States (US) Food and Drug Administration
 (FDA) for the treatment of multiple myeloma.

 -  Marizomib is an investigational drug being developed by Triphase that is being studied
 for the treatment of multiple myeloma. Investigational drugs are drugs that have not yet
 been approved by health authorities, such as the FDA, for general use but have been
 approved for use in specific clinical studies. Marizomib inhibits a cellular machine
 called the proteasome, which destroys unnecessary or damaged proteins. Other proteasome
 inhibitors have been shown to be effective in the treatment of multiple myeloma.

 -  Dexamethasone is a corticosteroid drug that affects the immune system (an
 immunomodulatory drug) that has been approved by the FDA for the treatment of multiple
 myeloma.

 This is the first study to evaluate the three-drug combination of pomalidomide (POM),
 marizomib (MRZ), and dexamethasone (LD-DEX) in humans. Pomalidomide, alone or in combination
 with dexamethasone, is approved by the FDA for the treatment of relapsed or refractory
 multiple myeloma.

 The primary objective of this study is to determine the best drug dosing levels for this
 three-drug combination, including the highest safe doses and/or the recommended doses for
 future clinical studies of this drug combination. The secondary purposes of this study are to
 determine the safety of this drug combination and its effectiveness in treating relapsed or
 refractory multiple myeloma. The study will include examination of levels of all three drugs
 in the blood during various time points during treatment.
Inclusion Criteria

 Subjects must meet the following criteria to be eligible for study participation:

 1. At least 18 years at the time of signing the informed consent form.

 2. Able to understand and voluntarily sign an informed consent form prior to any
 study-related assessments/procedures.

 3. Able to adhere to the study visit schedule and other protocol requirements.

 4. Documented diagnosis of multiple myeloma and measurable disease by serum or urine
 protein electrophoresis (SPEP or UPEP): SPEP ≥0.5 g/dL, UPEP ≥200 mg/24 hours, or
 involved serum free light chain (FLC) level ≥10 mg/dL provided the serum FLC ratio is
 abnormal.

 5. Previously received 1 or more lines of anti-myeloma therapy that must have included
 both lenalidomide and bortezomib (either separately or in combination).

 6. Documented disease progression during or within 60 days after their most recent line
 of anti myeloma therapy.

 7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.

 8. All study participants in the USA must be registered into the mandatory POMALYST REMS™
 (Risk Evaluation & Mitigation Strategy) program, and be willing and able to comply
 with the requirements of the POMALYST REMS™ program.

 9. All study participants in the USA who are females of child-bearing potential (FCBP)
 must adhere to the scheduled pregnancy testing as required in the POMALYST REMS™
 program.

 10. All study participants outside the USA must agree to comply with the POMALYST® PPRMP
 requirements.

 11. All subjects must be able and agree to take aspirin (81 or 325 mg) daily as
 prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low
 molecular weight heparin).

 12. For females of child bearing potential (FCBP): Agree to use 2 reliable forms of
 contraception simultaneously or practice complete abstinence from heterosexual contact
 for at least 28 days before starting study treatment, while participating in the study
 (including dose interruptions), and for at least 28 days after study treatment
 discontinuation; must follow pregnancy testing requirements as outlined in the
 POMALYST REMS™ program or the PPRMP.

 13. For all females: Agree to abstain from breastfeeding during study participation and
 for at least 28 days after study treatment discontinuation.

 14. For all males: Agree to use a latex or synthetic condom during any sexual contact with
 FCBP while participating in the study and for at least 28 days following
 discontinuation from study treatment, even if he has undergone a successful vasectomy.

 15. For all males: Agree to refrain from donating semen or sperm while on study and for at
 least 28 days after discontinuation from study treatment.

 16. Refrain from donating blood while on study treatment and for at least 28 days after
 discontinuation from study treatment.

 17. Agree not to share medication.

 Exclusion Criteria

 Subjects with any of the following will be excluded from participation in the study:

 1. Peripheral neuropathy Grade ≥2.

 2. Non-secretory multiple myeloma.

 3. Any of the following laboratory abnormalities:

 -  ANC <1,000/µL;

 -  Platelet count <50,000/µL for subjects in whom <50% of bone marrow nucleated
 cells are plasma cells; or a platelet count <30,000/µL for subjects in whom ≥50%
 of bone marrow nucleated cells are plasma cells;

 -  Creatinine clearance (CrCL) <45 mL/min as measured directly or as calculated
 according to Cockcroft Gault formula;

 -  Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L);

 -  Hemoglobin <8 g/dL (<4.9 mmol/L; prior red blood cell [RBC] transfusion or
 recombinant human erythropoietin use is permitted before study entry);

 -  Serum aspartate aminotransferase (AST) >3.0 x upper limit of normal (ULN);

 -  Serum alanine aminotransferase (ALT) >3.0 x ULN;

 -  Serum total bilirubin >1.5 x ULN (>3.0 x ULN for subjects with known Gilbert's
 disease).

 4. Prior history of malignancies, other than MM, unless the subject has been free of the
 disease for ≥5 years. Subjects may be entered earlier than 5 years if they have
 received curative treatment for the following:

 -  Basal cell carcinoma of the skin;

 -  Squamous cell carcinoma of the skin;

 -  Carcinoma in situ of the cervix;

 -  Carcinoma in situ of the breast;

 Or if they have:

 o Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor,
 nodes, metastasis] clinical staging system) or non metastatic prostate cancer that is
 in complete remission or does not require treatment.

 5. Previous therapy with POM and/or MRZ.

 6. History of allergic reaction or hypersensitivity to thalidomide, lenalidomide,
 bortezomib, carfilzomib, boron, mannitol, or DEX.

 7. Grade ≥3 rash during prior thalidomide or lenalidomide therapy.

 8. Gastrointestinal disease that may significantly alter the absorption of POM.

 9. History of the following:

 -  Congestive heart failure of Class III or IV of the New York Heart Association
 (NYHA) classification;

 -  Myocardial infarction within 12 months prior to starting study treatment;

 -  Unstable or poorly controlled angina pectoris, including Prinzmetal variant
 angina pectoris.

 10. Any of the following within 14 days prior to initiation of study treatment:

 -  Plasmapheresis;

 -  Major surgery (kyphoplasty is not considered major surgery);

 -  Radiation therapy;

 -  Anti-myeloma drug therapy.

 11. Received any investigational agents within 28 days or 5 half-lives (whichever is
 longer) prior to initiation of study treatment.

 12. Conditions requiring chronic steroid or immunosuppressive treatment (eg, rheumatoid
 arthritis, multiple sclerosis, or lupus), which likely need additional steroid or
 immunosuppressive treatments in addition to the study treatment.

 13. Subjects may not receive corticosteroids (>10 mg/day of prednisone or equivalent)
 within 3 weeks prior to enrollment (use of steroidal inhalation aerosol for asthma is
 permitted).

 14. Unable or unwilling to undergo antithrombotic prophylactic treatment.

 15. Any condition, including the presence of laboratory abnormalities, which places the
 subject at unacceptable risk if he/she were to participate in the study, as determined
 by the Investigator.

 16. Pregnant and/or breastfeeding females.

 17. Known seropositive for or active viral infection with human immunodeficiency virus
 (HIV).

 18. Known seropositive for or active viral infection with hepatitis B virus (HBV), with
 the following exceptions:

 -  negative are eligible.

 -  Subjects who had hepatitis B but have received an antiviral treatment and show
 non-detectable viral DNA for 6 months are eligible.

 -  Subjects who are seropositive because of hepatitis B virus vaccine are eligible.

 19. Known seropositive for or active viral infection with hepatitis C virus (HCV), with
 the following exception: Subjects who had hepatitis C but have received an antiviral
 treatment and show no detectable viral ribonucleic acid (RNA) for 6 months are
 eligible.