A Study of Carfilzomib vs Best Supportive Care in Subjects With Relapsed and Refractory Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib; Best Supportive Care
Intervention description: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).; Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid).
Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 315.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens
      for subjects with multiple myeloma who have received all available approved treatment options
      and may therefore be considered candidates for palliative care.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Multiple myeloma

          2. Measurable disease based on central laboratory values, as defined by one or both of
             the following criteria (assessed within 21 days prior to randomization):

               -  Serum M-protein

                    -  Serum protein electrophoresis (SPEP): ≥ 0.5 g/dL

                    -  For immunoglobulin A (IgA) patients whose disease can only be reliably
                       measured by serum quantitative immunoglobulin (qIgA): > 750 mg/dL (0.75
                       g/dL)

               -  Urine Bence Jones protein: ≥ 200 mg/24 h

          3. Responsive (defined as a 25% or greater decrease in M-protein or total protein) to at
             least one line of prior therapy

          4. Relapsed multiple myeloma, defined as disease progression while on or after at least 1
             prior treatment regimen

          5. Refractory multiple myeloma, defined as meeting one or more of the following:

               -  Nonresponsive to most recent therapy (eg, stable disease only, or progressive
                  disease while on treatment)

               -  Disease progression within 60 days of discontinuation from most recent therapy

          6. Received 3 or more prior therapeutic regimens for multiple myeloma

          7. Adequate prior treatment with bortezomib (if less than 4 complete cycles, the reason
             for discontinuation must be reviewed by the Medical Monitor and the reason documented)

          8. Prior treatment with an immunomodulatory agent (lenalidomide, if available, and/or
             thalidomide)

          9. Prior treatment with an alkylating agent (standard or high-dose)

         10. Prior treatment with a corticosteroid

         11. Criterion no longer applicable (with Amendment 2, Criterion 11, the requirement of
             "prior treatment with an anthracycline unless not clinically indicated" is removed.)

         12. Age ≥ 18 years

         13. Life expectancy of at least 1 month

         14. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

         15. Adequate hepatic function, with serum alanine aminotransferase (ALT) < 4 times the
             upper limit of normal and serum bilirubin < 2.5 mg/dL (42.5 µmol/L). Patients with
             total bilirubin ≥ 2.5 mg/dL may enrol if their serum direct bilirubin is < 2.5 mg/dL.

         16. Total white blood cell (WBC) count ≥ 1.5 × 10^9/L and absolute neutrophil count (ANC)
             ≥ 1.0 × 10^9/L (use of colony-stimulating factors to achieve these counts is allowed)

         17. Hemoglobin ≥ 7.5 g/dL (75 g/L)

             -Use of erythropoietic stimulating factors is allowed:

               -  For all patients who receive a red blood cell (RBC) transfusion within 28 days of
                  obtaining the Screening hemoglobin value. The following information must be
                  provided for the Medical Monitor's review for assessment for eligibility:

                    -  Pre-transfusion hemoglobin (Hb)

                    -  Number of RBC units administered

                    -  Use of erythropoietic stimulating factors

         18. Platelet count ≥ 30 × 10^9/L

             -There is no restriction on platelet transfusions or thrombopoietic growth factor
             before or during the screening period

               -  For all patients who receive a platelet transfusion within 7 days of obtaining
                  the Screening platelet value, the following information must be provided for the
                  Medical Monitor's review for assessment of eligibility

                    -  Pre-transfusion platelet count

                    -  Number of platelet units administered

                    -  Use of thrombopoietic growth factors

         19. Creatinine clearance (CrCl) ≥ 15 mL/minute (either measured or calculated using a
             standard formula such as Cockcroft and Gault) and dialysis-independent

         20. Written informed consent in accordance with regulatory guidelines

         21. Female patients of childbearing potential must have a negative serum or urine
             pregnancy test within 7 days of the first dose of study treatment and agree to use an
             effective method of contraception during the study and for 3 months following the last
             dose of study treatment. Post-menopausal females (> 45 years old and without menses
             for > 1 year) and surgically sterilized females are exempt from these requirements.
             Male patients must use an effective barrier method of contraception during the study
             and for 3 months following the last dose if sexually active with a female of
             childbearing potential.

        Exclusion Criteria:

          1. Waldenström's macroglobulinemia or IgM myeloma

          2. Refractory to all prior therapies

          3. Disease measurable only by serum free light chain assay (SFLC)

          4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
             skin changes)

          5. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard
             differential)

          6. Prior carfilzomib treatment

          7. Chemotherapy (approved or investigational) within 14 days prior to randomization

          8. Immunotherapy or antibody therapy within 28 days prior to randomization

          9. Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 14 days
             prior to randomization

         10. Radiotherapy within 7 days prior to randomization

         11. Major surgery within 21 days prior to randomization

         12. Congestive heart failure (NYHA Class III or IV) or symptomatic cardiac ischemia,
             conduction system abnormalities uncontrolled by conventional intervention (conduction
             abnormalities not clinically warranting intervention are allowed)

         13. Myocardial infarction in the previous 3 months

         14. Acute active infection requiring systemic treatment (antibiotics, antivirals, or
             antifungals) within 14 days prior to randomization

         15. Known human immunodeficiency virus seropositivity

         16. Active hepatitis A, B, or C infection

         17. Other malignancy within the past 3 years with the exception of a) adequately treated
             basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in
             situ of the cervix, vulva, or breast; c) prostate cancer of Gleason Score 6 or less
             with stable prostate-specific antigen levels; or d) cancer considered cured by
             surgical resection or unlikely to impact survival during the duration of the study,
             such as localized transitional cell carcinoma of the bladder, carcinoma in situ of the
             breast, or benign tumors of the adrenal or pancreas

         18. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of randomization

         19. Any other clinically significant medical disease or condition that, in the
             Investigator's opinion, may interfere with protocol adherence or a patient's ability
             to give informed consent

         20. Pregnant or lactating females

         21. Contraindication to any of the required concomitant drugs or supportive treatments,
             including hypersensitivity or known history of allergy to carfilzomib, Captisol® (a
             cyclodextrin derivative used to solubilize carfilzomib) all anticoagulation and
             antiplatelet options, antiviral drugs; or intolerance to hydration due to preexisting
             pulmonary or cardiac impairment