Study of High Dose Carfilzomib in Multiple Myeloma Patients Who Have Progressed On Standard Dose Carfilzomib
Condition: Relapse Multiple Myeloma; Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib
Intervention description: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed Multiple Myeloma; Refractory Multiple Myeloma; High-Dose Carfilzomib; Standard Dose Carfilzomib; Carfilzomib

Summary:

      The purpose of this study is to determine the safety and activity of the investigational drug
      known as carfilzomib in the treatment of multiple myeloma (MM) when it is given at doses
      above the usual dose after the standard dosing has become ineffective. The other purpose of
      this study is to understand what causes the multiple myeloma to become resistant to
      carfilzomib and whether this can be overcome in the laboratory.
    

Eligibility criteria:

        Inclusion Criteria:

        Disease-related:

          1. Multiple myeloma

          2. Subjects must have measurable disease, defined as one or both of the following:

               1. Serum M-protein ≥ 1.0 g/dL

               2. Urine M-protein ≥ 200 mg/24 hours

               3. Free light chains: Only in patients without measureable serum and urine M-protein
                  levels: the difference between involved and uninvolved FLC levels must be at
                  least 10 mg/dl.

          3. Refractory to the most recently received therapy. Refractory disease is defined as ≤
             25% response or progression during therapy or within 60 days after completion of
             therapy.

          4. Subjects must have progressed on standard dose 20/27 mg/m2 and schedule of carfilzomib
             without having had any carfilzomib related grade 3 or 4 toxicities.

          5. Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy
             and stem cell transplant will be considered as one regimen

          6. Subjects must have received prior treatment with bortezomib, and either thalidomide or
             lenalidomide

          7. Subjects must have received an alkylating agent unless contraindicated. Subjects may
             have received these agents alone or in combination with other myeloma treatments.

        Demographic:

          1. Age ≥ 18 years

          2. Life expectancy ≥ 3 months

          3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

        Laboratory/Radiology

          1. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and
             serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization

          2. Uric acid, if elevated, must be corrected to within laboratory normal range prior to
             dosing

          3. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization
             independent of G-CSF for ≥ 1 week and pegylated G-CSF for ≥ 2 weeks

          4. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be
             receiving red blood cell [RBC] transfusions in accordance with institutional
             guidelines)

          5. Screening platelet count ≥ 50 × 109/L independent of platelet transfusions for at
             least 2 weeks

          6. Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization,
             either measured or calculated using a standard formula (eg, Cockcroft and Gault)

          7. LVEF ≥ 40% within 30 days before Cycle 1 Day 1. 2-D Transthoracic Echocardiogram
             (ECHO) is the preferred method of evaluation; MUGA is acceptable if ECHO is not
             available.

        Exclusion Criteria:

        Disease-related

          1. Glucocorticoid therapy (prednisone > 10 mg/day or equivalent) within the last three
             weeks

          2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
             skin changes)

          3. Chemotherapy with approved or investigative anticancer therapeutics including steroid
             therapy within the three weeks prior to first dose (unless enrolling on this study
             after progression CMAP compassionate use carfilzomib protocol, in which case subject
             may proceed with current study treatment on next expected date of treatment)

          4. Radiation therapy or immunotherapy in the previous four weeks; localized radiation
             therapy within 1 week prior to first dose

          5. Participation in an investigational therapeutic study within three weeks or within
             five drug half-lives (t1/2) prior to first dose, whichever time is greater (unless
             enrolling after progression on CMAP compassionate use carfilzomib protocol)

        Concurrent Conditions

          1. Pregnant or lactating females

          2. Major surgery within 21 days prior to randomization

          3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or
             antifungals) within 14 days prior to randomization

          4. Known human immunodeficiency virus infection

          5. Known active hepatitis B or C infection

          6. Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA
             Class III or IV heart failure, uncontrolled angina, history of severe coronary artery
             disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or
             electrocardiographic evidence of acute ischemia or Grade 3 conduction system
             abnormalities unless subject has a pacemaker

          7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to
             randomization

          8. Nonhematologic 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 or breast; c) prostate cancer of Gleason Grade 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 or benign tumors of the
             adrenal or pancreas

          9. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to
             randomization

         10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize
             carfilzomib)

         11. Contraindication to any of the required concomitant drugs or supportive treatments,
             including antiviral drugs, or intolerance to hydration due to preexisting pulmonary or
             cardiac impairment

         12. Subjects with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis within 14 days prior to randomization

         13. Any other clinically significant medical disease or condition that, in the
             Investigator's opinion, may interfere with protocol adherence or a subject's ability
             to give informed consent