Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

Inclusion criteria

• Disease Related

• Multiple myeloma
• Subjects must have measurable disease defined as one of the following:

• Serum M-protein ≥ 1 g/dL
• Urine M-protein ≥ 200 mg/24 hours
• Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only)
• Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only)
• Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy
• 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.
• Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only)
• Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide
• Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only)
• Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only)
• Demographic

• Males and females > 18 years of age
• Life expectancy of more than three months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Laboratory

• Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal
• Uric acid within normal range (A0 Only)
• Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only)
• Absolute neutrophil count > 1,000/mm3, hemoglobin > 8.0 g/dL, and platelet count > 50,000/mm3 (A1 Only)

• Subjects should be platelet transfusion independent
• Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
• Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
• Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female.
• Ethical / Other

• Written informed consent in accordance with federal, local, and institutional guidelines
• Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

Exclusion criteria

• Disease Related

• Multiple Myeloma IgM (A1 Only)
• Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only)
• Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum and < 200 mg/24 hr M-protein in urine
• Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only)
• Glucocorticoid therapy (prednisone > 10 mg/day orally or equivalent) within the last three weeks
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia
• Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose
• Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose
• Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater
• Prior treatment with carfilzomib
• Concurrent Conditions

• Major surgery within three weeks before Day 1
• Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF < 40
• Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
• Known or suspected HIV infection or subjects who are HIV seropositive
• Active hepatitis A,B,or C infection
• Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer <Gleason Grade 6 with stable PSA
• Subjects with treatment related myelodysplastic syndrome
• Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
• Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac or renal impairment (A1 Only)
• Subjects with known or suspected amyloidosis (A1 Only)
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only)
• Any 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 (A1 Only)
• Ethical / Other

• Female subjects who are pregnant or lactating
• Serious psychiatric or medical conditions that could interfere with treatment