A Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma

This is a Phase 1/2, multicenter, single-arm, nonrandomized, open-label and dose-escalation study of weekly carfilzomib and dexamethasone for patients with progressive multiple myeloma. The Phase 1 dose escalation portion will enroll patients into sequential dose-escalating cohorts consisting of 3 patients each to establish the maximum tolerated dose (MTD) of carfilzomib administered weekly as a 30 minute intravenous (IV) infusion with dexamethasone. The Phase 2 portion will enroll patients using the MTD established for carfilzomib from the Phase 1 portion of the study. Dexamethasone will be administered IV or orally at the same dose and schedule as used in the Phase 1 portion of the study.

Inclusion criteria

• Multiple myeloma with relapsing or progressive disease at study entry
• Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment):

• Serum M-protein ≥ 0.5 g/dL, or
• Urine M-protein ≥ 200 mg/24 hours, or
• Only in patients who do not meet a or b, then use serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa/lambda ratio
• Prior treatment with 1 to 3 prior regimens for multiple myeloma for Phase 1 and Phase 2 (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy
• Age ≥ 18 years
• Life expectancy ≥ 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate hepatic function within 21 days prior to enrollment, with bilirubin < 1.5 × the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN
• Left ventricular ejection fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated acquisition scan (MUGA) is acceptable if ECHO is not available
• Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to enrollment. Screening ANC is to be independent of growth factor support for ≥ 1 week
• Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion must have been at least 7 days prior to obtaining screening hemoglobin
• Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%) within 21 days prior to enrollment. Patients must not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count
• Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min within 21 days prior to enrollment. Calculation based on standard formula, such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female
• Written informed consent in accordance with federal, local, and institutional guidelines
• Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test
• Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with an FCBP

Exclusion criteria

• Multiple myeloma of Immunoglobulin M (IgM) subtype
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
• Waldenström's macroglobulinemia
• Amyloidosis
• Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to enrollment
• Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment
• Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment
• Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to < 30% of the bone marrow)
• Immunotherapy within 21 days prior to enrollment
• Major surgery within 21 days prior to enrollment
• Active congestive heart failure (New York Heart Association [NYHA] Classes III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment
• Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B virus [HBV]), or antifungal agents within 14 days prior to enrollment
• Known human immunodeficiency virus (HIV) seropositivity
• Known hepatitis B or C virus infection (except for patients with HBV who are receiving and responding to HBV antiviral therapy: these patients are allowed)
• Patients with known cirrhosis
• Second malignancy within the past 3 years, except:

• Adequately treated basal cell or squamous cell skin cancer
• Carcinoma in situ of the cervix
• Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
• Breast carcinoma in situ with full surgical resection
• Treated medullary or papillary thyroid cancer
• Patients with myelodysplastic syndrome
• Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment
• Female patients who are pregnant or lactating
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
• Prior carfilzomib treatment
• Prior participation in any Onyx-sponsored Phase 3 trial
• Patients with contraindication to dexamethasone
• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
• Ongoing graft-versus-host disease
• Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
• Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent