A Study in Subjects With Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination With Dexamethasone, Comparing Once-weekly Versus Twice-weekly Carfilzomib Dosing (ARROW)
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The purpose of the study is to compare once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).
A Randomized, Open-label, Phase 3 Study in Subjects With Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination With Dexamethasone, Comparing Once-weekly Versus Twice-weekly Carfilzomib Dosing
Actual Study Start Date :
September 9, 2015
Actual Primary Completion Date :
June 15, 2017
Estimated Study Completion Date :
December 31, 2018
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Overall Response Rate (ORR) [ Time Frame: 19 months ]
Overall Response Rate (ORR) is defined as the proportion of subjects who achieve a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) in accordance with International Myeloma Working Group-Uniform Response Criteria (IMWG-URC).
Progression Free Survival (PFS) [ Time Frame: 19 months ]
Progression Free Survival (PFS) is defined as the time in months from randomization to the earlier of disease progression or death due to any cause
Secondary Outcome Measures :
Progression-Free Survival (PFS) [ Time Frame: 25 months ]
Progression-free survival (PFS) is defined as the time from randomization to the earlier of disease progression or death due to any cause.
Overall Survival (OS) [ Time Frame: 25 months ]
Overall Survival (OS) is defined as the time from randomization to death due to any cause.
Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 25 months ]
Safety and tolerability will be assessed by the incidence and severity of Adverse Events (AEs).
Laboratory Values [ Time Frame: 25 months ]
For laboratory values, the baseline values and changes from baseline to the minimum, maximum, and last observed values will be summarized descriptively by visit. Laboratory test results will be graded using the NCI-CTCAE (version 4.03).
Vital Signs [ Time Frame: 25 months ]
Vital sign results will be summarized descriptively for baseline values and changes from baseline to the minimum, maximum, and last observed values.
Electrocardiogram (ECG) QT-interval [ Time Frame: 25 months ]
Twelve-lead electrocardiograms (ECGs) including corrected QT-interval (QTc; representing the corrected duration of ventricular electrical activity) will be performed locally.
Pharmacokinetics (PK) Plasma Samples (Concentrations of carfilzomib) [ Time Frame: 17 months ]
Concentrations of carfilzomib will be measured in plasma with a validated assay method.
Overall Response Rate (ORR) [ Time Frame: 19 months ]
Overall Response Rate (ORR) is defined as the proportion of subjects who achieve a best overall response of partial response (PR), very good partial response (VGPR), complete response (sCR), or stringent complete response (CR) in accordance with International Myeloma Working Group-Uniform Response Criteria (IMWG-URC).
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Ages Eligible for Study:
18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Key Inclusion Criteria:
Relapsed multiple myeloma
Refractory multiple myeloma defined as meeting 1 or more of the following:
Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or
Disease progression within 60 days of discontinuation from most recent therapy
At least 2 but no more than 3 prior therapies for multiple myeloma
Prior exposure to an immunomodulatory agent (IMiD)
Prior exposure to a proteasome inhibitor (PI)
Documented response of at least partial response (PR) to 1 line of prior therapy
Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization:
Serum M-protein ≥ 0.5 g/dL
Urine M-protein ≥ 200 mg/24 hours
In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization
Adequate organ and bone marrow function within the 21 days prior to randomization defined by:
Bilirubin < 1.5 times the upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN
Absolute neutrophil count (ANC) ≥ 1000/mm3 (screening ANC should be independent of growth factor support for ≥ 1 week)
Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)
Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is > 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.)
Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min
Key Exclusion Criteria:
Multiple myeloma of Immunoglobin M (IgM) subtype
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
Second malignancy within the past 5 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
Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
Treated medullary or papillary thyroid cancer
Similar condition with an expectation of > 95% five-year disease-free survival
History of or current amyloidosis
Cytotoxic chemotherapy within the 28 days prior to randomization
Immunotherapy within the 21 days prior to randomization
Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone
Focal therapy within the 7 days prior to randomization
Extended field therapy within the 21 days prior to randomization
Prior treatment with either carfilzomib or oprozomib
Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment
Active congestive heart failure (New York Heart Association [NYHA] Class III or IV, refer to Appendix F), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment
Active infection within the 14 days prior to randomization requiring systemic antibiotics
Pleural effusions requiring thoracentesis within the 14 days prior to randomization
Ascites requiring paracentesis within the 14 days prior to randomization
Ongoing graft-versus-host disease
Uncontrolled hypertension or uncontrolled diabetes despite medication
Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization