Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).

Official Title
-----------------
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

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Carfilzomib
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
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: Waldenström macroglobulinemia 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) Myelodysplastic syndrome 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 Radiation therapy: 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), 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 Known cirrhosis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone<br>Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. | Drug: Carfilzomib<br>* Carfilzomib was administered as an IV infusion<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Dexamethasone<br>* Commercially available dexamethasone was obtained by the investigational site.<br>|
| Experimental: Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone<br>Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. | Drug: Carfilzomib<br>* Carfilzomib was administered as an IV infusion<br>* Other names: Kyprolis® (carfilzomib) for Injection;Drug: Dexamethasone<br>* Commercially available dexamethasone was obtained by the investigational site.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment. | From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. | Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively. | 
| Overall Survival | Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive. | From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively. | 
| Number of Participants With Adverse Events (AEs) | The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship. | From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively. | 
| Plasma Carfilzomib Concentration During Cycle 2 | Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL. | Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion |