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Trial record 1 of 1 for:    NCT02412878
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Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma (ARROW)

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ClinicalTrials.gov Identifier: NCT02412878
Recruitment Status : Completed
First Posted : April 9, 2015
Results First Posted : December 13, 2018
Last Update Posted : January 30, 2019
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Multiple Myeloma
Interventions Drug: Carfilzomib
Drug: Dexamethasone
Enrollment 478
Recruitment Details

Participants were enrolled from September 2015 to August 2016 at 118 sites in Australia, New Zealand, Japan, North America, and Europe.

The analysis of results was conducted after 274 progression-free survival events were observed (cut-off date of June 15, 2017). The study is currently ongoing.

Pre-assignment Details

Participants were randomized in a 1:1 ratio to receive a regimen consisting of either once-weekly carfilzomib in combination with dexamethasone.

Randomization was stratified by International Staging System (ISS) stage (stage 1 versus stages 2 or 3), refractory to bortezomib treatment (yes versus no), and age (< 65 versus ≥ 65 years).

Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Period Title: Overall Study
Started 238 240
Received Carfilzomib 235 238
Completed [1] 64 57
Not Completed 174 183
Reason Not Completed
Withdrawal by Subject             18             6
Continuing Study             156             176
Missing             0             1
[1]
Defined as participants who discontinued due to death.
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Total
Hide Arm/Group Description

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Total of all reporting groups
Overall Number of Baseline Participants 238 240 478
Hide Baseline Analysis Population Description
The intention-to-treat population consisted of all randomly assigned participants.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 238 participants 240 participants 478 participants
66.0
(35 to 83)
66.0
(39 to 85)
66.0
(35 to 85)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
18 - 64 years
104
  43.7%
104
  43.3%
208
  43.5%
65 - 74 years
102
  42.9%
90
  37.5%
192
  40.2%
75 - 84 years
32
  13.4%
45
  18.8%
77
  16.1%
≥ 85 years
0
   0.0%
1
   0.4%
1
   0.2%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
Female
110
  46.2%
108
  45.0%
218
  45.6%
Male
128
  53.8%
132
  55.0%
260
  54.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
Hispanic or Latino
5
   2.1%
2
   0.8%
7
   1.5%
Not Hispanic or Latino
226
  95.0%
235
  97.9%
461
  96.4%
Unknown or Not Reported
7
   2.9%
3
   1.3%
10
   2.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
Asian
15
   6.3%
30
  12.5%
45
   9.4%
Black or African American
2
   0.8%
3
   1.3%
5
   1.0%
White
202
  84.9%
200
  83.3%
402
  84.1%
Other
9
   3.8%
4
   1.7%
13
   2.7%
Missing
10
   4.2%
3
   1.3%
13
   2.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
0 (Fully active)
118
  49.6%
118
  49.2%
236
  49.4%
1 (Restrictive but ambulatory)
120
  50.4%
121
  50.4%
241
  50.4%
2 (Ambulatory but unable to work)
0
   0.0%
1
   0.4%
1
   0.2%
[1]
Measure Description: A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Stratification Factor: International Staging System (ISS) stage   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
Stage 1
100
  42.0%
100
  41.7%
200
  41.8%
Stage 2 or 3
138
  58.0%
140
  58.3%
278
  58.2%
[1]
Measure Description:

The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group:

  • Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
  • Stage II: β2M < 3.5 mg/L and albumin < 3.5 g/dL; or β2M 3.5 mg/L - 5.5 mg/L irrespective of the serum albumin
  • Stage III: β2M ≥ 5.5 mg/L
Stratification Factor: Refractory to Bortezomib Treatment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 238 participants 240 participants 478 participants
Yes
88
  37.0%
88
  36.7%
176
  36.8%
No
150
  63.0%
152
  63.3%
302
  63.2%
[1]
Measure Description:

Participants were classified as refractory to bortezomib in prior regimens if the data collected on prior multiple myeloma therapy indicated that any of the following criteria were met:

  1. Best Response to any regimen containing bortezomib was stable disease or progressive disease.
  2. Reason bortezomib was stopped was progression in any regimen.
  3. Date of relapse/progression was after start date and within 60 days after stop date of bortezomib in any regimen.
1.Primary Outcome
Title Progression Free Survival
Hide Description

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.

Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description:

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Overall Number of Participants Analyzed 238 240
Median (95% Confidence Interval)
Unit of Measure: months
7.6
(5.8 to 9.2)
11.2
(8.6 to 13.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments To ensure proper control of type I error, analysis of PFS was performed under a group sequential design framework with the stopping boundaries constructed using the Lan-DeMets spending function with an O'Brien-Fleming approach. The inferential comparison between the 2 treatment groups for PFS used the 1-sided log-rank test stratified by the randomization stratification factors. A 1-sided p-value was compared against the prespecified adjusted alpha value of 0.011 to determine significance.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments Progression-free survival, overall response rate, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
Method Log Rank
Comments One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.693
Confidence Interval (2-Sided) 95%
0.544 to 0.883
Estimation Comments Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using a Cox proportional hazards model stratified by the randomization stratification factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0033
Comments [Not Specified]
Method Log Rank
Comments One-sided unstratified log-rank test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.720
Confidence Interval (2-Sided) 95%
0.567 to 0.913
Estimation Comments Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.
2.Secondary Outcome
Title Overall Response Rate
Hide Description

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.

Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description:

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Overall Number of Participants Analyzed 238 240
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
40.8
(34.5 to 47.3)
62.9
(56.5 to 69.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
Method Cochran-Mantel-Haenszel
Comments One-sided p-value from CMH test stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.485
Confidence Interval (2-Sided) 95%
1.716 to 3.598
Estimation Comments Odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method stratified by the randomization stratification factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.466
Confidence Interval (2-Sided) 95%
1.707 to 3.563
Estimation Comments Odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method.
3.Secondary Outcome
Title Overall Survival
Hide Description

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.

Time Frame 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description:

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Overall Number of Participants Analyzed 238 240
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(18.1 to NA)
NA [1] 
(NA to NA)
[1]
Could not be estimated due to the low number of events
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1070
Comments Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
Method Log Rank
Comments One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.800
Confidence Interval (2-Sided) 95%
0.563 to 1.138
Estimation Comments Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using a Cox proportional hazards model stratified by the randomization stratification factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1326
Comments [Not Specified]
Method Log Rank
Comments One-sided unstratified log-rank test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.820
Confidence Interval (2-Sided) 95%
0.578 to 1.164
Estimation Comments Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.
4.Secondary Outcome
Title Number of Participants With Adverse Events (AEs)
Hide Description

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.

Time Frame From first dose of study drug up to 30 days after last dose, as of the data cutoff of 15 June 2017; median (minimum, maximum) duration of treatment was 29.1 (0.1, 84.3) weeks and 38.0 (0.1, 84.1) weeks in each treatment group respectively.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of study drug
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description:

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Overall Number of Participants Analyzed 235 238
Measure Type: Count of Participants
Unit of Measure: Participants
Adverse events (AEs)
229
  97.4%
227
  95.4%
Adverse events Grade ≥ 3
145
  61.7%
161
  67.6%
Serious adverse events
96
  40.9%
103
  43.3%
AEs leading to discontinuation of carfilzomib
27
  11.5%
30
  12.6%
AEs leading to discontinuation of dexamethasone
27
  11.5%
35
  14.7%
Fatal adverse events
18
   7.7%
22
   9.2%
Treatment-related adverse events (TRAEs)
173
  73.6%
173
  72.7%
Treatment-related adverse events Grade ≥ 3
77
  32.8%
97
  40.8%
Serious treatment-related adverse events
31
  13.2%
50
  21.0%
TRAE leading to discontinuation of carfilzomib
11
   4.7%
19
   8.0%
TRAEs leading to discontinuation of dexamethasone
11
   4.7%
25
  10.5%
Fatal treatment-related adverse events
2
   0.9%
5
   2.1%
5.Secondary Outcome
Title Plasma Carfilzomib Concentration During Cycle 2
Hide Description Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants at a subset of sites who participated in the sparse pharmacokinetic sampling, with available data at each time point.
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description:

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

Overall Number of Participants Analyzed 36 55
Mean (Standard Deviation)
Unit of Measure: ng/mL
Predose Number Analyzed 36 participants 55 participants
36.2  (162) 203  (1380)
15 minutes after start of infusion Number Analyzed 0 participants 46 participants
1370  (1410)
End of infusion Number Analyzed 10 participants 51 participants
1640  (1900) 1130  (928)
30 minutes after end of infusion Number Analyzed 27 participants 46 participants
104  (293) 480  (2300)
Time Frame Mortality - Deaths that occurred from the first dose of study drug until the data cutoff of 15 June 2017; median (minimum, maximum) follow-up time was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively. Adverse Events - From the first dose of study drug until 30 days after the last dose up to the data cutoff of 15 June 2017; median (minimum, maximum) duration of treatment was 29.1 (0.1, 84.3) weeks and 38.0 (0.1, 84.1) weeks in each treatment group respectively.
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Hide Arm/Group Description

Participants received carfilzomib administered by intravenous (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.

Participants received carfilzomib administered by 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.

All-Cause Mortality
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Affected / at Risk (%) Affected / at Risk (%)
Total   67/235 (28.51%)   57/238 (23.95%) 
Show Serious Adverse Events Hide Serious Adverse Events
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Affected / at Risk (%) Affected / at Risk (%)
Total   96/235 (40.85%)   103/238 (43.28%) 
Blood and lymphatic system disorders     
Anaemia  1  7/235 (2.98%)  4/238 (1.68%) 
Anaemia folate deficiency  1  1/235 (0.43%)  0/238 (0.00%) 
Anaemia vitamin B12 deficiency  1  1/235 (0.43%)  0/238 (0.00%) 
Febrile neutropenia  1  0/235 (0.00%)  1/238 (0.42%) 
Haemolytic uraemic syndrome  1  0/235 (0.00%)  1/238 (0.42%) 
Hyperviscosity syndrome  1  0/235 (0.00%)  1/238 (0.42%) 
Thrombocytopenia  1  3/235 (1.28%)  3/238 (1.26%) 
Thrombotic microangiopathy  1  0/235 (0.00%)  1/238 (0.42%) 
Cardiac disorders     
Acute myocardial infarction  1  1/235 (0.43%)  1/238 (0.42%) 
Atrial fibrillation  1  3/235 (1.28%)  2/238 (0.84%) 
Atrial flutter  1  0/235 (0.00%)  1/238 (0.42%) 
Cardiac arrest  1  0/235 (0.00%)  1/238 (0.42%) 
Cardiac failure  1  3/235 (1.28%)  2/238 (0.84%) 
Cardiac failure acute  1  2/235 (0.85%)  3/238 (1.26%) 
Cardiac failure congestive  1  3/235 (1.28%)  1/238 (0.42%) 
Cardiopulmonary failure  1  0/235 (0.00%)  1/238 (0.42%) 
Left ventricular dysfunction  1  1/235 (0.43%)  0/238 (0.00%) 
Myocardial ischaemia  1  0/235 (0.00%)  1/238 (0.42%) 
Stress cardiomyopathy  1  1/235 (0.43%)  0/238 (0.00%) 
Supraventricular tachycardia  1  1/235 (0.43%)  0/238 (0.00%) 
Eye disorders     
Cataract  1  2/235 (0.85%)  0/238 (0.00%) 
Retinal detachment  1  0/235 (0.00%)  1/238 (0.42%) 
Gastrointestinal disorders     
Diarrhoea  1  1/235 (0.43%)  1/238 (0.42%) 
Gastric haemorrhage  1  0/235 (0.00%)  1/238 (0.42%) 
Gastritis  1  0/235 (0.00%)  1/238 (0.42%) 
Nausea  1  0/235 (0.00%)  1/238 (0.42%) 
Pancreatitis  1  1/235 (0.43%)  0/238 (0.00%) 
Peritoneal haematoma  1  0/235 (0.00%)  1/238 (0.42%) 
Rectal haemorrhage  1  1/235 (0.43%)  0/238 (0.00%) 
Retroperitoneal haematoma  1  0/235 (0.00%)  1/238 (0.42%) 
General disorders     
Asthenia  1  0/235 (0.00%)  2/238 (0.84%) 
Catheter site vesicles  1  1/235 (0.43%)  0/238 (0.00%) 
Chest pain  1  0/235 (0.00%)  1/238 (0.42%) 
Critical illness  1  1/235 (0.43%)  0/238 (0.00%) 
Death  1  1/235 (0.43%)  1/238 (0.42%) 
Disease progression  1  3/235 (1.28%)  2/238 (0.84%) 
Fatigue  1  0/235 (0.00%)  3/238 (1.26%) 
Papillitis  1  1/235 (0.43%)  0/238 (0.00%) 
Pyrexia  1  5/235 (2.13%)  4/238 (1.68%) 
Hepatobiliary disorders     
Cholecystitis acute  1  1/235 (0.43%)  0/238 (0.00%) 
Hepatic failure  1  1/235 (0.43%)  0/238 (0.00%) 
Infections and infestations     
Bronchitis  1  4/235 (1.70%)  0/238 (0.00%) 
Bronchitis bacterial  1  0/235 (0.00%)  1/238 (0.42%) 
Bronchopulmonary aspergillosis  1  1/235 (0.43%)  0/238 (0.00%) 
Diverticulitis  1  1/235 (0.43%)  0/238 (0.00%) 
Erysipelas  1  1/235 (0.43%)  0/238 (0.00%) 
Gastroenteritis  1  1/235 (0.43%)  1/238 (0.42%) 
Infected skin ulcer  1  1/235 (0.43%)  0/238 (0.00%) 
Infection  1  2/235 (0.85%)  4/238 (1.68%) 
Influenza  1  2/235 (0.85%)  3/238 (1.26%) 
Lower respiratory tract infection  1  1/235 (0.43%)  2/238 (0.84%) 
Lower respiratory tract infection viral  1  1/235 (0.43%)  0/238 (0.00%) 
Lung infection  1  0/235 (0.00%)  3/238 (1.26%) 
Lung infection pseudomonal  1  0/235 (0.00%)  1/238 (0.42%) 
Neutropenic infection  1  1/235 (0.43%)  0/238 (0.00%) 
Osteomyelitis  1  1/235 (0.43%)  0/238 (0.00%) 
Otitis media acute  1  0/235 (0.00%)  1/238 (0.42%) 
Periodontitis  1  1/235 (0.43%)  0/238 (0.00%) 
Pneumonia  1  17/235 (7.23%)  20/238 (8.40%) 
Pneumonia bacterial  1  3/235 (1.28%)  3/238 (1.26%) 
Pneumonia haemophilus  1  0/235 (0.00%)  1/238 (0.42%) 
Pneumonia streptococcal  1  1/235 (0.43%)  0/238 (0.00%) 
Pyelonephritis acute  1  1/235 (0.43%)  0/238 (0.00%) 
Respiratory syncytial virus infection  1  2/235 (0.85%)  0/238 (0.00%) 
Respiratory tract infection  1  1/235 (0.43%)  2/238 (0.84%) 
Sepsis  1  3/235 (1.28%)  6/238 (2.52%) 
Septic shock  1  1/235 (0.43%)  5/238 (2.10%) 
Spinal cord infection  1  1/235 (0.43%)  0/238 (0.00%) 
Upper respiratory tract infection  1  4/235 (1.70%)  0/238 (0.00%) 
Urinary tract infection  1  1/235 (0.43%)  2/238 (0.84%) 
Wound infection bacterial  1  1/235 (0.43%)  0/238 (0.00%) 
Injury, poisoning and procedural complications     
Contusion  1  1/235 (0.43%)  0/238 (0.00%) 
Fall  1  1/235 (0.43%)  0/238 (0.00%) 
Femoral neck fracture  1  0/235 (0.00%)  1/238 (0.42%) 
Femur fracture  1  1/235 (0.43%)  1/238 (0.42%) 
Infusion related reaction  1  1/235 (0.43%)  1/238 (0.42%) 
Limb traumatic amputation  1  1/235 (0.43%)  0/238 (0.00%) 
Rib fracture  1  2/235 (0.85%)  0/238 (0.00%) 
Upper limb fracture  1  0/235 (0.00%)  1/238 (0.42%) 
Investigations     
Alanine aminotransferase increased  1  0/235 (0.00%)  1/238 (0.42%) 
Aspartate aminotransferase increased  1  0/235 (0.00%)  1/238 (0.42%) 
Blood creatinine increased  1  2/235 (0.85%)  2/238 (0.84%) 
Blood lactate dehydrogenase increased  1  0/235 (0.00%)  1/238 (0.42%) 
C-reactive protein increased  1  0/235 (0.00%)  1/238 (0.42%) 
Ejection fraction decreased  1  1/235 (0.43%)  1/238 (0.42%) 
Liver function test abnormal  1  1/235 (0.43%)  0/238 (0.00%) 
Platelet count decreased  1  2/235 (0.85%)  2/238 (0.84%) 
Metabolism and nutrition disorders     
Dehydration  1  0/235 (0.00%)  1/238 (0.42%) 
Diabetes mellitus  1  1/235 (0.43%)  0/238 (0.00%) 
Hypercalcaemia  1  4/235 (1.70%)  2/238 (0.84%) 
Hyperglycaemia  1  1/235 (0.43%)  0/238 (0.00%) 
Hyperuricaemia  1  0/235 (0.00%)  1/238 (0.42%) 
Tumour lysis syndrome  1  1/235 (0.43%)  4/238 (1.68%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/235 (0.43%)  0/238 (0.00%) 
Back pain  1  2/235 (0.85%)  0/238 (0.00%) 
Bone pain  1  1/235 (0.43%)  2/238 (0.84%) 
Osteolysis  1  1/235 (0.43%)  1/238 (0.42%) 
Pain in extremity  1  1/235 (0.43%)  0/238 (0.00%) 
Pathological fracture  1  1/235 (0.43%)  3/238 (1.26%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung adenocarcinoma  1  0/235 (0.00%)  1/238 (0.42%) 
Myelodysplastic syndrome  1  0/235 (0.00%)  1/238 (0.42%) 
Plasma cell leukaemia  1  1/235 (0.43%)  0/238 (0.00%) 
Plasma cell myeloma  1  7/235 (2.98%)  4/238 (1.68%) 
Plasmacytoma  1  1/235 (0.43%)  1/238 (0.42%) 
Urethral neoplasm  1  1/235 (0.43%)  0/238 (0.00%) 
Nervous system disorders     
Altered state of consciousness  1  0/235 (0.00%)  1/238 (0.42%) 
Cerebral haemorrhage  1  0/235 (0.00%)  1/238 (0.42%) 
Cerebrovascular accident  1  0/235 (0.00%)  1/238 (0.42%) 
Intracranial mass  1  0/235 (0.00%)  1/238 (0.42%) 
Spinal cord compression  1  0/235 (0.00%)  1/238 (0.42%) 
Syncope  1  0/235 (0.00%)  1/238 (0.42%) 
Psychiatric disorders     
Bradyphrenia  1  0/235 (0.00%)  1/238 (0.42%) 
Delirium  1  1/235 (0.43%)  0/238 (0.00%) 
Renal and urinary disorders     
Acute kidney injury  1  8/235 (3.40%)  10/238 (4.20%) 
Renal failure  1  3/235 (1.28%)  1/238 (0.42%) 
Renal impairment  1  1/235 (0.43%)  0/238 (0.00%) 
Reproductive system and breast disorders     
Pelvic pain  1  1/235 (0.43%)  0/238 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute lung injury  1  0/235 (0.00%)  2/238 (0.84%) 
Acute respiratory distress syndrome  1  0/235 (0.00%)  1/238 (0.42%) 
Aspiration  1  1/235 (0.43%)  0/238 (0.00%) 
Dyspnoea  1  1/235 (0.43%)  0/238 (0.00%) 
Epistaxis  1  1/235 (0.43%)  1/238 (0.42%) 
Hypoxia  1  1/235 (0.43%)  0/238 (0.00%) 
Interstitial lung disease  1  0/235 (0.00%)  1/238 (0.42%) 
Lung consolidation  1  1/235 (0.43%)  0/238 (0.00%) 
Pleural effusion  1  2/235 (0.85%)  1/238 (0.42%) 
Pulmonary alveolar haemorrhage  1  0/235 (0.00%)  1/238 (0.42%) 
Pulmonary arterial hypertension  1  0/235 (0.00%)  1/238 (0.42%) 
Pulmonary congestion  1  0/235 (0.00%)  1/238 (0.42%) 
Pulmonary embolism  1  0/235 (0.00%)  4/238 (1.68%) 
Pulmonary hypertension  1  0/235 (0.00%)  1/238 (0.42%) 
Pulmonary oedema  1  1/235 (0.43%)  0/238 (0.00%) 
Respiratory failure  1  2/235 (0.85%)  0/238 (0.00%) 
Social circumstances     
Homicide  1  0/235 (0.00%)  1/238 (0.42%) 
Vascular disorders     
Deep vein thrombosis  1  2/235 (0.85%)  0/238 (0.00%) 
Hypertension  1  1/235 (0.43%)  0/238 (0.00%) 
Hypotension  1  1/235 (0.43%)  0/238 (0.00%) 
Pelvic venous thrombosis  1  0/235 (0.00%)  1/238 (0.42%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Affected / at Risk (%) Affected / at Risk (%)
Total   202/235 (85.96%)   207/238 (86.97%) 
Blood and lymphatic system disorders     
Anaemia  1  69/235 (29.36%)  61/238 (25.63%) 
Neutropenia  1  23/235 (9.79%)  18/238 (7.56%) 
Thrombocytopenia  1  19/235 (8.09%)  29/238 (12.18%) 
Gastrointestinal disorders     
Constipation  1  22/235 (9.36%)  19/238 (7.98%) 
Diarrhoea  1  46/235 (19.57%)  44/238 (18.49%) 
Nausea  1  26/235 (11.06%)  34/238 (14.29%) 
Vomiting  1  12/235 (5.11%)  19/238 (7.98%) 
General disorders     
Asthenia  1  25/235 (10.64%)  22/238 (9.24%) 
Fatigue  1  47/235 (20.00%)  47/238 (19.75%) 
Oedema peripheral  1  25/235 (10.64%)  18/238 (7.56%) 
Pyrexia  1  35/235 (14.89%)  53/238 (22.27%) 
Infections and infestations     
Bronchitis  1  21/235 (8.94%)  27/238 (11.34%) 
Respiratory tract infection  1  21/235 (8.94%)  16/238 (6.72%) 
Upper respiratory tract infection  1  25/235 (10.64%)  31/238 (13.03%) 
Viral upper respiratory tract infection  1  30/235 (12.77%)  24/238 (10.08%) 
Investigations     
Blood creatinine increased  1  5/235 (2.13%)  12/238 (5.04%) 
Neutrophil count decreased  1  5/235 (2.13%)  12/238 (5.04%) 
Platelet count decreased  1  21/235 (8.94%)  24/238 (10.08%) 
Metabolism and nutrition disorders     
Decreased appetite  1  12/235 (5.11%)  13/238 (5.46%) 
Hypokalaemia  1  10/235 (4.26%)  19/238 (7.98%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  12/235 (5.11%)  15/238 (6.30%) 
Back pain  1  27/235 (11.49%)  28/238 (11.76%) 
Bone pain  1  14/235 (5.96%)  19/238 (7.98%) 
Muscle spasms  1  20/235 (8.51%)  21/238 (8.82%) 
Musculoskeletal pain  1  11/235 (4.68%)  12/238 (5.04%) 
Pain in extremity  1  17/235 (7.23%)  15/238 (6.30%) 
Nervous system disorders     
Headache  1  23/235 (9.79%)  25/238 (10.50%) 
Psychiatric disorders     
Insomnia  1  47/235 (20.00%)  35/238 (14.71%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  30/235 (12.77%)  35/238 (14.71%) 
Dyspnoea  1  22/235 (9.36%)  23/238 (9.66%) 
Skin and subcutaneous tissue disorders     
Rash  1  12/235 (5.11%)  7/238 (2.94%) 
Vascular disorders     
Hypertension  1  47/235 (20.00%)  51/238 (21.43%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02412878     History of Changes
Other Study ID Numbers: CFZ014
2014-005325-12 ( EudraCT Number )
20140355 ( Other Identifier: Amgen Study ID )
First Submitted: April 6, 2015
First Posted: April 9, 2015
Results First Submitted: October 24, 2018
Results First Posted: December 13, 2018
Last Update Posted: January 30, 2019