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Study of the Pharmacokinetics and Safety of Carfilzomib in Patients With Advanced Malignancies and Hepatic Impairment

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ClinicalTrials.gov Identifier: NCT01949545
Recruitment Status : Completed
First Posted : September 24, 2013
Results First Posted : October 21, 2016
Last Update Posted : May 2, 2017
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Conditions Solid Tumors
Hematologic Malignancies
Hepatic Impairment
Intervention Drug: Carfilzomib
Enrollment 46
Recruitment Details  
Pre-assignment Details

Participants were assigned to 1 of 4 cohorts with varying degrees of hepatic impairment defined by the National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema for hepatic function.

Completed indicates participants who completed the safety follow-up visit 30 days after the last dose of carfilzomib.
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Period Title: Overall Study
Started 11 17 14 4
Completed 11 17 14 4
Not Completed 0 0 0 0
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment Total
Hide Arm/Group Description Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Total of all reporting groups
Overall Number of Baseline Participants 11 17 14 4 46
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 11 participants 17 participants 14 participants 4 participants 46 participants
68.5  (8.2) 59.5  (9.1) 61.0  (7.9) 56.3  (10.9) 61.8  (9.3)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 11 participants 17 participants 14 participants 4 participants 46 participants
< 65 years 3 12 8 3 26
≥ 65 years 8 5 6 1 20
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants 17 participants 14 participants 4 participants 46 participants
Female
2
  18.2%
8
  47.1%
5
  35.7%
3
  75.0%
18
  39.1%
Male
9
  81.8%
9
  52.9%
9
  64.3%
1
  25.0%
28
  60.9%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 11 participants 17 participants 14 participants 4 participants 46 participants
Black 0 1 1 0 2
White 11 13 13 4 41
Not reported 0 3 0 0 3
1.Primary Outcome
Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m²
Hide Description The area under the curve from time zero (defined as the start of carfilzomib infusion) to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population, defined as participants who received the intended carfilzomib dose (27 or 56 mg/m²) and who had plasma concentration versus time data for the estimation of each pharmacokinetic (PK) parameter by a non-compartmental analysis.
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
378
(40.8%)
546
(39.2%)
477
(33.1%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Hepatic Function, Mild Hepatic Impairment
Comments To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-last an analysis of variance (ANOVA) of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02232
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 144.43
Confidence Interval (2-Sided) 95%
111.48 to 187.12
Estimation Comments The geometric mean ratio was calculated by exponentiation of the differences in the least squares means, using log-transformed data, between the hepatic impairment cohort (test) and participants with normal hepatic function (reference).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Normal Hepatic Function, Moderate Hepatic Impairment
Comments To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-last an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1812
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 126.08
Confidence Interval (2-Sided) 95%
94.59 to 168.06
Estimation Comments The geometric mean ratio was calculated by exponentiation of the differences in the least squares means, using log-transformed data, between the hepatic impairment cohort (test) and participants with normal hepatic function (reference).
2.Primary Outcome
Title Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m²
Hide Description The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 12 7 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
348
(35.4%)
529
(40.3%)
500
(38.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Normal Hepatic Function, Mild Hepatic Impairment
Comments To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-inf an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02137
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 151.84
Confidence Interval (2-Sided) 95%
113.59 to 202.96
Estimation Comments The geometric mean ratio was calculated by exponentiation of the differences in the least squares means, using log-transformed data, between the hepatic impairment cohort (test) and participants with normal hepatic function (reference).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Normal Hepatic Function, Moderate Hepatic Impairment
Comments To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-inf an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.07247
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 143.53
Confidence Interval (2-Sided) 95%
103.28 to 199.45
Estimation Comments The geometric mean ratio was calculated by exponentiation of the differences in the least squares means, using log-transformed data, between the hepatic impairment cohort (test) and participants with normal hepatic function (reference).
3.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
932
(58.4%)
1290
(47.5%)
1020
(43.7%)
4.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Median (Full Range)
Unit of Measure: hours
0.292
(0.250 to 0.500)
0.458
(0.250 to 0.667)
0.483
(0.233 to 0.750)
5.Secondary Outcome
Title Clearance of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 12 7 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hour
157
(32.5%)
86.4
(50.9%)
103
(43.9%)
6.Secondary Outcome
Title Terminal Half-life of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 12 7 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
0.469
(22.8%)
0.541
(75.9%)
0.511
(219.4%)
7.Secondary Outcome
Title Mean Residence Time (MRT) of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 12 7 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
0.108
(60.6%)
0.167
(45.7%)
0.235
(70.4%)
8.Secondary Outcome
Title Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 12 7 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters
16.9
(37.0%)
14.4
(58.1%)
24.2
(66.0%)
9.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m²
Hide Description The area under the curve from time zero to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
765
(100.5%)
1107
(73.7%)
927
(45.8%)
10.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m²
Hide Description The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 6 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
609
(99.6%)
1108
(73.7%)
929
(46.2%)
11.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1697
(93.7%)
2733
(67.0%)
2119
(47.9%)
12.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 8 8 5 0
Median (Full Range)
Unit of Measure: hours
0.300
(0.250 to 0.583)
0.408
(0.250 to 0.683)
0.400
(0.250 to 0.583)
13.Secondary Outcome
Title Terminal Half-life of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 6 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
0.508
(54.7%)
0.621
(47.7%)
0.740
(137.7%)
14.Secondary Outcome
Title Clearance of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 6 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hour
181
(95.9%)
92.0
(77.2%)
121
(43.5%)
15.Secondary Outcome
Title Mean Residence Time (MRT) of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 6 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
0.0834
(195.6%)
0.161
(43.6%)
0.164
(30.7%)
16.Secondary Outcome
Title Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m²
Hide Description [Not Specified]
Time Frame Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 6 8 5 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters
15.0
(52.2%)
14.8
(51.9%)
19.8
(36.7%)
17.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population, defined as all participants who had adequate carfilzomib exposure and plasma concentration versus time data for the estimation of PK parameters by a non-compartmental analysis at each time point.
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
463
(42.5%)
417
(30.5%)
385
(26.8%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
837
(26.8%)
752
(29.7%)
786
(20.3%)
18.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 4 11 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0
400
(19.3%)
432
(29.9%)
437
(32.7%)
Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0
834
(6.3%)
770
(27.2%)
843
(22.3%)
19.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
189
(32.5%)
198
(22.7%)
201
(26.5%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
381
(15.0%)
345
(25.9%)
513
(24.3%)
20.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Median (Full Range)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
0.867
(0.583 to 1.52)
0.792
(0.633 to 1.50)
0.750
(0.583 to 1.00)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
0.842
(0.750 to 1.48)
0.992
(0.750 to 1.60)
0.750
(0.650 to 0.783)
21.Secondary Outcome
Title Terminal Half-life for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 4 11 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0
1.42
(10.3%)
1.20
(13.7%)
1.26
(18.0%)
Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0
1.32
(15.3%)
1.30
(16.1%)
1.07
(13.6%)
22.Secondary Outcome
Title Mean Residence Time (MRT) for Metabolite PR-389/M14
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 4 11 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0
2.42
(11.4%)
2.13
(12.2%)
2.14
(16.0%)
Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0
2.25
(10.8%)
2.27
(15.8%)
1.78
(11.2%)
23.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
50.1
(39.5%)
56.7
(33.9%)
85.5
(36.6%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
106
(33.7%)
119
(38.9%)
173
(17.8%)
24.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 13 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0
56.6
(43.7%)
60.8
(32.6%)
92.9
(41.7%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
116
(36.9%)
132
(41.0%)
186
(18.2%)
25.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
27.8
(30.5%)
33.9
(30.7%)
46.3
(26.6%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
59.4
(27.5%)
66.0
(37.2%)
103
(19.5%)
26.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Median (Full Range)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
0.750
(0.583 to 0.767)
0.767
(0.583 to 1.00)
0.650
(0.583 to 1.10)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
0.717
(0.600 to 1.00)
0.800
(0.467 to 1.08)
0.750
(0.617 to 0.750)
27.Secondary Outcome
Title Terminal Half-life for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 13 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0
1.34
(18.9%)
1.25
(13.6%)
1.23
(17.6%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
1.18
(21.8%)
1.24
(10.2%)
1.07
(16.0%)
28.Secondary Outcome
Title Mean Residence Time (MRT) for Metabolite PR-413/M15
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 13 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0
2.13
(15.8%)
2.02
(8.8%)
2.04
(14.6%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
1.96
(18.9%)
2.09
(8.0%)
1.83
(8.9%)
29.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
125
(27.6%)
136
(45.2%)
228
(37.3%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
278
(23.4%)
311
(42.9%)
463
(24.5%)
30.Secondary Outcome
Title Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0
127
(27.8%)
138
(44.9%)
235
(39.4%)
Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0
281
(25.6%)
314
(42.7%)
465
(24.4%)
31.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
145
(30.7%)
160
(42.0%)
257
(43.6%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
314
(33.6%)
349
(39.5%)
546
(23.4%)
32.Secondary Outcome
Title Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 9 0
Median (Full Range)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
0.500
(0.250 to 0.667)
0.600
(0.250 to 0.750)
0.700
(0.583 to 0.850)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
0.483
(0.250 to 0.617)
0.592
(0.250 to 0.850)
0.583
(0.467 to 0.650)
33.Secondary Outcome
Title Terminal Half-life for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description:
Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0
0.786
(14.0%)
0.728
(22.6%)
0.673
(13.6%)
Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0
0.748
(22.2%)
0.680
(10.7%)
0.601
(8.2%)
34.Secondary Outcome
Title Mean Residence Time (MRT) for Metabolite PR-519/M16
Hide Description [Not Specified]
Time Frame Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.
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Pharmacokinetic-evaluable population with data to allow terminal phase characterization
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
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Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 10 14 8 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0
1.01
(11.3%)
0.961
(29.1%)
0.994
(13.3%)
Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
0.994
(9.0%)
1.00
(14.2%)
0.909
(7.8%)
35.Secondary Outcome
Title Number of Participants With Adverse Events (AEs)
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Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship.

Adverse events were graded using National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, on a scale from 1 (mild) to 5 (death).
Time Frame From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks
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[Not Specified]
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
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Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
Overall Number of Participants Analyzed 11 17 14 4
Measure Type: Number
Unit of Measure: participants
Any adverse event 10 17 14 4
Adverse event Grade ≥ 3 7 12 13 3
Serious adverse events 3 10 8 4
Leading to discontinuation of carfilzomib 1 2 4 0
Fatal adverse events 1 4 1 3
Treatment-related adverse events (TRAE) 8 13 12 1
Treatment-related adverse events Grade ≥ 3 2 5 8 0
Treatment-related serious adverse events 0 3 4 0
TRAE leading to discontinuation of carfilzomib 1 0 3 0
Treatment-related fatal adverse events 0 2 0 0
Time Frame From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks.
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Hide Arm/Group Description Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death.
All-Cause Mortality
Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/11 (27.27%)   10/17 (58.82%)   8/14 (57.14%)   4/4 (100.00%) 
Blood and lymphatic system disorders         
Anaemia † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Splenic vein occlusion † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Thrombocytopenia † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Gastrointestinal disorders         
Abdominal pain † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Ascites † 1  0/11 (0.00%)  0/17 (0.00%)  3/14 (21.43%)  0/4 (0.00%) 
Duodenal ulcer haemorrhage † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Gastric varices haemorrhage † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Gastrointestinal haemorrhage † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Oral cavity fistula † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
General disorders         
Disease progression † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Fatigue † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Multi-organ failure † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Hepatobiliary disorders         
Acute hepatic failure † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Infections and infestations         
Bacterial sepsis † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Biliary sepsis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Cellulitis † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Lower respiratory tract infection † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Pneumonia † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Sepsis † 1  1/11 (9.09%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Septic shock † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Viral infection † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Injury, poisoning and procedural complications         
Hip fracture † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Infusion related reaction † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Investigations         
Alanine aminotransferase increased † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Blood bilirubin increased † 1  0/11 (0.00%)  0/17 (0.00%)  2/14 (14.29%)  0/4 (0.00%) 
Metabolism and nutrition disorders         
Hyperkalaemia † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Nervous system disorders         
Hepatic encephalopathy † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  2/4 (50.00%) 
Spinal cord compression † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Renal and urinary disorders         
Acute kidney injury † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  2/4 (50.00%) 
Respiratory, thoracic and mediastinal disorders         
Acute respiratory distress syndrome † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Haemoptysis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Pneumonitis † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Vascular disorders         
Deep vein thrombosis † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Hypotension † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/11 (90.91%)   17/17 (100.00%)   14/14 (100.00%)   3/4 (75.00%) 
Blood and lymphatic system disorders         
Anaemia † 1  6/11 (54.55%)  10/17 (58.82%)  3/14 (21.43%)  2/4 (50.00%) 
Lymphopenia † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Neutropenia † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Thrombocytopenia † 1  0/11 (0.00%)  1/17 (5.88%)  4/14 (28.57%)  0/4 (0.00%) 
Cardiac disorders         
Left ventricular dysfunction † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Tachycardia † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Eye disorders         
Eye discharge † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Lacrimation increased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Ocular icterus † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Gastrointestinal disorders         
Abdominal discomfort † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Abdominal distension † 1  1/11 (9.09%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Abdominal pain † 1  0/11 (0.00%)  3/17 (17.65%)  4/14 (28.57%)  1/4 (25.00%) 
Abdominal pain lower † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Abdominal pain upper † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Ascites † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  1/4 (25.00%) 
Constipation † 1  1/11 (9.09%)  5/17 (29.41%)  4/14 (28.57%)  0/4 (0.00%) 
Diarrhoea † 1  4/11 (36.36%)  4/17 (23.53%)  4/14 (28.57%)  1/4 (25.00%) 
Dry mouth † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Dyspepsia † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Epigastric discomfort † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Faecal incontinence † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  1/4 (25.00%) 
Gastrointestinal haemorrhage † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Gastrooesophageal reflux disease † 1  1/11 (9.09%)  2/17 (11.76%)  0/14 (0.00%)  0/4 (0.00%) 
Hyperchlorhydria † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Melaena † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Nausea † 1  3/11 (27.27%)  5/17 (29.41%)  5/14 (35.71%)  0/4 (0.00%) 
Retching † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Umbilical hernia † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Vomiting † 1  3/11 (27.27%)  2/17 (11.76%)  3/14 (21.43%)  0/4 (0.00%) 
General disorders         
Asthenia † 1  1/11 (9.09%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Chest pain † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Chills † 1  2/11 (18.18%)  0/17 (0.00%)  2/14 (14.29%)  0/4 (0.00%) 
Early satiety † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Face oedema † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Fatigue † 1  8/11 (72.73%)  7/17 (41.18%)  8/14 (57.14%)  0/4 (0.00%) 
General physical health deterioration † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Infusion site discomfort † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Mucosal inflammation † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Non-cardiac chest pain † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Oedema peripheral † 1  4/11 (36.36%)  2/17 (11.76%)  5/14 (35.71%)  0/4 (0.00%) 
Pyrexia † 1  1/11 (9.09%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Temperature intolerance † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Thirst † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Hepatobiliary disorders         
Hyperbilirubinaemia † 1  0/11 (0.00%)  3/17 (17.65%)  2/14 (14.29%)  0/4 (0.00%) 
Portal vein thrombosis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Infections and infestations         
Bronchitis † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Candida infection † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Cellulitis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Cystitis † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Liver abscess † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Nasopharyngitis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Pneumonia † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Sinusitis † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Urinary tract infection † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  1/4 (25.00%) 
Injury, poisoning and procedural complications         
Fall † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Skin abrasion † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Investigations         
Alanine aminotransferase increased † 1  1/11 (9.09%)  5/17 (29.41%)  4/14 (28.57%)  0/4 (0.00%) 
Ammonia increased † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Aspartate aminotransferase increased † 1  1/11 (9.09%)  4/17 (23.53%)  4/14 (28.57%)  0/4 (0.00%) 
Basophil count increased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Blood albumin decreased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Blood alkaline phosphatase decreased † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Blood alkaline phosphatase increased † 1  1/11 (9.09%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Blood bicarbonate decreased † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Blood bilirubin increased † 1  0/11 (0.00%)  1/17 (5.88%)  9/14 (64.29%)  0/4 (0.00%) 
Blood calcium decreased † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Blood creatinine increased † 1  2/11 (18.18%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Blood lactate dehydrogenase increased † 1  1/11 (9.09%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Blood potassium increased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Blood urea increased † 1  1/11 (9.09%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Creatinine renal clearance decreased † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Haematocrit decreased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Haemoglobin decreased † 1  2/11 (18.18%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Lymphocyte count decreased † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Monocyte count increased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Platelet count decreased † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Red blood cell count decreased † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Urine output decreased † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Weight decreased † 1  2/11 (18.18%)  2/17 (11.76%)  0/14 (0.00%)  0/4 (0.00%) 
White blood cell count increased † 1  1/11 (9.09%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Metabolism and nutrition disorders         
Decreased appetite † 1  3/11 (27.27%)  5/17 (29.41%)  2/14 (14.29%)  0/4 (0.00%) 
Dehydration † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  1/4 (25.00%) 
Hyperglycaemia † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Hyperphosphataemia † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Hyperuricaemia † 1  1/11 (9.09%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Hypoalbuminaemia † 1  2/11 (18.18%)  3/17 (17.65%)  0/14 (0.00%)  0/4 (0.00%) 
Hypocalcaemia † 1  1/11 (9.09%)  0/17 (0.00%)  2/14 (14.29%)  0/4 (0.00%) 
Hypoglycaemia † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Hypokalaemia † 1  1/11 (9.09%)  2/17 (11.76%)  1/14 (7.14%)  1/4 (25.00%) 
Hypomagnesaemia † 1  0/11 (0.00%)  0/17 (0.00%)  2/14 (14.29%)  0/4 (0.00%) 
Hyponatraemia † 1  1/11 (9.09%)  2/17 (11.76%)  0/14 (0.00%)  0/4 (0.00%) 
Hypophosphataemia † 1  0/11 (0.00%)  2/17 (11.76%)  0/14 (0.00%)  0/4 (0.00%) 
Malnutrition † 1  1/11 (9.09%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Tumour lysis syndrome † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  0/11 (0.00%)  2/17 (11.76%)  0/14 (0.00%)  0/4 (0.00%) 
Back pain † 1  0/11 (0.00%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Flank pain † 1  2/11 (18.18%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Groin pain † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Muscle spasms † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Muscular weakness † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Musculoskeletal chest pain † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Musculoskeletal pain † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Tumour pain † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Nervous system disorders         
Dizziness † 1  2/11 (18.18%)  1/17 (5.88%)  3/14 (21.43%)  0/4 (0.00%) 
Dizziness postural † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Encephalopathy † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Headache † 1  3/11 (27.27%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Lethargy † 1  1/11 (9.09%)  3/17 (17.65%)  1/14 (7.14%)  0/4 (0.00%) 
Neuropathy peripheral † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Paraesthesia † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Restless legs syndrome † 1  1/11 (9.09%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Psychiatric disorders         
Confusional state † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Depression † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Insomnia † 1  3/11 (27.27%)  1/17 (5.88%)  2/14 (14.29%)  0/4 (0.00%) 
Mental disorder † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Renal and urinary disorders         
Acute kidney injury † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Cystitis noninfective † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Renal failure † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Renal pain † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Urinary incontinence † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Cough † 1  0/11 (0.00%)  4/17 (23.53%)  0/14 (0.00%)  0/4 (0.00%) 
Dyspnoea † 1  3/11 (27.27%)  4/17 (23.53%)  3/14 (21.43%)  0/4 (0.00%) 
Dyspnoea exertional † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Epistaxis † 1  0/11 (0.00%)  1/17 (5.88%)  1/14 (7.14%)  0/4 (0.00%) 
Hiccups † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Hypoxia † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Pleural effusion † 1  1/11 (9.09%)  0/17 (0.00%)  1/14 (7.14%)  1/4 (25.00%) 
Pneumonitis † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Sinus congestion † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Wheezing † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Skin and subcutaneous tissue disorders         
Hyperhidrosis † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Night sweats † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Palmar-plantar erythrodysaesthesia syndrome † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Pruritus generalised † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Rash † 1  1/11 (9.09%)  2/17 (11.76%)  2/14 (14.29%)  0/4 (0.00%) 
Rash pruritic † 1  0/11 (0.00%)  1/17 (5.88%)  0/14 (0.00%)  0/4 (0.00%) 
Skin oedema † 1  0/11 (0.00%)  0/17 (0.00%)  0/14 (0.00%)  1/4 (25.00%) 
Urticaria † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Vascular disorders         
Flushing † 1  0/11 (0.00%)  0/17 (0.00%)  1/14 (7.14%)  0/4 (0.00%) 
Hypertension † 1  2/11 (18.18%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
Hypotension † 1  1/11 (9.09%)  0/17 (0.00%)  1/14 (7.14%)  1/4 (25.00%) 
Orthostatic hypotension † 1  1/11 (9.09%)  0/17 (0.00%)  0/14 (0.00%)  0/4 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
[Not Specified]
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
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Name/Title: Study Director
Organization: Amgen, Inc.
Phone: 866-572-6436
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01949545     History of Changes
Other Study ID Numbers: CFZ002
20130402 ( Other Identifier: Amgen )
First Submitted: September 6, 2013
First Posted: September 24, 2013
Results First Submitted: August 25, 2016
Results First Posted: October 21, 2016
Last Update Posted: May 2, 2017