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

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT01949545
Collaborator
(none)
46
Enrollment
11
Locations
4
Arms
23
Duration (Months)
4.2
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the safety and efficacy of carfilzomib, including measuring the amount of the study drug in the blood at certain times following dosing. This study is being done in people with varying degrees of liver function to see if they respond differently to the study drug.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
46 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
An Open-Label, Single Arm, Phase 1 Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects With Advanced Malignancies and Varying Degrees of Hepatic Impairment
Study Start Date :
Oct 1, 2013
Actual Primary Completion Date :
Aug 1, 2015
Actual Study Completion Date :
Sep 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Normal Hepatic Function

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.

Drug: Carfilzomib
Carfilzomib was administered by IV injection over 30 minutes
Other Names:
  • Kyprolis® (carfilzomib) for Injection

    		•
    Experimental: Mild Hepatic Impairment

    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.

    Drug: Carfilzomib
    Carfilzomib was administered by IV injection over 30 minutes
    Other Names:
  • Kyprolis® (carfilzomib) for Injection

    		•
    Experimental: Moderate Hepatic Impairment

    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.

    Drug: Carfilzomib
    Carfilzomib was administered by IV injection over 30 minutes
    Other Names:
  • Kyprolis® (carfilzomib) for Injection

    		•
    Experimental: Severe Hepatic Impairment

    (Bilirubin > 3 × ULN; any AST) 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.

    Drug: Carfilzomib
    Carfilzomib was administered by IV injection over 30 minutes
    Other Names:
  • Kyprolis® (carfilzomib) for Injection

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² [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.]

      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.

    2. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² [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.]

      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.

    Secondary Outcome Measures

    1. Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² [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.]

    2. Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² [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.]

    3. Clearance of Carfilzomib 27 mg/m² [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.]

    4. Terminal Half-life of Carfilzomib 27 mg/m² [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.]

    5. Mean Residence Time (MRT) of Carfilzomib 27 mg/m² [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.]

    6. Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² [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.]

    7. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² [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.]

      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.

    8. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² [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.]

      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.

    9. Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² [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.]

    10. Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² [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.]

    11. Terminal Half-life of Carfilzomib 56 mg/m² [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.]

    12. Clearance of Carfilzomib 56 mg/m² [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.]

    13. Mean Residence Time (MRT) of Carfilzomib 56 mg/m² [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.]

    14. Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² [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.]

    15. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 [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.]

    16. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 [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.]

    17. Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 [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.]

    18. Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 [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.]

    19. Terminal Half-life for Metabolite PR-389/M14 [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.]

    20. Mean Residence Time (MRT) for Metabolite PR-389/M14 [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.]

    21. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 [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.]

    22. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 [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.]

    23. Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 [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.]

    24. Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 [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.]

    25. Terminal Half-life for Metabolite PR-413/M15 [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.]

    26. Mean Residence Time (MRT) for Metabolite PR-413/M15 [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.]

    27. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 [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.]

    28. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 [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.]

    29. Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 [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.]

    30. Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 [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.]

    31. Terminal Half-life for Metabolite PR-519/M16 [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.]

    32. Mean Residence Time (MRT) for Metabolite PR-519/M16 [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.]

    33. Number of Participants With Adverse Events (AEs) [From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks]

      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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    1. Relapsed or progressive advanced malignancies (solid tumors or hematologic malignancies)

    2. At least ≥ 2 prior treatment regimens for the underlying malignancy

    3. Confirmed advanced solid tumor or hematologic malignancy

    4. Measurable or evaluable disease

    5. Clinical diagnosis of chronic hepatic impairment that is stable with no acute worsening of liver failure within one month prior to enrollment. Hepatic impairment will be assessed as per National Cancer Institute Organ Dysfunction Working Group

    Criteria (NCI-ODWG) schema and will fall into one of the following three categories:

    • Cohort 2 (mild): Bilirubin > 1-1.5 × upper limit of the normal range (ULN) or aspartate aminotransferase (AST) > ULN, but bilirubin ≤ ULN

    • Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST

    • Cohort 4 (severe): Bilirubin > 3 × ULN; any AST

    Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function:

    All subjects enrolled with normal hepatic function (N=10) must meet all inclusion criteria as outlined with the exception of Inclusion Criterion

    #5, which should be substituted with the following criterion to be enrolled into the study:

    • Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN

    1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

    2. Left ventricular ejection fraction (LVEF) ≥ 40%

    3. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min)

    4. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollment

    Key Exclusion Criteria:

    1. Subjects with symptomatic brain metastasis or central nervous system (CNS) disease

    2. Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment

    3. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests [bilirubin, AST] will be allowed)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Karmanos Cancer Institute Detroit Michigan United States
    2 Duke Cancer Institute Durham North Carolina United States
    3 Gabrail Cancer Center Canton Ohio United States
    4 Tennessee Oncology, PLLC Nashville Tennessee United States
    5 Evergreen Hematology and Oncology Spokane Washington United States
    6 Institut Gustave Roussy Paris Villejuif Cedex France
    7 University Medical Centre Utrecht Utrecht Netherlands
    8 Northern Ireland Cancer Trials Centre - Queen's University Belfast TriaIs Centre Belfast Northern Ireland United Kingdom
    9 Beatson West of Scotland Cancer Centre Glasgow Scotland United Kingdom
    10 Velindre Hospital Cardlff Wales United Kingdom
    11 Sir Bobby Robson Cancer Trials Research Centre Newcastle United Kingdom

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01949545
    Other Study ID Numbers:
    • CFZ002
    • 20130402
    First Posted:
    Sep 24, 2013
    Last Update Posted:
    May 2, 2017
    Last Verified:
    Apr 1, 2017
    Additional relevant MeSH terms:
    Neoplasms
    Hematologic Neoplasms
    Liver Diseases

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 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
    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

    Baseline Characteristics

    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment Total
    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 Participants 11 17 14 4 46
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    68.5
    (8.2)
    59.5
    (9.1)
    61.0
    (7.9)
    56.3
    (10.9)
    61.8
    (9.3)
    Age, Customized (participants) [Number]
    < 65 years
    3
    27.3%
    12
    70.6%
    8
    57.1%
    3
    75%
    26
    56.5%
    ≥ 65 years
    8
    72.7%
    5
    29.4%
    6
    42.9%
    1
    25%
    20
    43.5%
    Sex: Female, Male (Count of Participants)
    Female
    2
    18.2%
    8
    47.1%
    5
    35.7%
    3
    75%
    18
    39.1%
    Male
    9
    81.8%
    9
    52.9%
    9
    64.3%
    1
    25%
    28
    60.9%
    Race/Ethnicity, Customized (participants) [Number]
    Black
    0
    0%
    1
    5.9%
    1
    7.1%
    0
    0%
    2
    4.3%
    White
    11
    100%
    13
    76.5%
    13
    92.9%
    4
    100%
    41
    89.1%
    Not reported
    0
    0%
    3
    17.6%
    0
    0%
    0
    0%
    3
    6.5%

    Outcome Measures

    1. Primary Outcome
    Title Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m²
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 14 9 0
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    378
    (40.8)
    546
    (39.2)
    477
    (33.1)
    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
    Statistical Test of Hypothesis p-Value 0.02232
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 144.43
    Confidence Interval (2-Sided) 95%
    111.48 to 187.12
    Parameter Dispersion Type:
    Value:
    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).
    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
    Statistical Test of Hypothesis p-Value 0.1812
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 126.08
    Confidence Interval (2-Sided) 95%
    94.59 to 168.06
    Parameter Dispersion Type:
    Value:
    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
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 8 12 7 0
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    348
    (35.4)
    529
    (40.3)
    500
    (38.4)
    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
    Statistical Test of Hypothesis p-Value 0.02137
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 151.84
    Confidence Interval (2-Sided) 95%
    113.59 to 202.96
    Parameter Dispersion Type:
    Value:
    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).
    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
    Statistical Test of Hypothesis p-Value 0.07247
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 143.53
    Confidence Interval (2-Sided) 95%
    103.28 to 199.45
    Parameter Dispersion Type:
    Value:
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    Median (Full Range) [hours]
    0.292
    0.458
    0.483
    5. Secondary Outcome
    Title Clearance of Carfilzomib 27 mg/m²
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 8 12 7 0
    Geometric Mean (Geometric Coefficient of Variation) [L/hour]
    157
    (32.5)
    86.4
    (50.9)
    103
    (43.9)
    6. Secondary Outcome
    Title Terminal Half-life of Carfilzomib 27 mg/m²
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 8 12 7 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 8 12 7 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 8 12 7 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 8 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 6 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 8 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 8 8 5 0
    Median (Full Range) [hours]
    0.300
    0.408
    0.400
    13. Secondary Outcome
    Title Terminal Half-life of Carfilzomib 56 mg/m²
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 6 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    0.508
    (54.7)
    0.621
    (47.7)
    0.740
    (137.7)
    14. Secondary Outcome
    Title Clearance of Carfilzomib 56 mg/m²
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 6 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 6 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 6 8 5 0
    Geometric Mean (Geometric Coefficient of Variation) [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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 4 11 8 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
    0.867
    0.792
    0.750
    Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
    0.842
    0.992
    0.750
    21. Secondary Outcome
    Title Terminal Half-life for Metabolite PR-389/M14
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 4 11 8 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 4 11 8 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 13 8 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
    0.750
    0.767
    0.650
    Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
    0.717
    0.800
    0.750
    27. Secondary Outcome
    Title Terminal Half-life for Metabolite PR-413/M15
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 13 8 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 13 8 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 14 8 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    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
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic-evaluable population
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 10 14 9 0
    Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0
    0.500
    0.600
    0.700
    Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0
    0.483
    0.592
    0.583
    33. Secondary Outcome
    Title Terminal Half-life for Metabolite PR-519/M16
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 14 8 0
    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
    Description
    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.

    Outcome Measure Data

    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
    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.
    Measure Participants 10 14 8 0
    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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    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.
    Measure Participants 11 17 14 4
    Any adverse event
    10
    90.9%
    17
    100%
    14
    100%
    4
    100%
    Adverse event Grade ≥ 3
    7
    63.6%
    12
    70.6%
    13
    92.9%
    3
    75%
    Serious adverse events
    3
    27.3%
    10
    58.8%
    8
    57.1%
    4
    100%
    Leading to discontinuation of carfilzomib
    1
    9.1%
    2
    11.8%
    4
    28.6%
    0
    0%
    Fatal adverse events
    1
    9.1%
    4
    23.5%
    1
    7.1%
    3
    75%
    Treatment-related adverse events (TRAE)
    8
    72.7%
    13
    76.5%
    12
    85.7%
    1
    25%
    Treatment-related adverse events Grade ≥ 3
    2
    18.2%
    5
    29.4%
    8
    57.1%
    0
    0%
    Treatment-related serious adverse events
    0
    0%
    3
    17.6%
    4
    28.6%
    0
    0%
    TRAE leading to discontinuation of carfilzomib
    1
    9.1%
    0
    0%
    3
    21.4%
    0
    0%
    Treatment-related fatal adverse events
    0
    0%
    2
    11.8%
    0
    0%
    0
    0%

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/11 (27.3%) 10/17 (58.8%) 8/14 (57.1%) 4/4 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Splenic vein occlusion 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Thrombocytopenia 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Ascites 0/11 (0%) 0/17 (0%) 3/14 (21.4%) 0/4 (0%)
    Duodenal ulcer haemorrhage 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Gastric varices haemorrhage 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Gastrointestinal haemorrhage 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Oral cavity fistula 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    General disorders
    Disease progression 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Fatigue 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Multi-organ failure 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Hepatobiliary disorders
    Acute hepatic failure 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Infections and infestations
    Bacterial sepsis 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Biliary sepsis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Cellulitis 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Lower respiratory tract infection 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Pneumonia 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Sepsis 1/11 (9.1%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Septic shock 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Viral infection 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Injury, poisoning and procedural complications
    Hip fracture 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Infusion related reaction 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Investigations
    Alanine aminotransferase increased 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Blood bilirubin increased 0/11 (0%) 0/17 (0%) 2/14 (14.3%) 0/4 (0%)
    Metabolism and nutrition disorders
    Hyperkalaemia 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Nervous system disorders
    Hepatic encephalopathy 0/11 (0%) 0/17 (0%) 0/14 (0%) 2/4 (50%)
    Spinal cord compression 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 2/4 (50%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Haemoptysis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Pneumonitis 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Vascular disorders
    Deep vein thrombosis 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Hypotension 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Other (Not Including Serious) Adverse Events
    Normal Hepatic Function Mild Hepatic Impairment Moderate Hepatic Impairment Severe Hepatic Impairment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/11 (90.9%) 17/17 (100%) 14/14 (100%) 3/4 (75%)
    Blood and lymphatic system disorders
    Anaemia 6/11 (54.5%) 10/17 (58.8%) 3/14 (21.4%) 2/4 (50%)
    Lymphopenia 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Neutropenia 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Thrombocytopenia 0/11 (0%) 1/17 (5.9%) 4/14 (28.6%) 0/4 (0%)
    Cardiac disorders
    Left ventricular dysfunction 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Tachycardia 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Eye disorders
    Eye discharge 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Lacrimation increased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Ocular icterus 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Abdominal distension 1/11 (9.1%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Abdominal pain 0/11 (0%) 3/17 (17.6%) 4/14 (28.6%) 1/4 (25%)
    Abdominal pain lower 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Abdominal pain upper 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Ascites 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 1/4 (25%)
    Constipation 1/11 (9.1%) 5/17 (29.4%) 4/14 (28.6%) 0/4 (0%)
    Diarrhoea 4/11 (36.4%) 4/17 (23.5%) 4/14 (28.6%) 1/4 (25%)
    Dry mouth 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Dyspepsia 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Epigastric discomfort 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Faecal incontinence 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 1/4 (25%)
    Gastrointestinal haemorrhage 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Gastrooesophageal reflux disease 1/11 (9.1%) 2/17 (11.8%) 0/14 (0%) 0/4 (0%)
    Hyperchlorhydria 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Melaena 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Nausea 3/11 (27.3%) 5/17 (29.4%) 5/14 (35.7%) 0/4 (0%)
    Retching 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Umbilical hernia 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Vomiting 3/11 (27.3%) 2/17 (11.8%) 3/14 (21.4%) 0/4 (0%)
    General disorders
    Asthenia 1/11 (9.1%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Chest pain 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Chills 2/11 (18.2%) 0/17 (0%) 2/14 (14.3%) 0/4 (0%)
    Early satiety 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Face oedema 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Fatigue 8/11 (72.7%) 7/17 (41.2%) 8/14 (57.1%) 0/4 (0%)
    General physical health deterioration 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Infusion site discomfort 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Mucosal inflammation 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Non-cardiac chest pain 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Oedema peripheral 4/11 (36.4%) 2/17 (11.8%) 5/14 (35.7%) 0/4 (0%)
    Pyrexia 1/11 (9.1%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Temperature intolerance 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Thirst 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/11 (0%) 3/17 (17.6%) 2/14 (14.3%) 0/4 (0%)
    Portal vein thrombosis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Infections and infestations
    Bronchitis 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Candida infection 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Cellulitis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Cystitis 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Liver abscess 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Nasopharyngitis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Pneumonia 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Sinusitis 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Urinary tract infection 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 1/4 (25%)
    Injury, poisoning and procedural complications
    Fall 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Skin abrasion 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Investigations
    Alanine aminotransferase increased 1/11 (9.1%) 5/17 (29.4%) 4/14 (28.6%) 0/4 (0%)
    Ammonia increased 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Aspartate aminotransferase increased 1/11 (9.1%) 4/17 (23.5%) 4/14 (28.6%) 0/4 (0%)
    Basophil count increased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Blood albumin decreased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Blood alkaline phosphatase decreased 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Blood alkaline phosphatase increased 1/11 (9.1%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Blood bicarbonate decreased 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Blood bilirubin increased 0/11 (0%) 1/17 (5.9%) 9/14 (64.3%) 0/4 (0%)
    Blood calcium decreased 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Blood creatinine increased 2/11 (18.2%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Blood lactate dehydrogenase increased 1/11 (9.1%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Blood potassium increased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Blood urea increased 1/11 (9.1%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Creatinine renal clearance decreased 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Haematocrit decreased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Haemoglobin decreased 2/11 (18.2%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Lymphocyte count decreased 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Monocyte count increased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Platelet count decreased 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Red blood cell count decreased 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Urine output decreased 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Weight decreased 2/11 (18.2%) 2/17 (11.8%) 0/14 (0%) 0/4 (0%)
    White blood cell count increased 1/11 (9.1%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 3/11 (27.3%) 5/17 (29.4%) 2/14 (14.3%) 0/4 (0%)
    Dehydration 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 1/4 (25%)
    Hyperglycaemia 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Hyperphosphataemia 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Hyperuricaemia 1/11 (9.1%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Hypoalbuminaemia 2/11 (18.2%) 3/17 (17.6%) 0/14 (0%) 0/4 (0%)
    Hypocalcaemia 1/11 (9.1%) 0/17 (0%) 2/14 (14.3%) 0/4 (0%)
    Hypoglycaemia 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Hypokalaemia 1/11 (9.1%) 2/17 (11.8%) 1/14 (7.1%) 1/4 (25%)
    Hypomagnesaemia 0/11 (0%) 0/17 (0%) 2/14 (14.3%) 0/4 (0%)
    Hyponatraemia 1/11 (9.1%) 2/17 (11.8%) 0/14 (0%) 0/4 (0%)
    Hypophosphataemia 0/11 (0%) 2/17 (11.8%) 0/14 (0%) 0/4 (0%)
    Malnutrition 1/11 (9.1%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Tumour lysis syndrome 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/11 (0%) 2/17 (11.8%) 0/14 (0%) 0/4 (0%)
    Back pain 0/11 (0%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Flank pain 2/11 (18.2%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Groin pain 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Muscle spasms 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Muscular weakness 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Musculoskeletal chest pain 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Musculoskeletal pain 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Nervous system disorders
    Dizziness 2/11 (18.2%) 1/17 (5.9%) 3/14 (21.4%) 0/4 (0%)
    Dizziness postural 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Encephalopathy 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Headache 3/11 (27.3%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Lethargy 1/11 (9.1%) 3/17 (17.6%) 1/14 (7.1%) 0/4 (0%)
    Neuropathy peripheral 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Paraesthesia 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Restless legs syndrome 1/11 (9.1%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Psychiatric disorders
    Confusional state 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Depression 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Insomnia 3/11 (27.3%) 1/17 (5.9%) 2/14 (14.3%) 0/4 (0%)
    Mental disorder 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Renal and urinary disorders
    Acute kidney injury 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Cystitis noninfective 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Renal failure 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Renal pain 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Urinary incontinence 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/11 (0%) 4/17 (23.5%) 0/14 (0%) 0/4 (0%)
    Dyspnoea 3/11 (27.3%) 4/17 (23.5%) 3/14 (21.4%) 0/4 (0%)
    Dyspnoea exertional 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Epistaxis 0/11 (0%) 1/17 (5.9%) 1/14 (7.1%) 0/4 (0%)
    Hiccups 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Hypoxia 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Pleural effusion 1/11 (9.1%) 0/17 (0%) 1/14 (7.1%) 1/4 (25%)
    Pneumonitis 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Sinus congestion 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Wheezing 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Night sweats 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Palmar-plantar erythrodysaesthesia syndrome 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Pruritus generalised 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Rash 1/11 (9.1%) 2/17 (11.8%) 2/14 (14.3%) 0/4 (0%)
    Rash pruritic 0/11 (0%) 1/17 (5.9%) 0/14 (0%) 0/4 (0%)
    Skin oedema 0/11 (0%) 0/17 (0%) 0/14 (0%) 1/4 (25%)
    Urticaria 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Vascular disorders
    Flushing 0/11 (0%) 0/17 (0%) 1/14 (7.1%) 0/4 (0%)
    Hypertension 2/11 (18.2%) 0/17 (0%) 0/14 (0%) 0/4 (0%)
    Hypotension 1/11 (9.1%) 0/17 (0%) 1/14 (7.1%) 1/4 (25%)
    Orthostatic hypotension 1/11 (9.1%) 0/17 (0%) 0/14 (0%) 0/4 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen, Inc.
    Phone 866-572-6436
    Email
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01949545
    Other Study ID Numbers:
    • CFZ002
    • 20130402
    First Posted:
    Sep 24, 2013
    Last Update Posted:
    May 2, 2017
    Last Verified:
    Apr 1, 2017