Study of the Pharmacokinetics and Safety of Carfilzomib in Patients With Multiple Myeloma and Renal Disease

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01949532
• Collaborator: (none)
• Enrollment: 26
• Locations: 13
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to see how the body and the cancer react to 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 normal kidney function and those with end-stage renal disease to see if they respond differently to the study drug.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Multiple Myeloma; End-stage Renal Disease	Drug: Carfilzomib	Phase 1

Detailed Description

Specifically, the purpose of this study is to assess the influence of end-stage renal disease (ESRD) on area under the curve (both area under the curve, from time 0 to the last concentration measured [AUC0-last] and area under the curve, from time 0 extrapolated to infinity [AUC0-inf]) of carfilzomib 56 mg/m² at Cycle 2 Day 1 (C2D1) in patients with relapsed multiple myeloma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 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 Relapsed Multiple Myeloma and End-stage Renal Disease
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Normal Renal Function Participants with normal renal function (creatinine clearance [CrCl] ≥ 75 mL/min) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.	Drug: Carfilzomib; Carfilzomib was administered by IV injection.; Other Names: Kyprolis®
Experimental: End Stage Renal Disease Participants with end-stage renal disease (on hemodialysis) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.	Drug: Carfilzomib; Carfilzomib was administered by IV injection.; Other Names: Kyprolis®

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.]

   Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL.

2. Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.]

Secondary Outcome Measures

1. Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 [Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.]

8. Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.]

9. Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 [Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration for Metabolite PR-389/M14 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Metabolite PR-389/M14 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Terminal Half-life (T½) of Metabolite PR-413/M15 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Terminal Half-life (T½) of Metabolite PR-519/M16 [Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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. Number of Participants With Adverse Events (AEs) [From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group.]

    Determination of the severity of all adverse events was assessed following the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Fatal. A Serious AE is an AE that meets one or more of the following criteria: Death, Life-threatening experience; Requires in-patient hospitalization or prolongation of an existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Important medical events that may not result in death, be life-threatening, or require hospitalization. Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship.

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 multiple myeloma

2. Evaluable disease (serum protein electrophoresis [SPEP]/urine protein electrophoresis [UPEP]/serum free light chain [SFLC] criteria)

3. Received at least 1 prior treatment regimen or line of therapy for multiple myeloma

4. End-stage renal disease (ESRD) on hemodialysis or CrCl ≥ 75 mL/min

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

6. Adequate organ and bone marrow function

7. 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. Immunoglobulin M (IgM) multiple myeloma

2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

3. Waldenström Macroglobulinemia

4. Active congestive heart failure (NYHA Class III-IV) ischemia, conduction abnormalities

5. Known human immunodeficiency virus (HIV), recent hepatitis B virus (HBV), hepatitis C virus (HCV)

6. Myelodysplastic Syndrome

7. Contraindication to test article, constituents, or required concomitant medications

8. Other investigational drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karmanos Cancer Institute	Detroit	Michigan	United States
2	North Shore-LIJ Health System/Center for Advanced Medicine - North Shore University Hospital	Lake Success	New York	United States
3	Gabrail Cancer Center	Canton	Ohio	United States
4	Vanderbilt-Ingram Cancer Center, Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States
5	Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States
6	UT Southwestern Medical Center	Dallas	Texas	United States
7	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia
8	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia
9	Monash Health, Monash Medical Centre	Clayton	Victoria	Australia
10	St. Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia
11	The Alfred Hospital, Malignant Haematology and Stem Cell Transplant Department	Melbourne	Victoria	Australia
12	QEII Health Sciences Centre	Halifax	Nova Scotia	Canada
13	Sir Mortimer B. Davis-Jewish General Hospital	Montreal	Quebec	Canada

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: NCT01949532
• Other Study ID Numbers: CFZ001; 20130401
• First Posted: Sep 24, 2013
• Last Update Posted: May 2, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Kidney Diseases; Kidney Failure, Chronic

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 13 investigative study centers (6 in the United States, 2 in Canada, and 5 in Australia) from 29 January 2014 to 25 March 2015. This study is ongoing, results are reported as of the data cut-off date of 12 October 2015.
Pre-assignment Detail	Participants with relapsed multiple myeloma were enrolled into cohorts according to renal function (normal creatinine clearance (CrCl) or end-stage renal disease (ESRD; patients on hemodialysis)). Renal function was based on calculated CrCl using the Cockcroft-Gault formula at baseline.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function (creatinine clearance [CrCl] ≥ 75 mL/min) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.	Participants with end-stage renal disease (on hemodialysis) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.
Period Title: Overall Study
STARTED	15	11
COMPLETED	12	8
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Normal Renal Function	End Stage Renal Disease	Total
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Total of all reporting groups
Overall Participants	15	11	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.8 (8.1)	62.8 (7.9)	64.0 (7.9)
Sex: Female, Male (Count of Participants)
Female	5 33.3%	6 54.5%	11 42.3%
Male	10 66.7%	5 45.5%	15 57.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%	0 0%	1 3.8%
Not Hispanic or Latino	14 93.3%	9 81.8%	23 88.5%
Unknown or Not Reported	0 0%	2 18.2%	2 7.7%
Race/Ethnicity, Customized (participants) [Number]
Asian	1 6.7%	0 0%	1 3.8%
Black	1 6.7%	1 9.1%	2 7.7%
White	12 80%	9 81.8%	21 80.8%
Other	1 6.7%	0 0%	1 3.8%
Not Reported	0 0%	1 9.1%	1 3.8%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0 (Fully active)	5 33.3%	3 27.3%	8 30.8%
1 (Restrictive but ambulatory)	10 66.7%	7 63.6%	17 65.4%
2 (Ambulatory but unable to work)	0 0%	1 9.1%	1 3.8%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Description	Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL.
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. The PK evaluable population is defined as participants with sufficient carfilzomib plasma concentration versus time data for the estimation of PK parameters by non-compartmental analysis on cycle 1, day 16 and/or cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	563 (41.9)	747 (143.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Renal Function, End Stage Renal Disease
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	132.75
	Confidence Interval	(2-Sided) 90%; 70.60 to 249.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimates of the geometric mean ratios for the PK parameters were calculated by exponentiation of the differences in the least-squares means between the renal impairment group (test) and participants with normal renal function (reference).

2. Primary Outcome

Title	Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	563 (41.8)	752 (144.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Renal Function, End Stage Renal Disease
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	133.62
	Confidence Interval	(2-Sided) 90%; 70.93 to 251.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1389 (26.8)	1567 (128.8)

4. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Median (Full Range) [hours]	0.467	0.467

5. Secondary Outcome

Title	Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Median (Full Range) [hours]	0.341	1.25

6. Secondary Outcome

Title	Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [liters/hour]	179 (38.9)	134 (136.9)

7. Secondary Outcome

Title	Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [hours]	0.135 (62.6)	0.245 (79.9)

8. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time Frame	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	8
Geometric Mean (Geometric Coefficient of Variation) [liters]	24.1 (44.8)	32.8 (133.9)

9. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	344 (24.8)	480 (36.0)

10. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the coefficient of correlation (R²) was < 0.8 were excluded.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	11	6
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	347 (26.3)	479 (46.6)

11. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	819 (29.8)	1022 (37.2)

12. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Median (Full Range) [hours]	0.583	0.467

13. Secondary Outcome

Title	Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants with a coefficient of correlation (R²) < 0.8 were excluded.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	11	6
Median (Full Range) [hours]	0.387	0.992

14. Secondary Outcome

Title	Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Geometric Mean (Geometric Coefficient of Variation) [liters/hour]	146 (23.0)	93 (56.8)

15. Secondary Outcome

Title	Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants with a coefficient of correlation (R²) < 0.8 were excluded.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	11	6
Geometric Mean (Geometric Coefficient of Variation) [hours]	0.222 (16.6)	0.426 (152.2)

16. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time Frame	Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Geometric Mean (Geometric Coefficient of Variation) [liters]	32.0 (29.7)	53.0 (185.5)

17. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. "n" indicates the number of participants included in the analyses at each time point.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	320 (32.8)	1486 (32.3)
Cycle 2, Day 1 (n = 10, 8)	584 (17.5)	2086 (132.8)

18. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population. Participants for whom the extrapolated portion of AUC0-∞ was > 20% were excluded. AUC0-∞ could not be calculated for the ESRD group as the extrapolated portion (AUCextr) was greater than 20% in all participants.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	0
Cycle 1, Day 16	355 (25.1)
Cycle 2, Day 1	650 (22.5)

19. Secondary Outcome

Title	Maximum Observed Plasma Concentration for Metabolite PR-389/M14
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	153 (25.4)	413 (32.9)
Cycle 2, Day 1 (n = 10, 8)	302 (16.5)	595 (128.4)

20. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	1.00	1.50
Cycle 2, Day 1 (n = 10, 8)	0.983	2.00

21. Secondary Outcome

Title	Terminal Half-life (T½) of Metabolite PR-389/M14
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population. Participants for whom the extrapolated portion of AUC0-∞ was > 20% were excluded. T½ could not be calculated for the ESRD group as the extrapolated portion (AUCextr) was greater than 20% in all participants.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	10	0
Cycle 1, Day 16	1.46
Cycle 2, Day 1	1.10

22. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	33.4 (53.9)	54.6 (45.0)
Cycle 2, Day 1 (n = 10, 8)	60.3 (48.4)	86.3 (199.1)

23. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the extrapolated portion of AUC0-∞ was > 20% were excluded.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	7
Cycle 1, Day 16 (n = 13, 7)	36.2 (54.1)	66.4 (48.7)
Cycle 2, Day 1 (n = 10, 5)	63.8 (48.0)	131 (35.8)

24. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	20.7 (43.5)	25.9 (42.5)
Cycle 2, Day 1 (n = 10, 8)	40.2 (38.5)	42.3 (163.9)

25. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	0.833	0.767
Cycle 2, Day 1 (n = 10, 8)	0.667	0.750

26. Secondary Outcome

Title	Terminal Half-life (T½) of Metabolite PR-413/M15
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the extrapolated portion of AUC0-∞ was > 20% were excluded.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	7
Cycle 1, Day 16 (n = 13, 7)	1.07	1.41
Cycle 2, Day 1 (n = 10, 5)	0.962	1.37

27. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	82.8 (53.1)	86.8 (44.3)
Cycle 2, Day 1 (n = 10, 8)	147 (52.8)	138 (126.6)

28. Secondary Outcome

Title	Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	84.4 (52.4)	89.6 (42.8)
Cycle 2, Day 1 (n = 10, 8)	148 (51.7)	139 (125.1)

29. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	93.4 (40.2)	90.4 (48.0)
Cycle 2, Day 1 (n = 10, 8)	180 (40.5)	151 (129.7)

30. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	0.617	0.600
Cycle 2, Day 1 (n = 10, 8)	0.525	0.533

31. Secondary Outcome

Title	Terminal Half-life (T½) of Metabolite PR-519/M16
Time Frame	Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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

PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	13	9
Cycle 1, Day 16 (n = 13, 9)	0.705	0.721
Cycle 2, Day 1 (n = 10, 8)	0.617	0.687

32. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	Determination of the severity of all adverse events was assessed following the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Fatal. A Serious AE is an AE that meets one or more of the following criteria: Death, Life-threatening experience; Requires in-patient hospitalization or prolongation of an existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Important medical events that may not result in death, be life-threatening, or require hospitalization. Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship.
Time Frame	From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group.

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Normal Renal Function	End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.	Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
Measure Participants	15	11
Any adverse event	15 100%	11 100%
Adverse event ≥ Grade 3	12 80%	9 81.8%
Serious adverse event	10 66.7%	9 81.8%
AE leading to discontinuation of carfilzomib	6 40%	0 0%
Fatal adverse events	2 13.3%	1 9.1%
Treatment-related adverse events	12 80%	8 72.7%
Treatment-related adverse event ≥ Grade 3	7 46.7%	6 54.5%
Serious treatment-related adverse event	5 33.3%	2 18.2%
TRAE leading to discontinuation of carfilzomib	4 26.7%	0 0%
Treatment-related fatal adverse events	0 0%	0 0%

Adverse Events

Time Frame	From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group.
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 Renal Function		End Stage Renal Disease
Arm/Group Description	Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.		Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles.
All Cause Mortality
	Normal Renal Function		End Stage Renal Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Normal Renal Function		End Stage Renal Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/15 (66.7%)		9/11 (81.8%)
Blood and lymphatic system disorders
Anaemia	0/15 (0%)		2/11 (18.2%)
Coagulopathy	0/15 (0%)		1/11 (9.1%)
Immune thrombocytopenic purpura	0/15 (0%)		1/11 (9.1%)
Leukocytosis	0/15 (0%)		1/11 (9.1%)
Microangiopathic haemolytic anaemia	1/15 (6.7%)		0/11 (0%)
Thrombocytopenia	1/15 (6.7%)		1/11 (9.1%)
Cardiac disorders
Atrial fibrillation	1/15 (6.7%)		1/11 (9.1%)
Cardio-respiratory arrest	1/15 (6.7%)		0/11 (0%)
Gastrointestinal disorders
Diarrhoea	0/15 (0%)		1/11 (9.1%)
Mouth ulceration	0/15 (0%)		1/11 (9.1%)
General disorders
Asthenia	0/15 (0%)		2/11 (18.2%)
Chills	0/15 (0%)		1/11 (9.1%)
Death	1/15 (6.7%)		1/11 (9.1%)
Pyrexia	2/15 (13.3%)		2/11 (18.2%)
Hepatobiliary disorders
Cholecystitis	1/15 (6.7%)		0/11 (0%)
Infections and infestations
Influenza	0/15 (0%)		1/11 (9.1%)
Lower respiratory tract infection	1/15 (6.7%)		2/11 (18.2%)
Pneumonia	3/15 (20%)		2/11 (18.2%)
Pneumonia klebsiella	1/15 (6.7%)		0/11 (0%)
Respiratory syncytial virus infection	0/15 (0%)		1/11 (9.1%)
Respiratory tract infection viral	0/15 (0%)		1/11 (9.1%)
Urosepsis	1/15 (6.7%)		0/11 (0%)
Injury, poisoning and procedural complications
Femur fracture	1/15 (6.7%)		0/11 (0%)
Procedural hypotension	0/15 (0%)		1/11 (9.1%)
Investigations
Troponin increased	1/15 (6.7%)		0/11 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/15 (0%)		1/11 (9.1%)
Nervous system disorders
Dizziness	0/15 (0%)		1/11 (9.1%)
Psychiatric disorders
Delirium	1/15 (6.7%)		0/11 (0%)
Renal and urinary disorders
Acute kidney injury	2/15 (13.3%)		0/11 (0%)
Respiratory, thoracic and mediastinal disorders
Acute interstitial pneumonitis	1/15 (6.7%)		0/11 (0%)
Dyspnoea	1/15 (6.7%)		0/11 (0%)
Hypoxia	1/15 (6.7%)		1/11 (9.1%)
Respiratory distress	1/15 (6.7%)		0/11 (0%)
Vascular disorders
Haematoma	0/15 (0%)		1/11 (9.1%)
Hypotension	0/15 (0%)		2/11 (18.2%)
Other (Not Including Serious) Adverse Events
	Normal Renal Function		End Stage Renal Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)		10/11 (90.9%)
Blood and lymphatic system disorders
Anaemia	8/15 (53.3%)		5/11 (45.5%)
Neutropenia	2/15 (13.3%)		0/11 (0%)
Thrombocytopenia	7/15 (46.7%)		1/11 (9.1%)
Cardiac disorders
Angina pectoris	1/15 (6.7%)		0/11 (0%)
Cardiovascular disorder	0/15 (0%)		1/11 (9.1%)
Sinus tachycardia	0/15 (0%)		1/11 (9.1%)
Tachycardia	1/15 (6.7%)		1/11 (9.1%)
Ear and labyrinth disorders
Ear congestion	1/15 (6.7%)		0/11 (0%)
Hypoacusis	0/15 (0%)		1/11 (9.1%)
Meniere's disease	0/15 (0%)		1/11 (9.1%)
Vertigo	0/15 (0%)		1/11 (9.1%)
Eye disorders
Cataract	0/15 (0%)		1/11 (9.1%)
Exophthalmos	1/15 (6.7%)		0/11 (0%)
Eye discharge	0/15 (0%)		1/11 (9.1%)
Eye inflammation	1/15 (6.7%)		0/11 (0%)
Eye pruritus	0/15 (0%)		1/11 (9.1%)
Eye swelling	2/15 (13.3%)		0/11 (0%)
Eyelid oedema	0/15 (0%)		1/11 (9.1%)
Lacrimation increased	1/15 (6.7%)		0/11 (0%)
Ocular discomfort	1/15 (6.7%)		0/11 (0%)
Photophobia	0/15 (0%)		1/11 (9.1%)
Vision blurred	1/15 (6.7%)		0/11 (0%)
Visual acuity reduced	0/15 (0%)		1/11 (9.1%)
Gastrointestinal disorders
Abdominal distension	2/15 (13.3%)		0/11 (0%)
Abdominal pain	2/15 (13.3%)		1/11 (9.1%)
Abdominal pain upper	1/15 (6.7%)		0/11 (0%)
Constipation	2/15 (13.3%)		4/11 (36.4%)
Diarrhoea	7/15 (46.7%)		5/11 (45.5%)
Dry mouth	2/15 (13.3%)		0/11 (0%)
Dyspepsia	1/15 (6.7%)		1/11 (9.1%)
Dysphagia	1/15 (6.7%)		0/11 (0%)
Flatulence	1/15 (6.7%)		0/11 (0%)
Gastrooesophageal reflux disease	1/15 (6.7%)		0/11 (0%)
Lip swelling	1/15 (6.7%)		0/11 (0%)
Mouth swelling	1/15 (6.7%)		0/11 (0%)
Nausea	10/15 (66.7%)		6/11 (54.5%)
Retching	1/15 (6.7%)		0/11 (0%)
Tooth disorder	1/15 (6.7%)		0/11 (0%)
Vomiting	3/15 (20%)		4/11 (36.4%)
General disorders
Application site reaction	1/15 (6.7%)		0/11 (0%)
Catheter site inflammation	0/15 (0%)		1/11 (9.1%)
Chest discomfort	2/15 (13.3%)		1/11 (9.1%)
Chest pain	2/15 (13.3%)		0/11 (0%)
Chills	3/15 (20%)		1/11 (9.1%)
Fatigue	8/15 (53.3%)		5/11 (45.5%)
General physical health deterioration	2/15 (13.3%)		0/11 (0%)
Influenza like illness	1/15 (6.7%)		0/11 (0%)
Infusion site erythema	1/15 (6.7%)		0/11 (0%)
Infusion site pain	2/15 (13.3%)		0/11 (0%)
Injury associated with device	1/15 (6.7%)		0/11 (0%)
Non-cardiac chest pain	1/15 (6.7%)		0/11 (0%)
Oedema	1/15 (6.7%)		0/11 (0%)
Oedema peripheral	1/15 (6.7%)		0/11 (0%)
Pain	0/15 (0%)		2/11 (18.2%)
Pyrexia	8/15 (53.3%)		2/11 (18.2%)
Sluggishness	1/15 (6.7%)		0/11 (0%)
Hepatobiliary disorders
Cholangitis	1/15 (6.7%)		0/11 (0%)
Infections and infestations
Bacteraemia	1/15 (6.7%)		0/11 (0%)
Candida infection	1/15 (6.7%)		0/11 (0%)
Catheter site infection	0/15 (0%)		2/11 (18.2%)
Clostridium difficile infection	0/15 (0%)		1/11 (9.1%)
Conjunctivitis	1/15 (6.7%)		0/11 (0%)
Ear infection	1/15 (6.7%)		0/11 (0%)
Infection	1/15 (6.7%)		0/11 (0%)
Influenza	1/15 (6.7%)		0/11 (0%)
Nasopharyngitis	3/15 (20%)		0/11 (0%)
Respiratory tract infection	3/15 (20%)		0/11 (0%)
Upper respiratory tract infection	2/15 (13.3%)		1/11 (9.1%)
Urinary tract infection	3/15 (20%)		0/11 (0%)
Injury, poisoning and procedural complications
Humerus fracture	0/15 (0%)		1/11 (9.1%)
Procedural nausea	1/15 (6.7%)		0/11 (0%)
Radiation skin injury	1/15 (6.7%)		0/11 (0%)
Skin abrasion	1/15 (6.7%)		0/11 (0%)
Investigations
Alanine aminotransferase increased	1/15 (6.7%)		2/11 (18.2%)
Aspartate aminotransferase increased	0/15 (0%)		1/11 (9.1%)
Blood alkaline phosphatase increased	0/15 (0%)		1/11 (9.1%)
Blood calcium decreased	0/15 (0%)		1/11 (9.1%)
Blood calcium increased	0/15 (0%)		1/11 (9.1%)
Blood uric acid increased	1/15 (6.7%)		0/11 (0%)
Carbon dioxide decreased	0/15 (0%)		1/11 (9.1%)
Eosinophil count increased	0/15 (0%)		1/11 (9.1%)
Haemoglobin decreased	0/15 (0%)		1/11 (9.1%)
Lymphocyte count decreased	0/15 (0%)		1/11 (9.1%)
Monocyte count decreased	0/15 (0%)		1/11 (9.1%)
Monocyte count increased	0/15 (0%)		1/11 (9.1%)
Neutrophil count increased	0/15 (0%)		1/11 (9.1%)
Olfactory test abnormal	1/15 (6.7%)		0/11 (0%)
Platelet count decreased	1/15 (6.7%)		1/11 (9.1%)
Protein total decreased	0/15 (0%)		1/11 (9.1%)
Red blood cell count decreased	0/15 (0%)		1/11 (9.1%)
Troponin increased	1/15 (6.7%)		0/11 (0%)
Weight decreased	1/15 (6.7%)		0/11 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/15 (20%)		0/11 (0%)
Dehydration	1/15 (6.7%)		0/11 (0%)
Fluid retention	1/15 (6.7%)		0/11 (0%)
Hyperglycaemia	0/15 (0%)		1/11 (9.1%)
Hyperkalaemia	0/15 (0%)		1/11 (9.1%)
Hypocalcaemia	0/15 (0%)		1/11 (9.1%)
Hypokalaemia	2/15 (13.3%)		3/11 (27.3%)
Hypomagnesaemia	1/15 (6.7%)		1/11 (9.1%)
Hyponatraemia	1/15 (6.7%)		0/11 (0%)
Hypophosphataemia	0/15 (0%)		1/11 (9.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/15 (6.7%)		1/11 (9.1%)
Arthritis	1/15 (6.7%)		0/11 (0%)
Back pain	2/15 (13.3%)		1/11 (9.1%)
Bone pain	2/15 (13.3%)		0/11 (0%)
Diastasis recti abdominis	1/15 (6.7%)		0/11 (0%)
Joint swelling	1/15 (6.7%)		0/11 (0%)
Limb discomfort	1/15 (6.7%)		0/11 (0%)
Muscle spasms	1/15 (6.7%)		1/11 (9.1%)
Muscular weakness	2/15 (13.3%)		0/11 (0%)
Musculoskeletal chest pain	3/15 (20%)		0/11 (0%)
Musculoskeletal discomfort	0/15 (0%)		1/11 (9.1%)
Musculoskeletal pain	2/15 (13.3%)		0/11 (0%)
Neck pain	0/15 (0%)		1/11 (9.1%)
Pain in extremity	1/15 (6.7%)		2/11 (18.2%)
Soft tissue mass	1/15 (6.7%)		0/11 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal neoplasm	1/15 (6.7%)		0/11 (0%)
Plasmacytoma	1/15 (6.7%)		0/11 (0%)
Nervous system disorders
Areflexia	0/15 (0%)		1/11 (9.1%)
Dizziness	2/15 (13.3%)		1/11 (9.1%)
Dysgeusia	1/15 (6.7%)		0/11 (0%)
Headache	5/15 (33.3%)		3/11 (27.3%)
Lethargy	1/15 (6.7%)		1/11 (9.1%)
Migraine	0/15 (0%)		1/11 (9.1%)
Neuropathy peripheral	1/15 (6.7%)		1/11 (9.1%)
Restless legs syndrome	0/15 (0%)		1/11 (9.1%)
Sciatica	1/15 (6.7%)		0/11 (0%)
Somnolence	1/15 (6.7%)		0/11 (0%)
Syncope	0/15 (0%)		1/11 (9.1%)
Psychiatric disorders
Confusional state	3/15 (20%)		0/11 (0%)
Depression	0/15 (0%)		2/11 (18.2%)
Insomnia	3/15 (20%)		1/11 (9.1%)
Mood altered	1/15 (6.7%)		0/11 (0%)
Renal and urinary disorders
Acute kidney injury	1/15 (6.7%)		0/11 (0%)
Dysuria	2/15 (13.3%)		0/11 (0%)
Micturition urgency	1/15 (6.7%)		0/11 (0%)
Pollakiuria	1/15 (6.7%)		0/11 (0%)
Renal failure	0/15 (0%)		1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
Cough	6/15 (40%)		3/11 (27.3%)
Dysphonia	1/15 (6.7%)		0/11 (0%)
Dyspnoea	7/15 (46.7%)		1/11 (9.1%)
Dyspnoea exertional	1/15 (6.7%)		0/11 (0%)
Dyspnoea paroxysmal nocturnal	0/15 (0%)		1/11 (9.1%)
Epistaxis	4/15 (26.7%)		1/11 (9.1%)
Hypoxia	1/15 (6.7%)		1/11 (9.1%)
Oropharyngeal pain	1/15 (6.7%)		0/11 (0%)
Oropharyngeal plaque	1/15 (6.7%)		0/11 (0%)
Pleural effusion	1/15 (6.7%)		0/11 (0%)
Productive cough	2/15 (13.3%)		1/11 (9.1%)
Pulmonary hypertension	1/15 (6.7%)		0/11 (0%)
Sinus congestion	1/15 (6.7%)		0/11 (0%)
Tachypnoea	1/15 (6.7%)		0/11 (0%)
Throat irritation	1/15 (6.7%)		0/11 (0%)
Wheezing	2/15 (13.3%)		1/11 (9.1%)
Skin and subcutaneous tissue disorders
Acne	1/15 (6.7%)		0/11 (0%)
Angioedema	1/15 (6.7%)		0/11 (0%)
Erythema	2/15 (13.3%)		0/11 (0%)
Hyperhidrosis	1/15 (6.7%)		1/11 (9.1%)
Hyperkeratosis	0/15 (0%)		1/11 (9.1%)
Pruritus	0/15 (0%)		1/11 (9.1%)
Rash	2/15 (13.3%)		0/11 (0%)
Rash erythematous	0/15 (0%)		1/11 (9.1%)
Swelling face	1/15 (6.7%)		0/11 (0%)
Vascular disorders
Flushing	2/15 (13.3%)		1/11 (9.1%)
Hypertension	3/15 (20%)		1/11 (9.1%)
Hypotension	2/15 (13.3%)		2/11 (18.2%)
Peripheral coldness	1/15 (6.7%)		0/11 (0%)
Venous thrombosis	1/15 (6.7%)		0/11 (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.