Trial Outcomes & Findings for Study of the Pharmacokinetics and Safety of Carfilzomib in Patients With Multiple Myeloma and Renal Disease (NCT NCT01949532)

NCT ID: NCT01949532

Last Updated: 2017-05-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

26 participants

Primary outcome timeframe

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.

Results posted on

2017-05-02

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	15	11
Overall Study COMPLETED	12	8
Overall Study NOT COMPLETED	3	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study On-study at the Data Cut-off Date	3	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Normal Renal Function n=15 Participants 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.	End Stage Renal Disease n=11 Participants 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 n=26 Participants Total of all reporting groups
Age, Continuous	64.8 years STANDARD_DEVIATION 8.1 • n=5 Participants	62.8 years STANDARD_DEVIATION 7.9 • n=7 Participants	64.0 years STANDARD_DEVIATION 7.9 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants	9 Participants n=7 Participants	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Black	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized White	12 participants n=5 Participants	9 participants n=7 Participants	21 participants n=5 Participants
Race/Ethnicity, Customized Other	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Not Reported	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active)	5 participants n=5 Participants	3 participants n=7 Participants	8 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory)	10 participants n=5 Participants	7 participants n=7 Participants	17 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work)	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
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	563 ng*h/mL Geometric Coefficient of Variation 41.9	747 ng*h/mL Geometric Coefficient of Variation 143.9

PRIMARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
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	563 ng*h/mL Geometric Coefficient of Variation 41.8	752 ng*h/mL Geometric Coefficient of Variation 144.7

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	1389 ng/mL Geometric Coefficient of Variation 26.8	1567 ng/mL Geometric Coefficient of Variation 128.8

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	0.467 hours Interval 0.25 to 0.733	0.467 hours Interval 0.25 to 0.583

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	0.341 hours Interval 0.111 to 0.498	1.25 hours Interval 0.0632 to 3.31

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	179 liters/hour Geometric Coefficient of Variation 38.9	134 liters/hour Geometric Coefficient of Variation 136.9

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	0.135 hours Geometric Coefficient of Variation 62.6	0.245 hours Geometric Coefficient of Variation 79.9

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease n=8 Participants 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.
Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	24.1 liters Geometric Coefficient of Variation 44.8	32.8 liters Geometric Coefficient of Variation 133.9

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
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	344 ng*h/mL Geometric Coefficient of Variation 24.8	480 ng*h/mL Geometric Coefficient of Variation 36.0

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=11 Participants 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.	End Stage Renal Disease n=6 Participants 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.
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	347 ng*h/mL Geometric Coefficient of Variation 26.3	479 ng*h/mL Geometric Coefficient of Variation 46.6

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	819 ng/mL Geometric Coefficient of Variation 29.8	1022 ng/mL Geometric Coefficient of Variation 37.2

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	0.583 hours Interval 0.467 to 0.733	0.467 hours Interval 0.233 to 0.75

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=11 Participants 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.	End Stage Renal Disease n=6 Participants 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.
Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	0.387 hours Interval 0.0938 to 0.599	0.992 hours Interval 0.918 to 16.0

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	146 liters/hour Geometric Coefficient of Variation 23.0	93 liters/hour Geometric Coefficient of Variation 56.8

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	Normal Renal Function n=11 Participants 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.	End Stage Renal Disease n=6 Participants 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.
Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	0.222 hours Geometric Coefficient of Variation 16.6	0.426 hours Geometric Coefficient of Variation 152.2

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1	32.0 liters Geometric Coefficient of Variation 29.7	53.0 liters Geometric Coefficient of Variation 185.5

SECONDARY outcome

Timeframe: 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.

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 Cycle 1, Day 16 (n = 13, 9)	320 ng*h/mL Geometric Coefficient of Variation 32.8	1486 ng*h/mL Geometric Coefficient of Variation 32.3
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 Cycle 2, Day 1 (n = 10, 8)	584 ng*h/mL Geometric Coefficient of Variation 17.5	2086 ng*h/mL Geometric Coefficient of Variation 132.8

SECONDARY outcome

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease 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.
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 Cycle 1, Day 16	355 ng*h/mL Geometric Coefficient of Variation 25.1	—
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 Cycle 2, Day 1	650 ng*h/mL Geometric Coefficient of Variation 22.5	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Maximum Observed Plasma Concentration for Metabolite PR-389/M14 Cycle 1, Day 16 (n = 13, 9)	153 ng/mL Geometric Coefficient of Variation 25.4	413 ng/mL Geometric Coefficient of Variation 32.9
Maximum Observed Plasma Concentration for Metabolite PR-389/M14 Cycle 2, Day 1 (n = 10, 8)	302 ng/mL Geometric Coefficient of Variation 16.5	595 ng/mL Geometric Coefficient of Variation 128.4

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 Cycle 2, Day 1 (n = 10, 8)	0.983 hours Interval 0.583 to 1.02	2.00 hours Interval 1.45 to 4.47
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 Cycle 1, Day 16 (n = 13, 9)	1.00 hours Interval 0.75 to 1.13	1.50 hours Interval 1.0 to 2.67

SECONDARY outcome

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=10 Participants 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.	End Stage Renal Disease 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.
Terminal Half-life (T½) of Metabolite PR-389/M14 Cycle 1, Day 16	1.46 hours Interval 0.975 to 1.73	—
Terminal Half-life (T½) of Metabolite PR-389/M14 Cycle 2, Day 1	1.10 hours Interval 0.903 to 1.7	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 Cycle 1, Day 16 (n = 13, 9)	33.4 ng*h/mL Geometric Coefficient of Variation 53.9	54.6 ng*h/mL Geometric Coefficient of Variation 45.0
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 Cycle 2, Day 1 (n = 10, 8)	60.3 ng*h/mL Geometric Coefficient of Variation 48.4	86.3 ng*h/mL Geometric Coefficient of Variation 199.1

SECONDARY outcome

Population: 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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=7 Participants 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.
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 Cycle 1, Day 16 (n = 13, 7)	36.2 ng*h/mL Geometric Coefficient of Variation 54.1	66.4 ng*h/mL Geometric Coefficient of Variation 48.7
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 Cycle 2, Day 1 (n = 10, 5)	63.8 ng*h/mL Geometric Coefficient of Variation 48.0	131 ng*h/mL Geometric Coefficient of Variation 35.8

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 Cycle 1, Day 16 (n = 13, 9)	20.7 ng/mL Geometric Coefficient of Variation 43.5	25.9 ng/mL Geometric Coefficient of Variation 42.5
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 Cycle 2, Day 1 (n = 10, 8)	40.2 ng/mL Geometric Coefficient of Variation 38.5	42.3 ng/mL Geometric Coefficient of Variation 163.9

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 Cycle 1, Day 16 (n = 13, 9)	0.833 hours Interval 0.683 to 1.0	0.767 hours Interval 0.733 to 1.05
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 Cycle 2, Day 1 (n = 10, 8)	0.667 hours Interval 0.25 to 1.0	0.750 hours Interval 0.717 to 1.52

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=7 Participants 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.
Terminal Half-life (T½) of Metabolite PR-413/M15 Cycle 1, Day 16 (n = 13, 7)	1.07 hours Interval 0.544 to 1.33	1.41 hours Interval 1.3 to 1.86
Terminal Half-life (T½) of Metabolite PR-413/M15 Cycle 2, Day 1 (n = 10, 5)	0.962 hours Interval 0.802 to 1.21	1.37 hours Interval 1.04 to 1.44

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 Cycle 2, Day 1 (n = 10, 8)	147 ng*h/mL Geometric Coefficient of Variation 52.8	138 ng*h/mL Geometric Coefficient of Variation 126.6
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 Cycle 1, Day 16 (n = 13, 9)	82.8 ng*h/mL Geometric Coefficient of Variation 53.1	86.8 ng*h/mL Geometric Coefficient of Variation 44.3

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 Cycle 1, Day 16 (n = 13, 9)	84.4 ng*h/mL Geometric Coefficient of Variation 52.4	89.6 ng*h/mL Geometric Coefficient of Variation 42.8
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 Cycle 2, Day 1 (n = 10, 8)	148 ng*h/mL Geometric Coefficient of Variation 51.7	139 ng*h/mL Geometric Coefficient of Variation 125.1

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 Cycle 1, Day 16 (n = 13, 9)	93.4 ng/mL Geometric Coefficient of Variation 40.2	90.4 ng/mL Geometric Coefficient of Variation 48.0
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 Cycle 2, Day 1 (n = 10, 8)	180 ng/mL Geometric Coefficient of Variation 40.5	151 ng/mL Geometric Coefficient of Variation 129.7

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 Cycle 1, Day 16 (n = 13, 9)	0.617 hours Interval 0.467 to 1.0	0.600 hours Interval 0.467 to 0.917
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 Cycle 2, Day 1 (n = 10, 8)	0.525 hours Interval 0.25 to 0.617	0.533 hours Interval 0.467 to 0.75

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Normal Renal Function n=13 Participants 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.	End Stage Renal Disease n=9 Participants 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.
Terminal Half-life (T½) of Metabolite PR-519/M16 Cycle 1, Day 16 (n = 13, 9)	0.705 hours Interval 0.473 to 0.993	0.721 hours Interval 0.518 to 1.42
Terminal Half-life (T½) of Metabolite PR-519/M16 Cycle 2, Day 1 (n = 10, 8)	0.617 hours Interval 0.555 to 0.673	0.687 hours Interval 0.473 to 0.933

SECONDARY outcome

Timeframe: 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.

Population: All treated participants

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.

Outcome measures

Outcome measures
Measure	Normal Renal Function n=15 Participants 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.	End Stage Renal Disease n=11 Participants 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.
Number of Participants With Adverse Events (AEs) Any adverse event	15 participants	11 participants
Number of Participants With Adverse Events (AEs) Adverse event ≥ Grade 3	12 participants	9 participants
Number of Participants With Adverse Events (AEs) Serious adverse event	10 participants	9 participants
Number of Participants With Adverse Events (AEs) AE leading to discontinuation of carfilzomib	6 participants	0 participants
Number of Participants With Adverse Events (AEs) Fatal adverse events	2 participants	1 participants
Number of Participants With Adverse Events (AEs) Treatment-related adverse events	12 participants	8 participants
Number of Participants With Adverse Events (AEs) Treatment-related adverse event ≥ Grade 3	7 participants	6 participants
Number of Participants With Adverse Events (AEs) Serious treatment-related adverse event	5 participants	2 participants
Number of Participants With Adverse Events (AEs) TRAE leading to discontinuation of carfilzomib	4 participants	0 participants
Number of Participants With Adverse Events (AEs) Treatment-related fatal adverse events	0 participants	0 participants

Adverse Events

Normal Renal Function

Serious events: 10 serious events

Other events: 14 other events

Deaths: 0 deaths

End Stage Renal Disease

Serious events: 9 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen, Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER