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

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

Official Title
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An Open-Label, Single Arm, Phase 1 Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects With Advanced Malignancies and Varying Degrees of Hepatic Impairment

Conditions
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Solid Tumors, Hematologic Malignancies, Hepatic Impairment

Intervention / Treatment
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* Drug: Carfilzomib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Relapsed or progressive advanced malignancies (solid tumors or hematologic malignancies) At least ≥ 2 prior treatment regimens for the underlying malignancy Confirmed advanced solid tumor or hematologic malignancy Measurable or evaluable disease Clinical diagnosis of chronic hepatic impairment that is stable with no acute worsening of liver failure within one month prior to enrollment. Hepatic impairment will be assessed as per National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema and will fall into one of the following three categories: Cohort 2 (mild): Bilirubin > 1-1.5 × upper limit of the normal range (ULN) or aspartate aminotransferase (AST) > ULN, but bilirubin ≤ ULN Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST Cohort 4 (severe): Bilirubin > 3 × ULN; any AST Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function: All subjects enrolled with normal hepatic function (N=10) must meet all inclusion criteria as outlined with the exception of Inclusion Criterion #5, which should be substituted with the following criterion to be enrolled into the study: - Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Left ventricular ejection fraction (LVEF) ≥ 40% Adequate renal function (calculated creatinine clearance ≥ 30 mL/min) 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: Subjects with symptomatic brain metastasis or central nervous system (CNS) disease Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests [bilirubin, AST] will be allowed)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Hepatic Function<br>Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | Drug: Carfilzomib<br>* Carfilzomib was administered by IV injection over 30 minutes<br>* Other names: Kyprolis® (carfilzomib) for Injection;|
| Experimental: Mild Hepatic Impairment<br>Participants with mild hepatic impairment (bilirubin > 1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | Drug: Carfilzomib<br>* Carfilzomib was administered by IV injection over 30 minutes<br>* Other names: Kyprolis® (carfilzomib) for Injection;|
| Experimental: Moderate Hepatic Impairment<br>Participants with moderate hepatic impairment (bilirubin > 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | Drug: Carfilzomib<br>* Carfilzomib was administered by IV injection over 30 minutes<br>* Other names: Kyprolis® (carfilzomib) for Injection;|
| Experimental: Severe Hepatic Impairment<br>(Bilirubin > 3 × ULN; any AST) Participants with severe hepatic impairment (bilirubin > 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | Drug: Carfilzomib<br>* Carfilzomib was administered by IV injection over 30 minutes<br>* Other names: Kyprolis® (carfilzomib) for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² | The area under the curve from time zero (defined as the start of carfilzomib infusion) to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² | The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² |  | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² |  | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Clearance of Carfilzomib 27 mg/m² |  | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Terminal Half-life of Carfilzomib 27 mg/m² |  | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Mean Residence Time (MRT) of Carfilzomib 27 mg/m² |  | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² |  | Cycle 1 day 16 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² | The area under the curve from time zero to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² | The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Terminal Half-life of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Clearance of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Mean Residence Time (MRT) of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² |  | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Terminal Half-life for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Mean Residence Time (MRT) for Metabolite PR-389/M14 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Terminal Half-life for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Mean Residence Time (MRT) for Metabolite PR-413/M15 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Terminal Half-life for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Mean Residence Time (MRT) for Metabolite PR-519/M16 |  | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | 
| Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship. Adverse events were graded using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, on a scale from 1 (mild) to 5 (death). | From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks |