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

Phase 1CompletedNCT01949545

Amgen46 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Solid Tumors Hematologic Malignancies Hepatic Impairment

Interventions

CarfilzomibDRUG

Carfilzomib was administered by IV injection over 30 minutes

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Relapsed or progressive advanced malignancies (solid tumors or hematologic malignancies) 2. At least ≥ 2 prior treatment regimens for the underlying malignancy 3. Confirmed advanced solid tumor or hematologic malignancy 4. Measurable or evaluable disease 5. Clinical diagnosis of chronic hepatic impairment that is stable with no acute worsening of liver failure within one month prior to enrollment. Hepatic impairment will be assessed as per National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema and will fall into one of the following three categories: * Cohort 2 (mild): Bilirubin \> 1-1.5 × upper limit of the normal range (ULN) or aspartate aminotransferase (AST) \> ULN, but bilirubin ≤ ULN * Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST * Cohort 4 (severe): Bilirubin \> 3 × ULN; any AST Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function: All subjects enrolled with normal hepatic function (N=10) must meet all inclusion criteria as outlined with the exception of Inclusion Criterion #5, which should be substituted with the following criterion to be enrolled into the study: \- Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN 6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 7. Left ventricular ejection fraction (LVEF) ≥ 40% 8. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min) 9. Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollment Key Exclusion Criteria: 1. Subjects with symptomatic brain metastasis or central nervous system (CNS) disease 2. Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment 3. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests \[bilirubin, AST\] will be allowed)

Locations (11)

Karmanos Cancer Institute

Detroit, Michigan, United States

Duke Cancer Institute

Durham, North Carolina, United States

Gabrail Cancer Center

Canton, Ohio, United States

Outcomes

Primary Outcomes

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.

Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

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.

Secondary Outcomes

Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m²

Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m²

Clearance of Carfilzomib 27 mg/m²

Data from ClinicalTrials.gov

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Tennessee Oncology, PLLC

Nashville, Tennessee, United States

Evergreen Hematology and Oncology

Spokane, Washington, United States

Institut Gustave Roussy

Paris, Villejuif Cedex, France

University Medical Centre Utrecht

Utrecht, Netherlands

Northern Ireland Cancer Trials Centre - Queen's University Belfast TriaIs Centre

Belfast, Northern Ireland, United Kingdom

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom

Velindre Hospital

Cardlff, Wales, United Kingdom

...and 1 more locations

Terminal Half-life of Carfilzomib 27 mg/m²

Mean Residence Time (MRT) of Carfilzomib 27 mg/m²

Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m²

Time frame: Cycle 1 day 16 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

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.

Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

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.

Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m²

Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m²

Terminal Half-life of Carfilzomib 56 mg/m²

Clearance of Carfilzomib 56 mg/m²

Mean Residence Time (MRT) of Carfilzomib 56 mg/m²

Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m²

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

Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion.

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

Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14

Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14

Terminal Half-life for Metabolite PR-389/M14

Mean Residence Time (MRT) for Metabolite PR-389/M14

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

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

Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15

Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15

Terminal Half-life for Metabolite PR-413/M15

Mean Residence Time (MRT) for Metabolite PR-413/M15

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

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

Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16

Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16

Terminal Half-life for Metabolite PR-519/M16

Mean Residence Time (MRT) for Metabolite PR-519/M16

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).

Time frame: From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks