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

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

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 Overview

• Status: Completed
• Conditions: Hepatic Impairment; Solid Tumors; Hematologic Malignancies
• Intervention / Treatment: Drug: Carfilzomib

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Villejuif Cedex
    • Paris, Villejuif Cedex, France
      • Institut Gustave Roussy
• Netherlands
  • Utrecht, Netherlands
    • University Medical Centre Utrecht
• United Kingdom
  • Newcastle, United Kingdom
    • Sir Bobby Robson Cancer Trials Research Centre
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom
      • Northern Ireland Cancer Trials Centre - Queen's University Belfast TriaIs Centre
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • Beatson West of Scotland Cancer Centre
  • Wales
    • Cardlff, Wales, United Kingdom
      • Velindre Hospital
• United States
  • Michigan
    • Detroit, Michigan, United States
      • Karmanos Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States
      • Duke Cancer Institute
  • Ohio
    • Canton, Ohio, United States
      • Gabrail Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States
      • Tennessee Oncology, PLLC
  • Washington
    • Spokane, Washington, United States
      • Evergreen Hematology and Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Brown J, Plummer R, Bauer TM, Anthony S, Sarantopoulos J, De Vos F, White M, Schupp M, Ou Y, Vaishampayan U. Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study. Exp Hematol Oncol. 2017 Oct 3;6:27. doi: 10.1186/s40164-017-0086-1. eCollection 2017.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: September 6, 2013
• First Submitted That Met QC Criteria: September 19, 2013
• First Posted (Estimate): September 24, 2013

Study Record Updates

• Last Update Posted (Actual): May 2, 2017
• Last Update Submitted That Met QC Criteria: April 28, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Hematologic Diseases; Liver Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: CFZ002; 20130402 (Other Identifier: Amgen)