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

• ClinicalTrials.gov Identifier: NCT01949545
• Recruitment Status: Completed
• First Posted: September 24, 2013
• Results First Posted: October 21, 2016
• Last Update Posted: May 2, 2017
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors; Hematologic Malignancies; Hepatic Impairment	Drug: Carfilzomib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: An Open-Label, Single Arm, Phase 1 Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects With Advanced Malignancies and Varying Degrees of Hepatic Impairment
• Study Start Date: October 2013
• Actual Primary Completion Date: August 2015
• Actual Study Completion Date: September 2015

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: Kyprolis® (carfilzomib) for Injection

Outcome Measures

Primary Outcome Measures :

1. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) 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. ]
   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.
2. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) 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. ]
   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 Outcome Measures :

1. Maximum Plasma Concentration (Cmax) 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. ]
2. Time to Maximum Plasma Concentration (Tmax) 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. ]
3. Clearance 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. ]
4. Terminal Half-life 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. ]
5. Mean Residence Time (MRT) 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. ]
6. 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. ]
7. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² [ 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. ]
   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.
8. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² [ 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. ]
   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.
9. Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² [ 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. ]
10. Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² [ 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. ]
11. Terminal Half-life of Carfilzomib 56 mg/m² [ 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. ]
12. Clearance of Carfilzomib 56 mg/m² [ 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. ]
13. Mean Residence Time (MRT) of Carfilzomib 56 mg/m² [ 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. ]
14. Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² [ 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. ]
15. 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. ]
16. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) 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. ]
17. Maximum Plasma Concentration (Cmax) 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. ]
18. Time to Maximum Plasma Concentration (Tmax) 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. ]
19. Terminal Half-life 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. ]
20. Mean Residence Time (MRT) 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. ]
21. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 [ 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. ]
22. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 [ 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. ]
23. Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 [ 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. ]
24. Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 [ 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. ]
25. Terminal Half-life for Metabolite PR-413/M15 [ 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. ]
26. Mean Residence Time (MRT) for Metabolite PR-413/M15 [ 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. ]
27. Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 [ 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. ]
28. Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 [ 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. ]
29. Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 [ 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. ]
30. Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 [ 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. ]
31. Terminal Half-life for Metabolite PR-519/M16 [ 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. ]
32. Mean Residence Time (MRT) for Metabolite PR-519/M16 [ 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. ]
33. Number of Participants With Adverse Events (AEs) [ Time Frame: From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks ]

    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).

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States

United States, North Carolina

Duke Cancer Institute

Durham, North Carolina, United States

United States, Ohio

Gabrail Cancer Center

Canton, Ohio, United States

United States, Tennessee

Tennessee Oncology, PLLC

Nashville, Tennessee, United States

United States, Washington

Evergreen Hematology and Oncology

Spokane, Washington, United States

France

Institut Gustave Roussy

Paris, Villejuif Cedex, France

Netherlands

University Medical Centre Utrecht

Utrecht, Netherlands

United Kingdom

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

Sir Bobby Robson Cancer Trials Research Centre

Newcastle, United Kingdom

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01949545
• Other Study ID Numbers: CFZ002; 20130402 ( Other Identifier: Amgen )
• First Posted: September 24, 2013
• Results First Posted: October 21, 2016
• Last Update Posted: May 2, 2017
• Last Verified: April 2017

Additional relevant MeSH terms:

Neoplasms; Hematologic Neoplasms; Liver Diseases; Neoplasms by Site; Hematologic Diseases; Digestive System Diseases