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

NCT01949545 | Completed Phase 1 Results

• 2 other identifiers: CFZ00220130402
• Study Type: interventional
• Target: 46
• Locations: 4 countries
• Sites: 11

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.

Conditions

Solid Tumors; Hematologic Malignancies; Hepatic Impairment

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (33)

• 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.

Study Arms (4)

Normal Hepatic Function

EXPERIMENTAL

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

Mild Hepatic Impairment

EXPERIMENTAL

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

Moderate Hepatic Impairment

EXPERIMENTAL

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

Severe Hepatic Impairment

EXPERIMENTAL

(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

Interventions

Carfilzomib DRUG

Carfilzomib was administered by IV injection over 30 minutes

Also known as: Kyprolis® (carfilzomib) for Injection

Mild Hepatic Impairment; Moderate Hepatic Impairment; Normal Hepatic Function; Severe Hepatic Impairment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• #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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Amgen: lead

Study Sites (11)

Karmanos Cancer Institute

Detroit, Michigan, United States

Location

Duke Cancer Institute

Durham, North Carolina, United States

Location

Gabrail Cancer Center

Canton, Ohio, United States

Location

Tennessee Oncology, PLLC

Nashville, Tennessee, United States

Location

Evergreen Hematology and Oncology

Spokane, Washington, United States

Location

Institut Gustave Roussy

Paris, Villejuif Cedex, France

Location

University Medical Centre Utrecht

Utrecht, Netherlands

Location

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

Belfast, Northern Ireland, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom

Location

Velindre Hospital

Cardlff, Wales, United Kingdom

Location

Sir Bobby Robson Cancer Trials Research Centre

Newcastle, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 29026685 DERIVED

MeSH Terms

Conditions

Hematologic Neoplasms

Interventions

carfilzomib; WW Domain-Containing Oxidoreductase

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Short Chain Dehydrogenase-Reductases; NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; Alcohol Oxidoreductases; Oxidoreductases; Enzymes; Enzymes and Coenzymes; Tumor Suppressor Proteins; Neoplasm Proteins; Proteins; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Study Director
• Organization: Amgen, Inc.

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2013
• First Posted: September 24, 2013
• Study Start: October 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: September 1, 2015
• Last Updated: May 2, 2017
• Results First Posted: October 21, 2016

Record last verified: 2017-04

Locations

NL (1); US (5); FR (1); GB (4)