Study of the Pharmacokinetics and Safety of Carfilzomib in Patients With Multiple Myeloma and Renal Disease

An Open-Label, Single Arm, Phase 1 Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects With Relapsed Multiple Myeloma and End-stage Renal Disease

The purpose of this study is to see how the body and the cancer react to 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 normal kidney function and those with end-stage renal disease to see if they respond differently to the study drug.

Study Overview

• Status: Completed
• Conditions: End-stage Renal Disease; Relapsed Multiple Myeloma
• Intervention / Treatment: Drug: Carfilzomib

Detailed Description

Specifically, the purpose of this study is to assess the influence of end-stage renal disease (ESRD) on area under the curve (both area under the curve, from time 0 to the last concentration measured [AUC0-last] and area under the curve, from time 0 extrapolated to infinity [AUC0-inf]) of carfilzomib 56 mg/m² at Cycle 2 Day 1 (C2D1) in patients with relapsed multiple myeloma.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
      • Royal Prince Alfred Hospital
  • Queensland
    • Herston, Queensland, Australia
      • Royal Brisbane and Women's Hospital
  • Victoria
    • Clayton, Victoria, Australia
      • Monash Health, Monash Medical Centre
    • Fitzroy, Victoria, Australia
      • St. Vincent's Hospital Melbourne
    • Melbourne, Victoria, Australia
      • The Alfred Hospital, Malignant Haematology and Stem Cell Transplant Department
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • QEII Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada
      • Sir Mortimer B. Davis-Jewish General Hospital
• United States
  • Michigan
    • Detroit, Michigan, United States
      • Karmanos Cancer Institute
  • New York
    • Lake Success, New York, United States
      • North Shore-LIJ Health System/Center for Advanced Medicine - North Shore University Hospital
  • Ohio
    • Canton, Ohio, United States
      • Gabrail Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt-Ingram Cancer Center, Henry-Joyce Cancer Clinic
  • Texas
    • Dallas, Texas, United States
      • UT Southwestern Medical Center
    • Dallas, Texas, United States
      • Baylor Charles A. Sammons Cancer Center

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 multiple myeloma
2. Evaluable disease (serum protein electrophoresis [SPEP]/urine protein electrophoresis [UPEP]/serum free light chain [SFLC] criteria)
3. Received at least 1 prior treatment regimen or line of therapy for multiple myeloma
4. End-stage renal disease (ESRD) on hemodialysis or CrCl ≥ 75 mL/min
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
6. Adequate organ and bone marrow function
7. 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. Immunoglobulin M (IgM) multiple myeloma
2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
3. Waldenström Macroglobulinemia
4. Active congestive heart failure (NYHA Class III-IV) ischemia, conduction abnormalities
5. Known human immunodeficiency virus (HIV), recent hepatitis B virus (HBV), hepatitis C virus (HCV)
6. Myelodysplastic Syndrome
7. Contraindication to test article, constituents, or required concomitant medications
8. Other investigational drugs

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal Renal Function; Participants with normal renal function (creatinine clearance [CrCl] ≥ 75 mL/min) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.	Drug: Carfilzomib; Carfilzomib was administered by IV injection.; Other Names: Kyprolis®
Experimental: End Stage Renal Disease; Participants with end-stage renal disease (on hemodialysis) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death.	Drug: Carfilzomib; Carfilzomib was administered by IV injection.; Other Names: Kyprolis®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2	Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL.	Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2		Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1		Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration for Metabolite PR-389/M14		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Metabolite PR-389/M14		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Metabolite PR-413/M15		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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 (T½) of Metabolite PR-519/M16		Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately 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)	Determination of the severity of all adverse events was assessed following the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Fatal. A Serious AE is an AE that meets one or more of the following criteria: Death,; Life-threatening experience;; Requires in-patient hospitalization or prolongation of an existing hospitalization,; Results in persistent or significant disability/incapacity,; Is a congenital anomaly/birth defect,; Important medical events that may not result in death, be life-threatening, or require hospitalization. Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship.	From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group.

Collaborators and Investigators

• Sponsor: Amgen

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): January 1, 2017

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: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Renal Insufficiency, Chronic; Kidney Diseases; Multiple Myeloma; Neoplasms, Plasma Cell; Kidney Failure, Chronic
• Other Study ID Numbers: CFZ001; 20130401 (Sponsor)