Study of the Safety and Pharmacokinetics of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Function

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Onyx Pharmaceuticals ( Onyx Therapeutics, Inc. )
ClinicalTrials.gov Identifier:
NCT00721734
First received: July 22, 2008
Last updated: January 8, 2016
Last verified: January 2016
Results First Received: November 2, 2015  
Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Multiple Myeloma
Renal Insufficiency
Intervention: Drug: Carfilzomib

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study enrolled patients with multiple myeloma (MM) who had relapsed or progressive disease (PD) after at least 1 (original protocol) or 2 (following protocol Amendment 1) prior therapeutic treatments or regimens. Five groups of MM patients, representing different levels of renal function, were evaluated.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Carfilzomib – Normal RF

Participants with normal renal function (RF; defined as 24-hour urine creatinine clearance (CrCL) > 80 mL/minute) received carfilzomib, 15 mg/m², administered intravenously (IV) on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Mild RI

Participants with mild renal impairment (RI; CrCL between 50-80 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Moderate RI

Participants with moderate renal impairment (CrCL between 30-49 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Severe RI

Participants with severe renal impairment (CrCL < 30 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Dialysis

Participants undergoing chronic hemodialysis received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.


Participant Flow:   Overall Study
    Carfilzomib – Normal RF     Carfilzomib – Mild RI     Carfilzomib – Moderate RI     Carfilzomib – Severe RI     Carfilzomib – Dialysis  
STARTED     12     12     10     8     8  
COMPLETED     4 [1]   0 [1]   2 [1]   2 [1]   2 [1]
NOT COMPLETED     8     12     8     6     6  
Progressive Disease                 3                 10                 4                 5                 2  
Adverse Event                 3                 1                 4                 0                 3  
Withdrawal by Subject                 2                 1                 0                 0                 1  
Other                 0                 0                 0                 1                 0  
[1] Completed 12 cycles of carfilzomib treatment



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
Carfilzomib – Normal RF

Participants with normal renal function (RF; defined as 24-hour urine creatinine clearance (CrCL) > 80 mL/minute) received carfilzomib, 15 mg/m², administered intravenously (IV) on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Mild RI

Participants with mild renal impairment (RI; CrCL between 50-80 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Moderate RI

Participants with moderate renal impairment (CrCL between 30-49 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Severe RI

Participants with severe renal impairment (CrCL < 30 mL/minute) received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Carfilzomib – Dialysis

Participants undergoing chronic hemodialysis received carfilzomib, 15 mg/m², administered intravenously on Days 1, 2, 8, 9, 15, and 16 of repeated 28-day cycles for a maximum of 12 cycles.

If the 15 mg/m² dose was tolerated the dose could be increased to 20 mg/m² starting at Cycle 2. If 20 mg/m² was tolerated, an additional dose escalation to 27 mg/m² was allowed at Cycle 3 or at subsequent cycles.

Total Total of all reporting groups

Baseline Measures
    Carfilzomib – Normal RF     Carfilzomib – Mild RI     Carfilzomib – Moderate RI     Carfilzomib – Severe RI     Carfilzomib – Dialysis     Total  
Number of Participants  
[units: participants]
  12     12     10     8     8     50  
Age  
[units: participants]
           
<=18 years     0     0     0     0     0     0  
Between 18 and 65 years     6     8     4     1     7     26  
>=65 years     6     4     6     7     1     24  
Age  
[units: years]
Mean (Standard Deviation)
  64.5  (5.70)     63.5  (7.85)     66.2  (9.65)     73.0  (8.23)     56.0  (7.91)     64.6  (9.01)  
Gender  
[units: participants]
           
Female     4     8     3     3     4     22  
Male     8     4     7     5     4     28  
Race/Ethnicity, Customized  
[units: participants]
           
African American     2     2     4     1     2     11  
Asian/Pacific Islander     0     2     0     0     1     3  
Caucasian     10     8     6     7     5     36  
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]
[units: participants]
           
0 (Fully active)     4     2     0     2     0     8  
1 (Restrictive but ambulatory)     8     9     9     1     5     32  
2 (Ambulatory but unable to work)     0     1     1     5     3     10  
[1] Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active; 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, no self-care, confined to bed or chair; 5 = Dead.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Clearance (CL) of Carfilzomib on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

2.  Secondary:   Clearance (CL) of Carfilzomib on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

3.  Secondary:   Clearance (CL) of Carfilzomib on Day 15 of Cycle 2   [ Time Frame: Cycle 2, Day 15, before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

4.  Secondary:   Maximum Observed Plasma Concentration of Carfilzomib on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1, before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

5.  Secondary:   Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

6.  Secondary:   Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 2   [ Time Frame: Cycle 2, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

7.  Secondary:   Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1, before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

8.  Secondary:   Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

9.  Secondary:   Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 2   [ Time Frame: Cycle 2, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

10.  Secondary:   Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

11.  Secondary:   Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

12.  Secondary:   Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 2   [ Time Frame: Cycle 2, Day 15 before dosing, at the end of the injection, 5, 15, 30, and 60 minutes, and 1.5, 2, 4, 6 and 24 hours postdose. ]

13.  Secondary:   Percentage of Carfilzomib Excreted Via Renal Elimination on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1, 0-5 and 5-24 hours post-dose ]

14.  Secondary:   Percentage of Carfilzomib Excreted Via Renal Elimination on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15, 0-5 and 5-24 hours post-dose ]

15.  Secondary:   Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 1 of Cycle 1   [ Time Frame: Cycle 1, Day 1, 0-5 and 5-24 hours post-dose ]

16.  Secondary:   Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 15 of Cycle 1   [ Time Frame: Cycle 1, Day 15, 0-5 and 5-24 hours post-dose ]

17.  Secondary:   Plasma Protein Binding (PPB) of Carfilzomib   [ Time Frame: End of injection and 5 minutes post-dose on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 15 ]

18.  Secondary:   Overall Response Rate (ORR)   [ Time Frame: From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days. ]

19.  Secondary:   Clinical Benefit Rate (CBR)   [ Time Frame: From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days. ]

20.  Secondary:   Duration of Response   [ Time Frame: Participants were followed for disease progression for up to 2 years. ]

21.  Secondary:   Time to Progression (TTP)   [ Time Frame: Participants were followed for disease progression for up to 2 years. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Amgen, Inc.
phone: 866-572-6436


No publications provided


Responsible Party: Onyx Pharmaceuticals ( Onyx Therapeutics, Inc. )
ClinicalTrials.gov Identifier: NCT00721734     History of Changes
Other Study ID Numbers: PX-171-005
Study First Received: July 22, 2008
Results First Received: November 2, 2015
Last Updated: January 8, 2016
Health Authority: United States: Food and Drug Administration