Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Renal Insufficiency

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Kidney Diseases

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Carfilzomib, 15 mg/m², was 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 was administered intravenously (IV) at a rate of approximately 10 mL/minute.

Carfilzomib

The purpose of this study is to assess the influence of renal impairment on carfilzomib in patients with Multiple Myeloma (MM).

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

Phase 2 Study of the Safety and Pharmacokinetics of Carfilzomib in Subjects With Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Function

Plasma concentrations of carfilzomib was determined by a validated liquid chromatography tandem mass spectrometry (LC MS/MS) method. The lower limit of quantitation (LLOQ) was 0.300 ng/mL. Concentration values that were below the LLOQ (BLQ) were set to zero. Pharmacokinetic (PK) parameters were calculated from the individual plasma concentrations of carfilzomib using a noncompartmental method.

The percentage of carfilzomib excreted in urine was calculated as the total amount excreted over 24 hours/dose.

The percentage of the metabolites of carfilzomib (PR-389/M14 and PR-413/M15) excreted in urine was calculated as the total amount excreted over 24 hours/dose.

The plasma protein binding (PPB) of carfilzomib in plasma samples was determined using a rapid equilibrium dialysis (RED) device. Data are averages of the 3 time points (Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 15).

ORR is defined as the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per the International Uniform Response Criteria for Multiple Myeloma.

sCR: CR as defined below plus normal serum free light chain (sFLC) ratio and absence of clonal plasma cells in bone marrow by immunohistochemistry or immunofluorescence; CR: absence of M-protein in serum and urine confirmed by immunofixation and \< 5% plasma cells in the bone marrow; VGPR: serum and urine M-proteins detectable by immunofixation, but not by electrophoresis or a ≥ 90% reduction in serum M-protein from baseline, plus a urine M-protein level of \< 100 mg/24 hours; PR: reduction of M-protein in serum of ≥ 50% and in urine of ≥ 90% from baseline. If serum and urine M-protein were not measureable at baseline, a ≥ 50% decrease in the difference between involved and uninvolved sFLC levels from baseline.

Clinical benefit rate is defined as the percentage of participants whose best response was sCR, CR, VGPR, PR, or minimal response (MR), where MR is defined by the European Group for Blood and Marrow Transplant (EBMT) criteria as a reduction of M-protein in serum of 25% to 49% and in urine of 50% to 89% from baseline, maintained for at least 6 weeks.

Duration of Response is defined as the time from first evidence of PR or better to confirmation of disease progression or death.

Progressive disease was defined as any of the following:

* An increase of more than 25% from nadir in any one of the following:

  * M-protein in serum (the absolute increase had to be ≥ 0.5 g/dL);
  * Urine (the absolute increase had to be ≥ 200 mg/24 hours);
  * The difference between involved and uninvolved sFLC (the absolute increase in the concentration of involved light chain had to be \> 10 mg/dL);
  * ≥ 10% bone marrow infiltration by plasma cells;
* Increased size of pre-existing bone lesions or plasmacytomas or new bone lesions or plasmacytomas.

Median duration of response was estimated using the Kaplan-Meier method.

Time to Progression is defined as the time from first dose of carfilzomib to disease progression. Median TTP was estimated using Kaplan-Meier methods.

Amgen

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

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 - Normal RF

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 - Mild 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 - Moderate 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 - Severe RI

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.

Carfilzomib - Dialysis

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

African American

Asian/Pacific Islander

Caucasian

Race/Ethnicity, Customized

0 (Fully active)

1 (Restrictive but ambulatory)

2 (Ambulatory but unable to work)

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.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Study Director

In order to estimate a possible effect of renal function, the relationship between the clearance of carfilzomib and creatinine clearance (CrCl) was explored using a mixed-effects model that included CrCl.

The slope of the regression of CL as a function of CrCL at Cycle 1, Day 1 was evaluated using a linear regression model that included CrCL as continuous variables (excluding the hemodialysis group).

The pharmacokinetic (PK) evaluable population includes participants with stable baseline renal function (Arms 1-4) who completed all protocol-specified treatment and PK blood sample collection through Cycle 1, Day 16. In Group 5, only samples collected before dialysis were included.

CL could not be estimated for 11 patients in the PK population.

Clearance (CL) of Carfilzomib on Day 1 of Cycle 1

The pharmacokinetic (PK) evaluable population with available data

Clearance (CL) of Carfilzomib on Day 15 of Cycle 1

Clearance (CL) of Carfilzomib on Day 15 of Cycle 2

Maximum Observed Plasma Concentration of Carfilzomib on Day 1 of Cycle 1

Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 1

Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 2

PK evaluable population; AUCinf could not be estimated for 11 participants in the PK population who did not have adequate PK data.

Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 1 of Cycle 1

PK evaluable population with available data

Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 1

Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 2

Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 1 of Cycle 1

Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 1

Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 2

Participants in Groups 1-4 with available data

Percentage of Carfilzomib Excreted Via Renal Elimination on Day 1 of Cycle 1

Percentage of Carfilzomib Excreted Via Renal Elimination on Day 15 of Cycle 1

Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 1 of Cycle 1

Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 15 of Cycle 1

End of Injection

5 minutes after injection

Plasma Protein Binding (PPB) of Carfilzomib

The response evaluable population included all participants with measurable disease and a baseline and at least 1 post-baseline disease assessment or who discontinued study treatment due to a related adverse event prior to obtaining an on-study disease assessment.

Overall Response Rate (ORR)

Clinical Benefit Rate (CBR)

Response Evaluable Population with a best overall response of sCR, CR, VGPR, or PR.

Spots Global Cancer Trial Database for Study of the Safety and Pharmacokinetics of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Function

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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