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

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

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

Conditions
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Multiple Myeloma, Renal Insufficiency

Intervention / Treatment
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* Drug: Carfilzomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent in accordance with federal, local, and institutional guidelines Males and females ≥ 18 years of age Multiple Myeloma Documented relapsed or progressive disease (PD) after receiving at least two prior treatment regimens (induction therapy with autologous stem cell transplant and maintenance is considered a single regimen), and must have achieved a minimal response or better to at least one of the regimens Current measurable disease, as indicated by one or more of the following: Serum M-protein ≥ 0.5 g/dL Urine M-protein ≥ 200 mg/24 hours Serum Free Light Chain (FLC) assay: Involved FLC level ≥ 10 mg/dL provided serum FLC ratio is abnormal Life expectancy of more than three months Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN Total white blood cell (WBC) count ≥ 2,000/mm³ Absolute neutrophil count (ANC) ≥ 1,000/mm³ Hemoglobin ≥ 7 gm/dL Subjects may receive red blood cell (RBC) transfusions or supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines Platelet count ≥ 30,000/ mm³ Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test Male subjects must use an effective barrier method of contraception during study and for three months following the last dose if sexually active with a female of child-bearing potential Exclusion Criteria: Glucocorticoid therapy in a dose equivalent to prednisone ≥ 20 mg/day within 14 days prior to first dose of study drug POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 14 days prior to first dose of study drug or antibody therapy within 6 weeks prior to first dose of study drug Radiation therapy or immunotherapy within 3 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose Participation in an investigational therapeutic study within 14 days prior to first dose of study drug Prior carfilzomib treatment Pregnant or lactating females Major surgery within 3 weeks prior to first dose of study drug Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities or myocardial infarction in the three months prior to first dose of study drug Uncontrolled hypertension Recent history of acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose of study drug Known or suspected human immunodeficiency virus (HIV) infection, known HIV seropositivity Active hepatitis A, B, or C infection Other malignancy within the past 3 years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer < Gleason Grade 7 with stable prostate specific antigen (PSA) levels Any clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days prior to enrollment Subjects in whom the required program of oral hydration and intravenous fluid hydration is contraindicated, e.g., due to preexisting pulmonary or cardiac impairment Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis Subjects with a known contraindication to receiving dexamethasone or allopurinol Receipt of granulocyte- and granulocyte/ macrophage- colony stimulating factor (G-CSF and GM-CSF) within 1 week prior to first dose of study drug Receipt of pegylated G-CSF within 2 weeks prior to first dose of study drug RBC and platelet transfusions within 7 days prior to first dose of study drug Subjects with known or suspected cardiac amyloidosis Subjects with myelodysplastic syndrome Subjects undergoing peritoneal dialysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib<br>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. | Drug: Carfilzomib<br>* Carfilzomib was administered intravenously (IV) at a rate of approximately 10 mL/minute.<br>* Other names: Kyprolis®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL) of Carfilzomib on Day 1 of Cycle 1 | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL) of Carfilzomib on Day 15 of Cycle 1 |  | 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. | 
| Clearance (CL) of Carfilzomib on Day 15 of Cycle 2 |  | 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. | 
| Maximum Observed Plasma Concentration of Carfilzomib on Day 1 of Cycle 1 |  | 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. | 
| Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 1 |  | 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. | 
| Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 2 |  | 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. | 
| Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 1 of Cycle 1 |  | 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. | 
| Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 1 |  | 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. | 
| Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 2 |  | 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. | 
| Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 1 of Cycle 1 |  | 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. | 
| Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 1 |  | 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. | 
| Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 2 |  | 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. | 
| Percentage of Carfilzomib Excreted Via Renal Elimination on Day 1 of Cycle 1 | The percentage of carfilzomib excreted in urine was calculated as the total amount excreted over 24 hours/dose. | Cycle 1, Day 1, 0-5 and 5-24 hours post-dose | 
| Percentage of Carfilzomib Excreted Via Renal Elimination on Day 15 of Cycle 1 | The percentage of carfilzomib excreted in urine was calculated as the total amount excreted over 24 hours/dose. | Cycle 1, Day 15, 0-5 and 5-24 hours post-dose | 
| Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 1 of Cycle 1 | 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. | Cycle 1, Day 1, 0-5 and 5-24 hours post-dose | 
| Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 15 of Cycle 1 | 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. | Cycle 1, Day 15, 0-5 and 5-24 hours post-dose | 
| Plasma Protein Binding (PPB) of Carfilzomib | 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). | End of injection and 5 minutes post-dose on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 15 | 
| Overall Response Rate (ORR) | 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. | From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days. | 
| Clinical Benefit Rate (CBR) | 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. | From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days. | 
| Duration of Response | 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. | Participants were followed for disease progression for up to 2 years. | 
| Time to Progression (TTP) | Time to Progression is defined as the time from first dose of carfilzomib to disease progression. Median TTP was estimated using Kaplan-Meier methods. | Participants were followed for disease progression for up to 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloma, Renal Insufficiency, Proteasome, Hematological, carfilzomib, PR-171