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

Multiple Myeloma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00721734
• Other study ID #: PX-171-005
• Status: Completed
• Phase: Phase 2
• First received: July 22, 2008
• Last updated: April 28, 2017
• Start date: November 2008
• Est. completion date: November 2012

Study information

• Verified date: April 2017
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Written informed consent in accordance with federal, local, and institutional guidelines

2. Males and females = 18 years of age

3. Multiple Myeloma

4. 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

5. 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

6. Life expectancy of more than three months

7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

8. Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN

9. Total white blood cell (WBC) count = 2,000/mm³

10. Absolute neutrophil count (ANC) = 1,000/mm³

11. Hemoglobin = 7 gm/dL

• Subjects may receive red blood cell (RBC) transfusions or supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines

12. Platelet count = 30,000/ mm³

13. 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

14. 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:

1. Glucocorticoid therapy in a dose equivalent to prednisone = 20 mg/day within 14 days prior to first dose of study drug

2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

3. Plasma cell leukemia

4. 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

5. Radiation therapy or immunotherapy within 3 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose

6. Participation in an investigational therapeutic study within 14 days prior to first dose of study drug

7. Prior carfilzomib treatment

8. Pregnant or lactating females

9. Major surgery within 3 weeks prior to first dose of study drug

10. 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

11. Uncontrolled hypertension

12. Recent history of acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose of study drug

13. Known or suspected human immunodeficiency virus (HIV) infection, known HIV seropositivity

14. Active hepatitis A, B, or C infection

15. 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

16. 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

17. 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

18. Subjects in whom the required program of oral hydration and intravenous fluid hydration is contraindicated, e.g., due to preexisting pulmonary or cardiac impairment

19. Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis

20. Subjects with a known contraindication to receiving dexamethasone or allopurinol

21. Receipt of granulocyte- and granulocyte/ macrophage- colony stimulating factor (G-CSF and GM-CSF) within 1 week prior to first dose of study drug

22. Receipt of pegylated G-CSF within 2 weeks prior to first dose of study drug

23. RBC and platelet transfusions within 7 days prior to first dose of study drug

24. Subjects with known or suspected cardiac amyloidosis

25. Subjects with myelodysplastic syndrome

26. Subjects undergoing peritoneal dialysis

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Renal Insufficiency

Intervention

Drug:
• Carfilzomib
Carfilzomib was administered intravenously (IV) at a rate of approximately 10 mL/minute.

Locations

Country	Name	City	State
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Cornell University	New York	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California- San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.