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

Condition Intervention Phase
Multiple Myeloma
Renal Insufficiency
Drug: Carfilzomib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Onyx Pharmaceuticals:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    The percentage of carfilzomib excreted in urine was calculated as the total amount excreted over 24 hours/dose.

  • 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 ] [ Designated as safety issue: No ]
    The percentage of carfilzomib excreted in urine was calculated as the total amount excreted over 24 hours/dose.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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. ] [ Designated as safety issue: No ]

    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 (CBR) [ Time Frame: From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Participants were followed for disease progression for up to 2 years. ] [ Designated as safety issue: No ]

    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 (TTP) [ Time Frame: Participants were followed for disease progression for up to 2 years. ] [ Designated as safety issue: No ]
    Time to Progression is defined as the time from first dose of carfilzomib to disease progression. Median TTP was estimated using Kaplan-Meier methods.


Enrollment: 50
Study Start Date: November 2008
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carfilzomib

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
Carfilzomib was administered intravenously (IV) at a rate of approximately 10 mL/minute.
Other Names:
  • PR-171
  • Kyprolis®

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00721734

Locations
United States, California
University of California- San Francisco
San Francisco, California, United States, 94143
United States, Maryland
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Cornell University
New York, New York, United States, 10021
Sponsors and Collaborators
Onyx Therapeutics, Inc.
Investigators
Study Director: Alvin Wong, PharmD Onyx Therapeutics, Inc.
  More Information

Responsible Party: 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

Keywords provided by Onyx Pharmaceuticals:
Myeloma
Renal Insufficiency
Proteasome
Hematological
carfilzomib
PR-171

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Renal Insufficiency
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Kidney Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on July 25, 2016