Clinical trial NCT00721734: Study of the Safety and Pharmacokinetics of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma and Varying Degrees of Renal Function
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Renal Insufficiency
Keywords: Myeloma
Renal Insufficiency
Proteasome
Hematological
carfilzomib
PR-171
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2008-07-24
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Clearance (CL) of Carfilzomib on Day 1 of Cycle 1
timeFrame: 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 outcomes:
measure: Clearance (CL) of Carfilzomib on Day 15 of Cycle 1
timeFrame: 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.
measure: Clearance (CL) of Carfilzomib on Day 15 of Cycle 2
timeFrame: 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.
measure: Maximum Observed Plasma Concentration of Carfilzomib on Day 1 of Cycle 1
timeFrame: 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.
measure: Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 1
timeFrame: 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.
measure: Maximum Observed Plasma Concentration of Carfilzomib on Day 15 of Cycle 2
timeFrame: 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.
measure: Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 1 of Cycle 1
timeFrame: 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.
measure: Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 1
timeFrame: 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.
measure: Area Under the Plasma Curve Extrapolated to Infinity (AUCinf) for Carfilzomib on Day 15 of Cycle 2
timeFrame: 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.
measure: Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 1 of Cycle 1
timeFrame: 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.
measure: Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 1
timeFrame: 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.
measure: Area Under the Concentration Time Curve to the Last Measurable Concentration (AUClast) for Carfilzomib on Day 15 of Cycle 2
timeFrame: 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.
measure: Percentage of Carfilzomib Excreted Via Renal Elimination on Day 1 of Cycle 1
timeFrame: Cycle 1, Day 1, 0-5 and 5-24 hours post-dose
measure: Percentage of Carfilzomib Excreted Via Renal Elimination on Day 15 of Cycle 1
timeFrame: Cycle 1, Day 15, 0-5 and 5-24 hours post-dose
measure: Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 1 of Cycle 1
timeFrame: Cycle 1, Day 1, 0-5 and 5-24 hours post-dose
measure: Percentage of Carfilzomib Metabolites Excreted Via Renal Elimination on Day 15 of Cycle 1
timeFrame: Cycle 1, Day 15, 0-5 and 5-24 hours post-dose
measure: Plasma Protein Binding (PPB) of Carfilzomib
timeFrame: End of injection and 5 minutes post-dose on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 15
measure: Overall Response Rate (ORR)
timeFrame: From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days.
measure: Clinical Benefit Rate (CBR)
timeFrame: From first dose until 30 days after the last dose; median duration of treatment across all groups was 121 days.
measure: Duration of Response
timeFrame: Participants were followed for disease progression for up to 2 years.
measure: Time to Progression (TTP)
timeFrame: Participants were followed for disease progression for up to 2 years.
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California- San Francisco
state: California
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Cornell University
state: New York
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: