Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

Phase 2

Completed

Conditions: Multiple Myeloma

Interventions: Drug: carfilzomib

Registration Number: NCT00530816

Lead Sponsor: Amgen

Brief Summary: To evaluate the best overall response rate, safety and tolerability of carfilzomib in patients with relapsed or refractory multiple myeloma.

Detailed Description: Two groups of patients with multiple myeloma were initially studied: bortezomib-naïve and bortezomib-treated. Following Amendment 2, only bortezomib-naïve patients were enrolled. Study results were reported in 2 parts, depending on whether a patient received prior bortezomib.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 164

Inclusion Criteria

Disease Related

Multiple myeloma
Subjects must have measurable disease, defined as one or more of the following:
- Serum M-protein ≥ 1 g/dL
- Urine M-protein ≥ 200 mg/24 hours
Subjects must have been responsive (i.e., achieve a minimal response [MR] or better) to standard, first line therapy
Relapsed and/or refractory or progressive disease after at least one, but no more than three, prior therapeutic treatments or regimens for multiple myeloma. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Induction therapy and stem cell transplant will be considered as one regimen

Demographic

Males and females ≥18 years of age
Life expectancy of more than three months
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Laboratory

Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal
Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing
Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count > 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count > 50,000/mm³
Subjects should be platelet transfusion independent
Screening absolute neutrophil count (ANC) should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
Subjects may receive red blood cell (RBC) transfusion or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
Calculated or measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female.
Serum creatinine ≤ 2 mg/dL

Ethical / Other

Written informed consent in accordance with federal, local, and institutional guidelines
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 3 months following the last dose if sexually active with a female of child-bearing potential.
Subjects must be able to receive outpatient treatment and laboratory monitoring at the institute that administers agent.

Exclusion Criteria

Disease Related

Multiple Myeloma Immunoglobulin M (IgM)
Subjects previously treated with any proteasome inhibitor (for Part 2 Proteasome Inhibitor - Naïve only, criteria added at Amendment 2)
Subjects must not be primary refractory to standard first-line therapy
Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum, < 200 mg/24 hour M-protein in urine
Subjects with disease measurable only by serum free light chain (SFLC) analysis
Glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last three weeks
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
Plasma cell leukemia
Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy, within the three weeks prior to first dose
Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose
Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater
Prior treatment with carfilzomib

Concurrent Conditions

Major surgery within three weeks before Day 1
Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months
Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
Known or suspected human immunodeficiency (HIV) infection or subjects who are HIV seropositive
Active hepatitis A, B, or C infection
Non-hematologic malignancy within the past three 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 6 with stable prostate-specific antigen (PSA)
Subjects with treatment related myelodysplastic syndrome
Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
Subjects with known contraindication to receiving allopurinol
Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
Subjects with known or suspected amyloidosis Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Ethical / Other

Female subjects who are pregnant or lactating
Serious psychiatric or medical conditions that could interfere with treatment

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Carfilzomib	carfilzomib	Participants received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles. Starting with Amendment 3, if all doses in Cycle 1 were well-tolerated the dose was escalated to 27 mg/m² IV for subsequent cycles.

Primary Outcome Measures

Name	Time	Method
Best Overall Response Rate (ORR) in the Response Evaluable Subset Population	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.	ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level \< 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to \< 200 mg per 24 hours.

Secondary Outcome Measures

Name	Time	Method
Time to Progression (TTP)	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.	Time to Progression is defined as the time from the start of treatment to IRC-determined disease progression. Patients who were lost to follow-up prior to documentation of disease progression, or who died before documentation of disease progression or who were alive and did not have documentation of disease progression before the data analysis cut-off date were censored at the last disease assessment. Median TTP was estimated using the Kaplan-Meier method.
Progression-free Survival (PFS)	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.	Progression-free Survival (PFS) is defined as the time from start of treatment to IRC determined disease progression or death due to any cause. Patients who were lost to follow-up prior to documentation of disease progression and patients who were alive without disease progression before a data analysis cut-off date were censored at the last disease assessment. Median PFS was estimated using the Kaplan-Meier method.
Overall Survival (OS)	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 19 November 2012 for Part 1 and 07 January 2013 for Part 2. Median follow-up time was 19.1 months for Part 1 and 35.9 months in Part 2.	Overall Survival is defined as the time from the start of study treatment to date of death due to any cause. Patients who were alive or lost to follow-up as of the data analysis cut-off date for the final OS analysis were censored at the date the patient was last known to be alive. Median OS was estimated using the Kaplan-Meier method.
Best Overall Response Rate (ORR) in the Response Evaluable Population	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, End of Study, 30 days after last dose; median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.	ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level \< 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to \< 200 mg per 24 hours.
Clinical Benefit Rate (CBR)	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.	Clinical Benefit Rate is defined as the percentage of participants with a best overall response of minimal response (MR) or better, i.e., a best overall response of sCR, CR, VGPR, PR, or MR. MR was defined as outlined by European Group for Blood and Marrow Transplantation (EBMT) criteria, defined as reduction of M-protein in serum of 25% to 49% and in urine of 50% to 89%, maintained for 6 weeks.
Duration of Response (DOR)	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2.	DOR is defined as the time from first evidence of PR or better to disease progression assessed by the IRC or death due to any cause. Patients lost to follow-up prior to disease progression or who were alive without disease progression before the analysis cutoff date were censored at the last disease assessment. Progressive disease was defined as any of the following: * An increase of M-protein in serum (absolute increase ≥ 0.5 g/dL) or urine (absolute increase ≥ 200 mg/24 hours) of \> 25% from the nadir (if not zero). * Percentage of plasma cells in bone marrow ≥ 10%. * New or increased size of bone lesions or new plasmacytomas. * Patients without measurable serum and urine M-protein: 25% increase from nadir in the difference between involved and uninvolved FLC levels and absolute increase \>10 mg/dL. * Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL) attributed solely to the proliferative disorder. Median DOR was estimated using Kaplan-Meier methods.

Trial Locations

Locations (30): Therapeutic Research Institute of Orange County
🇺🇸
Laguna Hills, California, United States
Emory University Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Gabrail Cancer Center
🇺🇸
Canton, Ohio, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Alberta Cross Cancer Institute
🇨🇦
Edmonton, Alberta, Canada
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
H. Lee Moffitt Cancer Center & Research Institute
🇺🇸
Tampa, Florida, United States
Jackson Oncology Associates
🇺🇸
Jackson, Mississippi, United States
Mayo Clinic Rochester
🇺🇸
Rochester, Minnesota, United States
Hattiesburg Clinic
🇺🇸
Hattiesburg, Mississippi, United States
St. Vincent's Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Texas Oncology Cancer Center
🇺🇸
Austin, Texas, United States
University of Calgary
🇨🇦
Calgary, Alberta, Canada
Royal Victoria Hospital
🇨🇦
Montreal, Quebec, Canada
Signal Point Clinical Research Center, LLC
🇺🇸
Middletown, Ohio, United States
Tower Cancer Research Foundation
🇺🇸
Beverly Hills, California, United States
Mayo Clinic Scottsdale
🇺🇸
Scottsdale, Arizona, United States
Rocky Mountain Blood and Marrow Transplant Program
🇺🇸
Denver, Colorado, United States
Oncology & Hematology Assoc. of W. Broward
🇺🇸
Tamarac, Florida, United States
Orchard Research
🇺🇸
Skokie, Illinois, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Montgomery Cancer Center
🇺🇸
Mount Sterling, Kentucky, United States
University of Kentucky College of Medicine
🇺🇸
Lexington, Kentucky, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Summa Health System
🇺🇸
Akron, Ohio, United States
University of Toronto Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
Dayton Clinical Oncology Program
🇺🇸
Dayton, Ohio, United States
Harrington Cancer Center
🇺🇸
Amarillo, Texas, United States