Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00530816
• Other study ID #: PX-171-004
• Status: Completed
• Phase: Phase 2
• First received: September 14, 2007
• Last updated: April 28, 2017
• Start date: September 2007
• Est. completion date: July 2013

Study information

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

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 164
• Est. completion date: July 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• carfilzomib
Intravenous (IV) injection over 2 to 10 minutes twice weekly for three weeks followed by 12 days of rest.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best Overall Response Rate (ORR) in the Response Evaluable Subset Population	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.	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.
Secondary	Best Overall Response Rate (ORR) in the Response Evaluable Population	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.	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.
Secondary	Clinical Benefit Rate (CBR)	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.	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.
Secondary	Duration of Response (DOR)	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.	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.
Secondary	Time to Progression (TTP)	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.	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.
Secondary	Progression-free Survival (PFS)	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.	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.
Secondary	Overall Survival (OS)	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.	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.