Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

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

Detailed Description
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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.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: carfilzomib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib<br>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. | Drug: carfilzomib<br>* Intravenous (IV) injection over 2 to 10 minutes twice weekly for three weeks followed by 12 days of rest.<br>* Other names: Kyprolis® (carfilzomib) for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. |