An Observational Study of Cardiovascular Complications of Carfilzomib Treatment in Clinical Practice
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Changes in endothelial function (Flow Mediated Dilatation in %) after drug administration
研究概览
简要总结
Accumulating evidence supports the hypothesis of a pathophysiological role of the Ubiquitin Proteasome System (UPS) in the process of atherosclerosis and vascular function. However the data are contradicting in respect to the direction of this association and therefore the net effect of UPS activity on the cardiovascular system is not known. Inhibitors of UPS are currently standard of care for patients with multiple myeloma (MM). Heart failure and hypertension have been reported in studies of carfilzomib, an irreversible 2nd generation proteasome inhibitor, both as a single agent and in combination with other drugs but their potential vascular toxicity is not adequately studied. Furthermore, as the role of the UPS has not been studied yet clinically but only in experimental and autopsy based studies, assessment of UPS inhibition in humans would facilitate understanding of the UPS-mediated pathophysiologic mechanisms in human atherosclerosis. Thus, this project may stimulate further research on the role of UPS in atherogenesis and potential new therapeutic approaches on vascular dysfunction may arise. We designed the following project in order to investigate the acute and chronic effect of Carfilzomib (CFZ) on cardiovascular function. Patients with an indication to receive CFZ will be recruited to be followed in the Clinical Therapeutics Department in pre-specified timepoints. Functional and structural measurements including markers of arterial stiffness and subclinical atherosclerosis will be performed using non-invasive well-validated techniques. Blood pressure will be also evaluated using 24h hour ambulatory monitoring. Evaluation of cardiac function will be performed at baseline and thereafter at 6 months or earlier if a suspicious event occurs necessitating evaluation of cardiac function. In parallel and at each time point, the activity of UPS and intracellular levels of ubiquitin conjugates will be measured in peripheral blood mononuclear cells (PBMCs) and red blood cells (RBCs) using enzymatic proteasome activity assays and western blot techniques, respectively.
详细描述
This is an observational, non interventional, prospective study. Patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy and who receive carfilzomib with dexamethasone according to the approved dose and schedule will be included in this observational study. No specific treatment intervention related to the study is going to be performed. No specific harms or benefits are expected due to study investigations.
Objectives and Purpose: The present study will assess patients with multiple myeloma receiving the proteasome inhibitor carfilzomib (CFZ), in order to investigate, in vivo, a wide spectrum of human atherosclerosis indices, from cardiovascular risk factors to subclinical atherosclerosis at multiple successive stages in a human model under conditions of global UPS inhibition, and correlate with cardiovascular complications associated with carfilzomib therapy, in patients receiving carfilzomib with dexamethasone.
Primary objective: To investigate cardiovascular complications and the role of the UPS inhibition on atheromatosis and vascular function and inflammation, in patients with relapsed or refractory myeloma who are receiving carfilzomib and dexamethasone.
Secondary objective(s): To outline the clinical significance of carfilzomib toxicity in hemodynamic parameters and vascular function and structure in humans
Duration of the study: Patients will receive therapy until disease progression or as per physician's decision regarding the patient's best interest and according to the approved indications. Study accrual and collection of data will be completed in two years. The study can be terminated for any reason and at any time by the Sponsor.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females at least 18 years of age
- •Voluntary written informed consent before performance of any study-related procedure
- •Documented relapsed or refractory multiple myeloma in need of therapy, after at least one previous line of therapy for myeloma
- •Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2
- •Willingness and ability to participate in study procedures
排除标准
- •Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1
- •Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for ≥4 days or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of dexamethasone for ≥4 days within the 2-week period prior to Cycle 1, Day 1
- •Previous allogeneic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 12 weeks before Cycle 1, Day 1
- •Clinical signs of meningeal involvement of multiple myeloma
- •Clinically significant cardiac disease, including:
- •Myocardial infarction within 6 months, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
- •Cardiac arrhythmia (CTCAE Grade 2 or higher) or clinically significant ECG abnormalities
- •ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec
- •Known active hepatitis B, or C.
- •Known HIV infection.
- •Prior or concurrent malignancy, except for the following:
- •Adequately treated basal cell or squamous cell skin cancer.
- •Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior to study entry.
- •Any of the following laboratory test results during Screening:
- •Absolute neutrophil count ≤1.0 × 109/L;
- •Hemoglobin level ≤7.5 g/dL (≤5 mmol/L);
- •Platelet count <75 × 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and <50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells;
- •Alanine aminotransferase level ≥2.5 times the upper limit of normal (ULN);
- •Pregnant or nursing women
结局指标
主要结局
Changes in endothelial function (Flow Mediated Dilatation in %) after drug administration
时间窗: baseline and 24 hours
FMD will be assessed with echo at specific timepoints and differences to baseline will be recorded
次要结局
- Changes in carotid intima-media thickness (IMT)(baseline and 24 weeks)
- Changes in systolic and diastolic strain and strain rate of LV(baseline and 6 months)
- Changes in LV Ejection fraction(baseline and 6 months)
研究者
Meletios A. Dimopoulos
Professor of Hematology, Department of Clinical Therapeutics National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
University of Athens