CARFILZOMIB IN COMBINATION WITH BENDAMUSTINE AND DEXAMETHASONE IN REFRACTORY OR RELAPSED MULTIPLE MYELOMA - A MULTICENTER PHASE IB/II TRIAL OF THE EUROPEAN MYELOMA NETWORK TRIALIST GROUP (EMNTG)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 3
- 主要终点
- Identification of dose-limiting toxicity (DLT)
研究概览
简要总结
Open-label phase Ib/II, multicenter, international non-comparative trial. This study is designed to determine the safety and efficacy of the novel salvage regimen (CBd) followed by a carfilzomib maintenance in patients with relapsed or refractory multiple myeloma.
Patients will be evaluated at scheduled visits in up to 4 study periods:
pretreatment, treatment, maintenance and long-term follow-up (LTFU).
详细描述
Multiple myeloma (MM) is one of the most common hematological diseases and besides the option of an allogeneic stem cell transplantation remains incurable.
Although autologous stem cell transplantation and new compounds such as bortezomib, thalidomide and lenalidomide have been implemented, treatment alternatives in patients who relapse or are refractory to these therapies are urgently needed. In addition, patients are often compromised by the toxicity of prior treatments not allowing further use of active drugs such as due to neurotoxicity when bortezomib was given. However, in contrast to bortezomib the investigative drug carfilzomib blocks, the proteasome irreversibly and shows minimal activity against off-target enzymes leading to more sustained proteasome inhibition with a distinctive toxicity profile [1-3]. Carfilzomib had promising single agent activity in a phase II trial with heavily pre-treated MM patients (overall response rate 24% [4]). Another drug with substantial activity in lymphoid malignancies is bendamustine, which was recently been found to be superior to chlorambucil in chronic lymphocytic leukemia (CLL) [5] as well as in Non-Hodgkin's lymphomas (NHL)[6]. In multiple myeloma, bendamustine combined with prednisone (BP) was superior to melphalan and prednisone (MP) as far as complete remission rate, time to treatment failure and life quality [7].
Therefore, bendamustine, an alkylating agent, was recently licensed in Europe for NHL, CLL and MM. The addition of bendamustine was able to overcome bortezomib resistance in an institutional treatment algorithm [8] in line with the observation that bortezomib enhanced the clinical activity of the alkylator melphalan in conventional doses as well as in the high dose setting [9-10]. Thus, there appears to be a rationale to combine both drugs in order to obtain clinical synergistic activity in relapsed and refractory MM patients.
STUDY OBJECTIVES
Primary objective:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient ≥ 18 years old.
- •Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
- •Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
- •Female patient is either post-menopausal or surgically sterilized or commits continued abstinence from heterosexual intercourse during the duration of the study or is willing to use two methods of birth control, one highly effective method and one additional effective method at the same time, at least 4 weeks before starting carfilzomib and bendamustine therapy, during carfilzomib and bendamustine therapy and for at least 4 weeks after stopping carfilzomib and bendamustine therapy. Highly effective methods are hormonal contraceptives (birth control pills, injections, and implants), intrauterine device, tubal ligation and partner's vasectomy. Additional effective methods are condom, diaphragm, and cervical cap. Women with child bearing potential must have two negative pregnancy tests (sensitivity at least 50 mIU/mL) prior starting carfilzomib and bendamustine therapy. The first pregnancy test must be performed 10 - 14 days and the second within 24 hours before starting carfilzomib and bendamustine therapy. Pregnancy testing for the first 4 weeks of study therapy must be performed weekly and thereafter every 4 weeks if menstrual cycles are regular or every 2 weeks if menstrual cycles are irregular.
- •Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) for the duration of the study and for 6 months after stopping study therapy.
- •Patient with relapsed or/and refractory multiple myeloma after failure of two or more treatment regimens (previous bortezomib is allowed).
- •Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein (M-protein) value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of >200 mg/24 hours. For patients with oligo- or non-secretory MM, it is required that they have measurable plasmacytoma > 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of patients admitted to this study will be oligo- or non-secretory MM with free light chains only in order to maximize interpretation of benefit results.
- •Patient has a Karnofsky performance status ≥60%.
- •Patient has a life expectancy >6 months.
- •Patient has the following laboratory values within 14 days before Baseline (day 1 of the Cycle 1, before study drug administration):
- •Platelet count ≥70 x 109/L (≥50 x 109 /L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to drug administration).
- •Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors.
- •Corrected serum calcium ≤14 mg/dL (3.5 mmol/L).
- •Alanine transaminase (ALT): ≤ 3 x the ULN.
- •Total bilirubin: ≤ 2 x the ULN.
- •Calculated or measured creatinine clearance ≥ 15 mL/min (or, as alternative serum creatinine <2 mg/dL).
- •LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available (not applicable in Germany).
排除标准
- •Pregnant or lactating females
- •Patient has active infectious hepatitis type B or C or HIV.
- •Patients with active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention.
- •Peripheral neuropathy (PN) > CTCAE grade 2 and ≥ grade 2 painful PN (with the difference being in the exclusion of patients with Grade 2 painful PN).
- •Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
- •Known history of intolerability to high dose dexamethasone
- •Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and anti-platelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
- •Subject with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to baseline;
- •Patient has any other clinically significant illness that would, in the investigator's opinion, increase the patient's risk for toxicity.
- •Patient with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma of the skin, or in situ cancer of the cervix or breast, or localized prostate cancer of Gleason score <7 with a stable PSA).
研究组 & 干预措施
CBD
干预措施: Carfilzomib (Drug)
结局指标
主要结局
Identification of dose-limiting toxicity (DLT)
时间窗: 1 year
DLTs are defined as the following: * Any CTCAE grade ≥3 non-hematologic event except the following: 1. Nausea or vomiting that responds symptomatic therapy. * Grade 4 neutropenia lasting more than 7 days. * Grade 4 hematologic toxicity except neutropenia * Development of febrile neutropenia defined as grade 3-4 neutropenia with fever 38.5°C and/or infection requiring antibiotic or antifungal treatment. Assessment of DLT defining adverse events will be performed after completion of the second cycle (only in phase Ib) according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0). Efficacy will be assessed by considering VGPR following the proposed regimen, according to the criteria of the International Myeloma Working Group
次要结局
- Determine the rate of very good partial response (VGPR) or more with the CBd association:(1 year)