A Prospective, Multi-center Phase II Study of Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Stem-cell Transplantation, in Chronic Lymphocytic Leukemia Which is Associated With 17p Deletion or is Refractory to Fludarabine
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 135
- 试验地点
- 38
- 主要终点
- Response rate
研究概览
简要总结
Aims and objectives
- Assessment of the efficacy of the study treatment in the study population in terms of response rate, progression-free survival, failure-free survival and overall survival.
- Acquisition of further data to expand the data base on the toxicity of the study treatment.
- Assessment of the efficacy of the study treatment in biological risk groups.
- Assessment of response in terms of minimal residual disease. Number of patients and estimated duration Total no. of patients: 122 (~29 with 17p deletion for first-line therapy, ~29 with 17p deletion for second- or higher-line treatment, ~65 fludarabine-refractory irrespective of 17p status).
Duration for each patient: Max. 12 weeks of treatment in three 4-week cycles, then up to two years maintenance treatment.
详细描述
CLL refractory to therapy based on fludarabine or with 17p deletion has a poor prognosis. Patients with F-refractory CLL have a remission rate of 20% after various salvage regimens and a median overall survival (OS) of <12 months (Keating et al., 2002a). CLL patients with 17p deletion have a median OS of 16 months after first-line treatment with fludarabine or FC in the CLL4 trial of the GCLLSG (Figure 2; Stilgenbauer et al., 2005b; Eichhorst et al., 2006).
Alemtuzumab is the most active single agent in fludarabine-refractory CLL, with remission rates of 30-40% and median OS of 16-28 months (Keating et al., 2002b, Rai et al., 2002). Furthermore, alemtuzumab is of proven efficacy in CLL with 17p deletion and the subcutaneous administration is as effective as the intravenous application (Stilgenbauer & Döhner, 2002, Lozanski et al., 2004, Stilgenbauer et al., 2004).
However, the outcome of fludarabine-refractory CLL is still poor, owing to the facts that the majority of patients do not achieve a remission and that the average duration of remission is short. Therefore, the current trial aims at achieving: (i) a higher remission rate, by adding high-dose dexamethasone to alemtuzumab, and (ii) prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (SCT). High-dose steroids have shown activity independently of 17p and p53 status, and are effective in debulking large lymph nodes, a weakness of alemtuzumab (Bellosillo et al., 2002, Thornton et al., 2003, Pettitt et al., 2006). Maintenance treatment with alemtuzumab improved remission duration in the CLL4B trial and allogeneic SCT resulted in disease control in high-risk CLL in the CLL3X trial (Wendtner et al., 2004, Dreger et al., 2005).
This is a prospective, open, multi-center Phase II study conducted by the Deutsche CLL Studiengruppe (DCLLSG; German CLL Study Group, GCLLSG). There will be only one treatment group and thus no randomization. The study will be conducted at approximately 40 investigation sites in Germany, Austria and France.
The study will be conducted according to the EG Directive on Good Clinical Practice, the German Arzneimittelgesetz (AMG, 12. Novelle) as well as - with respect to the local activities and regulations - to the corresponding laws in France and Austria.
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
- •The patient has CLL requiring treatment (Binet C or A/B with "active disease" according to the NCI criteria).
- •One or both of the following is true:
- •The patient's disease is refractory to a previous fludarabine-containing regimen, defined as no CR or PR according to NCI criteria, or progression within 6 months after a fludarabine-containing regime. (N.B.: Within the framework of this trial, the term "fludarabine-refractory" is synonymous to a refractory status to any established purine analogue (i.e. pentostatin, cladribine); this also encompasses bendamustine, as this drug molecule contains both an alkylating and a purine analogue moiety. Acc. to experimental findings and clinical experience, its mechanism of action differs distinctly from that of a pure alkylator (Cheson et al., 2009, Leoni et al., 2008)).
- •17p deletion is present (irrespective of whether previously treated or untreated).
- •The patient is at least 18 years of age.
- •The patient's performance status is 0, 1 or 2 on the WHO/ECOG scale.
- •Any previous chemotherapy and/or immunotherapy ended at least four weeks before the first study treatment with alemtuzumab.
- •The patient has recovered from all previous chemotherapy and/or immunotherapy.
- •For fertile men and for women of childbearing potential: Adequate contraception (oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
- •The patient has given written informed consent to participate in the study.
排除标准
- •The patient has received more than five different prior therapeutic regimens.
- •Any major organ dysfunction is present (e.g. unstable angina pectoris, NYHA III/IV heart insufficiency, significant coronary stenoses, uncontrolled diabetes mellitus, uncontrolled hypertension, pulmonary disease with hypoxemia, renal failure).
- •Any of the following laboratory values are found at the screening visit to be >2 × the upper limit of the normal range: serum creatinine, serum bilirubin, ASAT, ALAT.
- •Any active infection is present.
- •B-PLL or Richter transformation is diagnosed or suspected (e.g. symptoms or cytology).
- •There is involvement of the central nervous system.
- •The patient is known to be positive for human immunodeficiency virus (HIV).
- •CMV viremia is present, as demonstrated by pp65 EA or CMV-DNA.
- •The patient has previously been treated with alemtuzumab. (Exception: alemtuzumab used in a "non-therapeutic" context, i.e. administered as part of a conditioning regimen prior to SCT).
- •The patient has received autologous or allogeneic SCT within the past six months.
- •The patient is receiving long-term systemic treatment with corticosteroids or has received such treatment in the four weeks before first treatment with alemtuzumab.
- •Any additional active malignancy is present.
- •The patient has ever had an anaphylactic response to humanized antibodies.
- •For female patients: The patient is pregnant or lactating.
- •The patient has a history of drug or alcohol abuse that might lead to inability to comply with the protocol.
研究组 & 干预措施
Alemtuzumab
30 mg alemtuzumab will be administered subcutaneously 3 times weekly for 4 weeks (total of 12 doses of 30 mg alemtuzumab) with premedication (as needed) and infection prophylaxis; combined with oral dexamethasone 40 mg total dose for 4 days every 2 weeks; evaluation at end of cycle (i.e. after 12 doses of 30 mg alemtuzumab).
If CR is documented after week 4 (12 doses of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted at this time point.
After a maximum of three 4-week cycles (total of 36 doses of 30 mg alemtuzumab, in case of interruptions this may take longer than 12 weeks), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted. Maintenance treatment with alemtuzumab will continue for a maximum of two years, with evaluation every three months, unless there is PD.
干预措施: Alemtuzumab (Drug)
结局指标
主要结局
Response rate
时间窗: 2.5 years
Time points for response evaluation according to NCI criteria will be: * The end of each treatment cycle: after 12 doses (4 weeks actual treatment), 24 doses (8 weeks actual treatment), and 36 doses (12 weeks actual treatment) of alemtuzumab * During maintenance therapy, every three months * During follow-up, every three months * A final response assessment will be made at the end of study treatment if the patient's participation is ended at a point other than one of those specified above.
次要结局
- Progression-free-survival(up to five years)
- Overall survival(up to five years)
- Failure-free survival(up to five years)
- Number of participants with Adverse Events as a measure of safety and tolerability(up to 2.5 years)
研究者
Stephan Stilgenbauer
Prof. Dr. med.
University of Ulm