Dasatinib Combination for Chronic Lymphocytic Leukemia Patients With Chemo Refractory Disease
试验速览
- 阶段
- 2 期
- 入组人数
- 35
- 试验地点
- 4
- 主要终点
- response rate and response quality
研究概览
简要总结
Patients with chemo refractory CLL have a poor prognosis. 2 independent mechanisms are attributed to the development of chemoresistance in CLL. The first is a shift in the balance between pro- and anti-apoptotic regulators. The second mechanism is based on acquired mutations resulting in a dysfunctional p53 response. Recent studies indicate that the tyrosine kinase inhibitor dasatinib acts synergistically with both purine analogies and alkylating agents. Also, dasatinib has the potency to restore the apoptotic balance of CLL cells.
Hypothesis: Dasatinib will be clinically active in chemo-refractory CLL patients and will act synergistically with the purine-analogue fludarabine.
详细描述
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. The disease mostly affects the elderly. At present no curative therapy is available. Although the majority of patients initially do respond to chemotherapy, most patients eventually develop drug resistance. The prognosis for patients with chemotherapy resistant disease is very poor wit an overall survival of approximately 10 months. Standard therapy for these patients currently does not exist. Treatment with the monoclonal antibody alemtuzumab could be tried, however toxicity of this drug is high especially following multiple cycles of chemotherapy. Allogeneic stem cell transplantation is still considered experimental in this setting and is only available for a minority of patients.
The development of chemoresistant disease is highly correlated with a disturbed balance of apoptosis regulating molecules, resulting in a decrease in sensitivity to apoptotic stimuli. The tyrosine kinase inhibitor dasatinib (Sprycel®) is successfully being used in the treatment of chronic myeloid leukemia (CML). This form of chronic leukemia is also characterized by a disturbed balance between apoptosis regulating genes, which can be restored by tyrosine kinase inhibitors. Recent studies indicate that also in CLL, dasatinib has the potential to restore the apoptotic balance. In this clinical study we will investigate whether dasatinib is an effective drug in the treatment of chemoresistant CLL and whether treatment with dasatinib restores the sensitivity to chemotherapeutic agents.
Objective of the study:
Primary:
To determine the response rate and response quality of dasatinib monotherapy or dasatinib/fludarabine combination in fludarabine refractory CLL patients
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •CLL confirmed according to the IWCLL Working Group criteria;
- •Binet stages A or B with indication for treatment according to IWCLL guidelines, Binet C AND
- •Fludarabine refractory, defined as relapse (any sign of disease recurrence or progression with or without indication for treatment ≤ 6 months following fludarabine containing chemo(immuno)therapy;
- •Age 18-80 years inclusive;
- •WHO performance status ≤ 2;
- •No possibility for rapid reduced intensity allogeneic hematopoietic stem cell transplantation;
- •At least 4 weeks without any treatment before study entry;
- •Negative pregnancy test;
- •Written informed consent;
排除标准
- •Richter's transformation;
- •Suspected or documented CNS involvement by CLL;
- •Grade 3 cytopenia not due to bone marrow infiltration
- •Concurrent medical condition which may increase the risk of toxicity, including:
- •Pleural or pericardial effusion of any grade
- •Cardiac Symptoms, including:
- •Uncontrolled angina, congestive heart failure or MI within (6 months)
- •Diagnosed congenital long QT syndrome
- •Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
- •prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
- •Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration;
- •Severe pulmonary dysfunction (CTCAE grade III-IV);
- •Active hepatitis B infection;
- •History of significant bleeding disorder unrelated to the CLL, including:
- •Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
- •Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
- •Ongoing or recent (within 3 months) significant gastrointestinal bleeding
- •Known HIV positivity
- •Clinically significant auto-immune hemolytic anemia (AIHA)
- •Severe neurological or psychiatric disease;
- •Significant hepatic dysfunction (Total bilirubin < 2.0 times ULN; Hepatic enzymes (AST, ALT ) ≤ 2.5 times ULN) except when caused by leukemic infiltration;
- •Significant renal dysfunction (serum creatinine more than 150 uM/L after rehydration);
- •History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- •Concurrent use of CYP3A4 inducers or inhibitors, or QTc-prolonging agents*;
- •Active, uncontrolled infections;
- •Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
- •Female patients of reproductive potential who are not using effective contraception;
- •The following medications should be considered for exclusion:
- •Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib) quinidine, procainamide, disopyramide amiodarone, sotalol, ibutilide, dofetilide erythromycin, clarithromycin chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, zyprasidone, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
- •The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of dasatinib. Patient may not be receiving any prohibited CYP3A4
研究组 & 干预措施
Dasatinib
Patients will be treated with dasatinib monotherapy 100mg daily. At four weeks patients will be re-evaluated. Patients with less than a partial response will receive fludarabine (orally 40mg/daily for 3 days q28) in addition to dasatinib.
干预措施: Dasatinib (Drug)
结局指标
主要结局
response rate and response quality
时间窗: At 32 weeks of either dasatinib monotherapy or after 6 cycles of fludarabine and dasatinib combination
次要结局
- overall safety profile of these treatment approaches, event free survival, progression free survival, relapse or death, disease free survival(3 years)
研究者
A.P. Kater
A.P. Kater, MD, PhD
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)