A Phase 1 Study of Obatoclax Mesylate (GX15-070MS) in Combination With Fludarabine-Based Chemoimmunotherapy in Previously Treated Patients With B-Cell Chronic Lymphocytic Leukemia (B-CLL)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of obatoclax mesylate
研究概览
简要总结
Obatoclax may stop the growth of chronic lymphocytic leukemia by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving obatoclax together with fludarabine and rituximab may kill more cancer cells. This phase I trial is studying the side effects and best dose of obatoclax when given together with fludarabine and rituximab in treating patients with B-cell chronic lymphocytic leukemia.
详细描述
PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose of obatoclax mesylate in combination with fludarabine phosphate-rituximab (FR) in patients with relapsed chronic lymphocytic leukemia.
SECONDARY OBJECTIVES:
I. To evaluate toxicity of obatoclax mesylate in combination with FR in this patient population.
II. To determine objective response rate and progression-free survival of obatoclax mesylate in combination with FR.
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
- •Histologically or cytologically confirmed diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) or prolymphocytic leukemia (PLL) arising from CLL
- •No de novo PLL
- •Malignant B cells must co-express CD5 with CD19 or CD20
- •Patients who lack CD23 expression on their leukemia cells may not have t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma
- •Must have documented lymphocytosis of > 5,000/uL
- •Must require therapy based on any of the following criteria:
- •Massive or progressive splenomegaly and/or lymphadenopathy
- •Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100,000/uL)
- •Presence of weight loss > 10% over the preceding 6-month period
- •NCI grade 2 or 3 fatigue
- •Fevers > 100.5 F or night sweats for > 2 weeks without evidence of infection
- •Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 6 months
- •Must have received at least one prior therapy for B-CLL
- •No known brain metastases
- •ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
- •Total bilirubin normal (unless due to Gilbert syndrome or compensated hemolysis)
- •Life expectancy > 3 months
- •Creatinine normal
- •Fertile patients must use effective contraception
- •Not pregnant or nursing
- •Negative pregnancy test
- •Any number of prior therapies allowed
- •At least 1 year since prior fludarabine phosphate-rituximab combination therapy
- •No concurrent combination antiretroviral therapy for HIV-positive patients
- •No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)
- •No other concurrent investigational agents
- •AST and ALT < 2.5 times upper limit of normal
- •Recovered from all prior therapy
排除标准
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to obatoclax mesylate or other agents used in study
- •Active Coombs' positive autoimmune hemolytic anemia
- •Chronic active hepatitis B patients if not on appropriate antiviral therapy (e.g., lamivudine, adefovir)
- •Other neurological disorders or dysfunction or a history of seizure disorder
- •Uncontrolled intercurrent illness including, but not limited to, any of the following:
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia including QTc > 450 msec
- •Psychiatric illness/social situations that would limit compliance with study requirements
研究组 & 干预措施
Treatment (obatoclax mesylate, fludarabine, rituximab)
Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.
干预措施: obatoclax mesylate (Drug)
Treatment (obatoclax mesylate, fludarabine, rituximab)
Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.
干预措施: fludarabine phosphate (Drug)
Treatment (obatoclax mesylate, fludarabine, rituximab)
Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.
干预措施: rituximab (Biological)
Treatment (obatoclax mesylate, fludarabine, rituximab)
Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Maximum tolerated dose of obatoclax mesylate
时间窗: 28 days
DLT will be defined as any non-hematologic toxicity of grade 3 or greater severity (excluding asymptomatic grade 3 laboratory abnormalities that are not life-threatening and respond to treatment; grade 3 fatigue; grade 3 nausea, vomiting or diarrhea occurring without optimal prophylaxis; or expected grade 3 rituximab infusion reactions). Any grade 4 non-hematological toxicity, as well as any irreversible grade 2 cardiac, renal or neurologic toxicities, will be considered dose-limiting. Grading of non-hematologic toxicities will be according to NCI CTC version 3.0.
次要结局
- Response evaluated using the Revised National Cancer Institute-sponsored Working Group Guidelines(Up to 2 years)