Phase I Study of Decitabine (Dacogen) and Bortezomib (Velcade) in Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Specific toxicities
研究概览
简要总结
This phase I trial is studying the side effects and best dose of bortezomib when given together with decitabine in treating patients with acute myeloid leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with decitabine may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of bortezomib (Velcade, PS-341) in combination with decitabine in patients with acute myeloid leukemia (AML) II. To define the specific toxicities and the dose limiting toxicity (DLT) of decitabine plus bortezomib combination
SECONDARY OBJECTIVES:
I. To determine the overall response rate (ORR). II. To determine the rate of complete remission (CR) of decitabine plus bortezomib in AML III. To correlate the biological activity of decitabine as demethylating agent (changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation) with clinical endpoints and plasma pharmacokinetics of decitabine.
IV. To characterize the biological activity of bortezomib as a potential demethylating agent V. To correlate intracellular concentration of decitabine-triphosphate with global DNA methylation and other biological endpoints as well as clinical response.
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
- •Diagnosis of acute myeloid leukemia (AML), meeting one of the following criteria:
- •Relapsed or refractory disease (≥ 18 years of age)
- •Previously untreated disease (≥ 60 years of age)
- •Secondary AML or therapy-related AML allowed
- •No granulocytic sarcoma as the sole site of disease
- •No active or relapsed CNS disease
- •No advanced malignant solid tumors
- •ECOG performance status 0-2
- •Life expectancy > 6 months (if patient has co-morbid illness)
- •Total bilirubin < 2.0 mg/dL
- •AST and ALT < 2.5 times upper limit of normal
- •Creatinine < 2.0 mg/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •Patients with HIV infection are eligible provided the following criteria are met:
- •No history of AIDS
- •Has a sufficiently high CD4 count (> 400/mm³)
- •Has low HIV viral loads (< 30,000 copies/mL plasma)
- •Does not require anti-HIV therapy
- •No uncontrolled active infection
- •No history of allergic reactions attributed to compounds of similar chemical or biological composition to decitabine or bortezomib that are not easily managed
- •No hypersensitivity to boron or mannitol
- •No concurrent uncontrolled illness including, but not limited to, any of the following:
- •Symptomatic congestive heart failure
- •Unstable or uncontrolled angina pectoris
- •Serious cardiac arrhythmia
- •Myocardial infarction within the past 6 months
- •New York Heart Association class III-IV heart failure
- •Severe uncontrolled ventricular arrhythmias
- •Acute ischemia or active conduction system abnormalities by ECG
- •No serious medical or psychiatric illness or social situation that would preclude participation in this study
- •No pre-existing neuropathy ≥ grade 2
- •No other serious neurologic toxicity that would significantly increase the risk of complications from bortezomib therapy
- •Recovered from prior therapy (toxicity < grade 2)
- •More than 14 days since prior investigational agents
- •More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy
- •Prior decitabine or azacitidine for myelodysplastic syndromes (MDS) or AML allowed
- •More than 6 months since prior decitabine, azacitidine, or bortezomib
- •No concurrent palliative radiotherapy
- •No other concurrent investigational agents
- •No other concurrent direct anti-leukemia therapy
排除标准
- 未提供
研究组 & 干预措施
Treatment (enzyme inhibitor therapy and chemotherapy)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10 and bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined, an additional 6 patients are treated at the recommended phase II dose.
干预措施: bortezomib (Drug)
Treatment (enzyme inhibitor therapy and chemotherapy)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10 and bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined, an additional 6 patients are treated at the recommended phase II dose.
干预措施: decitabine (Drug)
Treatment (enzyme inhibitor therapy and chemotherapy)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10 and bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined, an additional 6 patients are treated at the recommended phase II dose.
干预措施: pharmacological study (Other)
Treatment (enzyme inhibitor therapy and chemotherapy)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10 and bortezomib IV on days 5 and 8 or days 5, 8, 12, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose is determined, an additional 6 patients are treated at the recommended phase II dose.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Specific toxicities
时间窗: Up to 30 days post-treatment
Toxicity will be characterized using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
Maximum-tolerated dose (MTD) of bortezomib in combination with decitabine
时间窗: During course 1 (28 days)
If a patient meets the definition of dose-limiting toxicity (DLT), the patient may continue on with study therapy provided that the toxicity can be managed according to the dose modification guidelines. For DLT = 2, dose level will stop. This dose level will be declared the MTD administered dose (highest dose administered). As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
DLT of bortezomib in combination with decitabine
时间窗: During course 1 (28 days)
Toxicity will be characterized using the National Cancer Institute CTCAE version 3.0. As an exploratory, phase I study, no inferential statistical tests of hypotheses are planned. Data collected will be descriptive and provide limited estimates of variability given the small sample sizes at each dose level.
次要结局
- Overall response rate(Up to 30 days post-treatment)
- Rate of complete remission (CR)(Up to 30 days post-treatment)