Multicenter, Phase III Study Comparing Imatinib (STI571, Glivec®) Standard Dose (400 Mg/Day) With Imatinib High Dose Induction (800 Mg/Day) Followed by Standard Dose Maintenance (400 Mg/Day) in Pretreated CML Patients in Chronic Phase
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 240
- 试验地点
- 2
- 主要终点
- To determine the efficacy regarding major cytogenetic response within 12 months after randomization
研究概览
简要总结
This study will investigate the efficacy and tolerability of a short (6 months) high dose therapy followed by a standard dose compared to a continuous treatment with a standard dose of imatinib (Glivec®) in pretreated Philadelphia chromosome- positive (Ph+)/BCR-ABL+ CML patients in chronic phase.
详细描述
Patients with CML not achieving or losing a major cytogenetic response on whatever palliative treatment for CML, are at high risk to progress to accelerated phase and blast crisis. A new promising treatment with Imatinib (Glivec®), a tyrosine-kinase inhibitor, has been introduced recently. High rates of hematologic and cytogenetic responses can be achieved with Imatinib (Glivec®) at > = 300 mg/day in chronic phase CML patients that are refractory, resistant or intolerant to interferon-alpha. However, about 10 - 20% of these high risk patients will lose their response to Imatinib (Glivec®) within 1-2 years. Therefore, improvement of the treatment is warranted.
Since cytogenetic response rate is correlated to survival and the resistance to Imatinib (Glivec®) might be caused by mutations in the receptor, a more rapid decrease could lead to longer survival and/or less resistance development. In the initial 6 months of treatment, monotherapy with Imatinib (Glivec®) with a dose of 800 mg/day (high dose) should be more effective in the reduction of a high leukemic tumor burden, thereby allowing the residual normal progenitor and stem cells to expand. In addition, high dose Imatinib (Glivec®) should further improve the induction of a molecular response, as determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), reducing the risk of relapse from residual malignant BCR-ABL positive cells.
This study will investigate the efficacy and tolerability of a short (6 months) high dose therapy followed by a standard dose compared to a continuous treatment with a standard dose of Imatinib (Glivec®).
In addition, the dynamics of the molecular and cytogenetic response will be investigated. Finally, the study will investigate the effect of this induction-maintenance concept on time-to-progression (TTP).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Patients > 18 years of age
- •BCR-ABL positive CML patients in chronic phase, confirmed by karyotype (Ph+) or RT-PCR.
- •Patients pretreated with any drug that is known to control the disease of CML in chronic phase except imatinib (Glivec®).
- •Patients without a major cytogenetic response at study entry (> 35% Ph+ metaphases in bone marrow cytogenetic analysis performed < 3 months before study entry).
- •Patients either intolerant to interferon-alpha (non-hematologic toxicity grade 3-4 for more than 2 weeks) or having received pretreatment for CML at least 12 months before study entry.
- •World Health Organization (WHO) status 0-2
- •Adequate end organ function, defined as the following:
- •total bilirubin < 1.5 x upper limit of normal (ULN)
- •SGOT and SGPT < 2.5 x ULN
- •creatinine < 1.5 x ULN
- •absolute neutrophil count (ANC) > 1.5 x 10 ^ 9/L
- •platelets > 100 x 10 ^ 9/L
- •Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
- •Written voluntary informed consent.
排除标准
- •Patients eligible for allogeneic bone marrow transplantation.
- •Patients in accelerated phase or blast crisis.
- •Known tuberculosis or other uncontrolled infection.
- •Other primary tumor of a different histological origin than the study indication (unless the relapse-free interval is > 5 years, and with the exception of cervical carcinoma in situ [CIS], basal cell epithelioma, or squamous cell carcinoma of the skin).
- •Major surgery within the last 14 days.
- •Known to be HIV positive.
- •Unstable medical disorder (except for indication) that excludes the patient in the opinion of the investigator.
- •Patient has received any other investigational agents within 28 days of first day of study drug dosing.
- •Patients with a WHO performance status score > 3
- •Patients with Grade III/IV cardiac problems as defined by the New York Heart Association criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study).
- •Female patients who are pregnant or breast-feeding.
- •Refusal by female patients of childbearing age to use a safe contraceptive.
- •Patients with known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
- •Patients with any significant history of non-compliance to medical regimens or an inability to grant reliable informed consent.
结局指标
主要结局
To determine the efficacy regarding major cytogenetic response within 12 months after randomization
次要结局
- To determine the major cytogenetic response after 3 months versus 6-12 months after randomization
- To determine the dynamics of the molecular response within 3 and 6 months after randomization expressed as the slope decreases in BCR-ABL-transcripts
- To determine the efficacy of the molecular response within 12 and 24 months after randomization
- To determine the time to molecular progression within 24 months
- To determine tolerability