A Phase 1 Study of 17-allylamino-17-demethoxygeldanamycin (17-AAG) (NSC 330507; IND 57,966) and Rituximab in Patients With Relapsed B-cell Chronic Lymphocytic Leukemia (CLL)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)
研究概览
简要总结
This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin when given with or without rituximab in treating patients with relapsed B-cell chronic lymphocytic leukemia or prolymphocytic leukemia. Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin, 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 find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Monoclonal antibodies may kill cancer cells that are left after chemotherapy. Giving 17-N-allylamino-17-demethoxygeldanamycin with or without rituximab may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of twice weekly 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination with weekly rituximab in patients with relapsed chronic lymphocytic leukemia (CLL).
II. To examine the pharmacology of twice weekly 17-AAG in combination with weekly rituximab in patients with relapsed CLL.
SECONDARY OBJECTIVES:
I. To evaluate toxicity (using NCI CTCAE v3.0 criteria) and preliminary efficacy of twice weekly 17-AAG when used in combination with weekly rituximab in this patient population.
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 confirmed B-cell chronic lymphocytic leukemia or prolymphocytic leukemia requiring treatment, defined by 1 of the following criteria:
- •Massive or progressive splenomegaly and/or lymphadenopathy
- •Anemia (hemoglobin < 11 g/dL) OR thrombocytopenia (platelet count < 100,000/mm^3)
- •Weight loss > 10% within the past 6 months
- •Grade 2 or 3 fatigue
- •Fevers > 100.5°F or night sweats for > 2 weeks with no evidence of infection
- •Progressive lymphocytosis with an increase of > 50% over a 2 month period OR an anticipated doubling time of < 6 months
- •Relapsed disease
- •Failed prior fludarabine or pentostatin therapy OR cannot receive fludarabine
- •Lymphocyte count ≥ 5,000/mm^3
- •Performance status - ECOG 0-2
- •Performance status - Karnofsky 60-100%
- •More than 12 weeks
- •Bilirubin < 1.5 times upper limit of normal (ULN)
- •AST and ALT ≤ 2.5 times ULN
- •Creatinine ≤ 2.0 mg/dL
- •LVEF > 40% by MUGA
- •QTc < 450 msec for male patients and < 470 msec for female patients
- •Resting ejection fraction ≥ 50% by MUGA or echocardiogram
- •No symptomatic congestive heart failure
- •No unstable angina pectoris
- •No cardiac arrhythmia
- •No significant cardiac disease including any of the following:
- •New York Heart Association class III or IV heart failure
- •History of myocardial infarction within the past year
- •History of uncontrolled dysrhythmias
- •Active ischemic heart disease within the past year
- •Poorly controlled angina
- •No history of serious ventricular arrhythmia (e.g., ventricular fibrillation, history of symptomatic or sustained ventricular tachycardia, nonsustained ventricular tachycardia > 3 beats within the past 6 months)
- •No history of cardiac toxicity due to anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, or mitoxantrone hydrochloride)
- •No other cardiac symptoms ≥ grade 2
- •DLCO (i.e., oxygen diffusion capacity) ≥ 80% by pulmonary function testing
- •Resting and exercise oxygen saturation ≥ 90% by pulse oximetry
- •No pulmonary symptoms ≥ grade 2
- •No history of pulmonary toxicity due to bleomycin or carmustine
- •No significant, symptomatic pulmonary disease requiring oxygen or medications
- •No ongoing pulmonary symptoms ≥ grade 2 including any of the following:
- •Dyspnea on or off exertion
- •Paroxysmal nocturnal dyspnea
- •Significant pulmonary disease (e.g., chronic obstructive or restrictive pulmonary disease)
- •No Medicare requirements for home oxygen (e.g., resting O_2 saturations ≥ 90% or desaturation to ≥ 90% with exertion)
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •HIV negative
- •No history of allergic reaction attributed to compounds of similar chemical or biologic composition to 17-N-allylamino-17-demethoxygeldanamycin
- •No history of serious allergic reaction to eggs
- •No ongoing or active infection
- •No psychiatric illness or social situation that would preclude study compliance
- •No other uncontrolled illness that would preclude study participation
- 另有 9 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment (17-AGG and rituximab)
Patients receive 17-AAG IV over 2 hours on days 1, 4, 8, 11, 15 and 18 (course 1). Patients achieving ≥ 25% reduction in measurable disease after course 1 receive an additional course of single-agent 17-AAG approximately 10 days later in the absence of disease progression or unacceptable toxicity and provided absolute lymphocyte count continues to decrease. Patients failing to achieve a 25% reduction in measurable disease after course 1 OR with disease progression after courses 1 or 2 of single-agent 17-AAG proceed to combination therapy comprising 17-AAG IV over 2 hours on days 1, 4, 8, 11, 15, 18, and 22; and rituximab IV over 4 hours on days 1 and 2 and over 1 hour on days 4, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.
干预措施: tanespimycin (Drug)
Treatment (17-AGG and rituximab)
Patients receive 17-AAG IV over 2 hours on days 1, 4, 8, 11, 15 and 18 (course 1). Patients achieving ≥ 25% reduction in measurable disease after course 1 receive an additional course of single-agent 17-AAG approximately 10 days later in the absence of disease progression or unacceptable toxicity and provided absolute lymphocyte count continues to decrease. Patients failing to achieve a 25% reduction in measurable disease after course 1 OR with disease progression after courses 1 or 2 of single-agent 17-AAG proceed to combination therapy comprising 17-AAG IV over 2 hours on days 1, 4, 8, 11, 15, 18, and 22; and rituximab IV over 4 hours on days 1 and 2 and over 1 hour on days 4, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.
干预措施: rituximab (Biological)
结局指标
主要结局
Maximum tolerated dose (MTD) of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)
时间窗: Week 4
Defined at the dose level of 17-AAG at which 2 (or more) of 6 patients develop dose-limiting toxicity (DLT).
次要结局
- Minimally effective pharmacological dose (MEPD) of 17-AAG based on down-modulation of the target protein Akt(Day 1)