A Phase I And Pharmacological Trial Of 17-Allylamino -17-demethoxygeldanamycin (17-AAG) And Cytarabine In Refractory Leukemia And Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Tolerability of tanespimycin with cytarabine in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or high-grade myelodysplastic syndromes
研究概览
简要总结
This phase I trial is studying the side effects and best dose of tanespimycin when given with cytarabine in treating patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes. Drugs used in chemotherapy, such as tanespimycin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Tanespimycin may also help cytarabine kill more cancer cells by making cancer cells more sensitive to the drug. Giving tanespimycin together with cytarabine may kill more cancer cells.
详细描述
OBJECTIVES:
I. Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin) when administered with cytarabine in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or high-grade myelodysplastic syndromes.
II. Determine the toxic effects of this regimen in these patients. III. Determine, preliminarily, the activity of this regimen in these patients. IV. Correlate the pharmacokinetics of this regimen with cytochrome p450 3A5 genotype in these patients.
V. Determine the effect of this regimen on client proteins in vivo and ex vivo using leukemic blasts from patients treated with this regimen.
OUTLINE: This is a multicenter, dose-escalation study of tanespimycin.
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 1 of the following:
- •Acute myeloid leukemia, except acute promyelocytic leukemia (M3 disease), meeting 1 of the following criteria:
- •Failed to achieve complete remission (CR) after initial induction therapy regimen*
- •First relapse within 1 year of initial CR
- •Failed re-induction therapy at first or second relapse
- •Second or third relapse after completing ≤ 3 different induction therapy regimens
- •Antecedent hematologic disorder (myelodysplastic syndromes [MDS], chronic myeloproliferative disease, or chronic myelomonocytic leukemia [CMML])
- •Received prior chemotherapy for a non-hematologic malignancy
- •High-risk cytogenetic abnormalities (abnormalities of chromosome 5, 7, 8, or 11 OR ≥ 3 karyotypic abnormalities)
- •Acute lymphoblastic leukemia, meeting 1 of the following criteria:
- •Failed to achieve CR after initial induction therapy regimen
- •First relapse within 1 year of initial CR
- •Failed re-induction therapy at first or second relapse
- •Second or third relapse after completing ≤ 3 different induction therapy regimens
- •Chronic myelogenous leukemia, meeting the following criteria:
- •Accelerated OR blast phase (> 10% increase in the blast percentage in bone marrow)
- •Failed prior imatinib mesylate
- •No more than 1 prior chemotherapy regimen in addition to imatinib mesylate
- •CMML, meeting the following criteria:
- •More than 10% increase in blast percentage AND organ infiltration OR impending marrow failure as evidenced by cytopenia
- •No t(5;12) by cytogenetics (unless failed prior trial of imatinib mesylate)
- •High-grade MDS, defined as > 10% blasts on marrow cellularity (refractory anemia with excess blasts in transformation) OR International Prognostic Scoring System MDS prognostic score > 1.5
- •Not a candidate for allogenic bone marrow transplantation* from a related sibling donor (i.e., HLA-identical sibling)
- •No known standard or potentially curative therapy exists or is capable of extending life expectancy
- •No clinical symptoms suggesting CNS leukemia
- •Performance status - ECOG 0-2
- •At least 60 days
- •See Disease Characteristics
- •Bilirubin ≤ 1.5 times upper limit of normal (unless attributed to underlying disease)
- •Creatinine clearance ≥ 60 mL/min
- •No New York Heart Association class III-IV heart failure
- •No myocardial infarction within the past year
- •LVEF ≥ 40% by MUGA
- •No cardiac symptoms ≥ grade 2
- •No uncontrolled dysrhythmia requiring medication
- •No poorly controlled angina
- •QTc ≤ 450 msec for men and ≤ 470 msec for women
- •No congenital long QT syndrome
- •No left bundle branch block
- •No ischemic heart disease within the past 6 months
- •No history of cardiac toxicity after treatment with anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine
- •No other significant cardiac disease
- •No active uncontrolled infection
- •No history of serious allergic reaction to eggs
- •No known HIV infection or AIDS (with or without highly active antiretroviral treatment)
- •DLCO > 80%
- •No pulmonary symptoms ≥ grade 2
- •No symptomatic pulmonary disease requiring medication including any of the following:
- •Dyspnea on or off exertion
- •Paroxysmal nocturnal dyspnea
- 另有 23 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment (chemotherapy)
Patients receive induction therapy comprising cytarabine IV continuously on days 1-5 and tanespimycin IV over 1 hour on days 3 and 6.
Patients achieving a morphologic complete response with CRi or partial response may be eligible to receive a second induction course of therapy after day 21 at the discretion of the principal investigator. Patients achieving a CR receive up to 4 courses of consolidation therapy with cytarabine and tanespimycin. Consolidation therapy repeats approximately every 60 days in the absence of disease progression or unacceptable toxicity. Patients who achieve CR and remain in remission for ⥠6 months may be retreated with cytarabine and tanespimycin (at the current dose level or the MTD) at the time of relapse. Cohorts of 3-6 patients receive escalating doses of tanespimycin until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 3 months.
干预措施: tanespimycin (Drug)
Treatment (chemotherapy)
Patients receive induction therapy comprising cytarabine IV continuously on days 1-5 and tanespimycin IV over 1 hour on days 3 and 6.
Patients achieving a morphologic complete response with CRi or partial response may be eligible to receive a second induction course of therapy after day 21 at the discretion of the principal investigator. Patients achieving a CR receive up to 4 courses of consolidation therapy with cytarabine and tanespimycin. Consolidation therapy repeats approximately every 60 days in the absence of disease progression or unacceptable toxicity. Patients who achieve CR and remain in remission for ⥠6 months may be retreated with cytarabine and tanespimycin (at the current dose level or the MTD) at the time of relapse. Cohorts of 3-6 patients receive escalating doses of tanespimycin until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 3 months.
干预措施: cytarabine (Drug)
结局指标
主要结局
Tolerability of tanespimycin with cytarabine in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, or high-grade myelodysplastic syndromes
时间窗: Day 21
Evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 standard toxicity grading.
次要结局
- Clinical response(Every 2 weeks)
- Plasma level of tanespimycin(Day 3)
- Effects on client proteins(Days 1, 3, and 4 of course 1)