A Phase 1 Study of UCN-01 in Combination With Perifosine in Patients With Relapsed and Refractory Acute Leukemias and High Risk MDS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine
研究概览
简要总结
This phase I trial is studying the side effects and best dose of 7-hydroxystaurosporine when given together with perifosine in treating patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. 7-Hydroxystaurosporine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as perifosine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving 7-hydroxystaurosporine together with perifosine may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. Define the maximum tolerated dose and recommended phase II dose of UCN-01 (7-hydroxystaurosporine) administered after perifosine in patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or high risk myelodysplastic disorders.
SECONDARY OBJECTIVES:
I. Evaluate the safety and toxicity of UCN-01 administered after perifosine in these patients.
II. Evaluate the safety and toxicity of perifosine administered after UCN-01 in these patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Histologically or cytologically confirmed hematologic malignancy of 1 of the following types:
- •Relapsed or refractory acute myelogenous leukemia (AML)
- •Patients with acute promyelocytic leukemia t(15;17) are eligible provided they failed a prior tretinoin and arsenic-containing regimen
- •Patients should be either refractory to both agents (absence of durable hematologic response) OR relapsed after a complete response duration of < 6 months
- •Relapsed or refractory pre-B-cell or T-cell acute lymphoblastic leukemia (ALL)
- •Chronic myelogenous leukemia (CML) in accelerated or blastic phase that is refractory to imatinib mesylate
- •Must have evidence of disease progression despite continued treatment with imatinib mesylate
- •AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or myeloproliferative disorders (MPD)
- •Secondary or therapy-related AML
- •De novo AML or pre-B-cell or T-cell ALL in adults > 60 years of age with poor-risk features, such as complex (≥ 3) or adverse cytogenetics
- •The following are considered adverse cytogenetic abnormalities for AML:
- •inv3/t(3;3)
- •t(9;22) refractory to imatinib mesylate
- •The following are considered adverse cytogenetic abnormalities for ALL:
- •t(9;22) refractory to imatinib mesylate
- •Hypodiploidy
- •Myelodysplastic Syndromes (MDS) meeting 1 of the following criteria:
- •Intermediate and high risk (i.e., International Prognostic Scoring System [IPSS] ≥ 1.5) MDS that is refractory or has progressed after treatment with azacitidine and/or decitabine
- •Intermediate and high risk (i.e., IPSS ≥ 1.5) MDS with a 5q- cytogenetic abnormality that is refractory or has progressed after treatment with lenalidomide, azacitidine, or decitabine
- •Intermediate 2 and high risk MDS without 5q- cytogenetic abnormality that is refractory or has progressed after azacitidine or decitabine
- •Original 5q must also be refractory to lenalidomide
- •Received OR ineligible for established curative regimens, including stem cell transplantation
- •No active CNS leukemia
- •ECOG performance status (PS) 0-2 OR Karnofsky PS ≥ 60%
- •Total or direct bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •AST/ALT ≤ 2.5 times ULN
- •Creatinine ≤ 2 mg/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during and for 3 months after completion of study treatment
- •No hyperleukocytosis (i.e., WBC > 30,000/mm^3) (recent treatment with hydroxyurea to prevent impending leukostasis allowed provided there has been no dose increase for ≥ 1 week)
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to UCN-01 or perifosine
- •No intrinsic impaired organ function
- •No active, uncontrolled infection
- •Infection that is controlled with antibiotics allowed
- •No symptomatic cardiac disease
- •No active ischemia on EKG
- •LVEF ≥ 40% by echocardiogram or MUGA
- •Patients with a history of cardiac disease or mediastinal radiation should undergo testing of ventricular function
- •No poorly controlled diabetes mellitus
- •No psychiatric illness or social situation that would preclude giving informed consent or complying with study requirements
- •No HIV positivity
- •See Disease Characteristics
- •At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for carmustine or mitomycin C) and recovered
- •At least 4 weeks since prior radiotherapy and recovered
- •At least 4 weeks since prior autologous stem cell transplantation (SCT)
- •At least 90 days since prior allogeneic SCT
- •No evidence of graft vs host disease
- •At least 2 weeks since prior immunosuppressive therapy
- •No concurrent hematopoietic growth factors or biologic agents
- 另有 2 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I (enzyme inhibitor, chemotherapy)
Patients receive a loading dose of oral perifosine every 6 hours on day 1 followed by a maintenance dose once daily on days 2-28 of course 1 and then once daily on days 1-28 in all subsequent courses. Patients also receive 7-hydroxystaurosporine IV over 3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine until the MTD is determined.
干预措施: 7-hydroxystaurosporine (Drug)
Arm I (enzyme inhibitor, chemotherapy)
Patients receive a loading dose of oral perifosine every 6 hours on day 1 followed by a maintenance dose once daily on days 2-28 of course 1 and then once daily on days 1-28 in all subsequent courses. Patients also receive 7-hydroxystaurosporine IV over 3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine until the MTD is determined.
干预措施: perifosine (Drug)
Arm I (enzyme inhibitor, chemotherapy)
Patients receive a loading dose of oral perifosine every 6 hours on day 1 followed by a maintenance dose once daily on days 2-28 of course 1 and then once daily on days 1-28 in all subsequent courses. Patients also receive 7-hydroxystaurosporine IV over 3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine until the MTD is determined.
干预措施: pharmacological study (Other)
Arm 2 (enzyme inhibitor, chemotherapy)
Patients receive 7-hydroxystaurosporine IV over 3 hours on day 1 at the MTD determined in group I. Patients also receive oral perifosine as a loading dose every 6 hours on day 4 followed by a maintenance dose once daily on days 5-28 of course 1 and then once daily on days 1-28 in all subsequent courses.
干预措施: 7-hydroxystaurosporine (Drug)
Arm 2 (enzyme inhibitor, chemotherapy)
Patients receive 7-hydroxystaurosporine IV over 3 hours on day 1 at the MTD determined in group I. Patients also receive oral perifosine as a loading dose every 6 hours on day 4 followed by a maintenance dose once daily on days 5-28 of course 1 and then once daily on days 1-28 in all subsequent courses.
干预措施: perifosine (Drug)
Arm 2 (enzyme inhibitor, chemotherapy)
Patients receive 7-hydroxystaurosporine IV over 3 hours on day 1 at the MTD determined in group I. Patients also receive oral perifosine as a loading dose every 6 hours on day 4 followed by a maintenance dose once daily on days 5-28 of course 1 and then once daily on days 1-28 in all subsequent courses.
干预措施: pharmacological study (Other)
结局指标
主要结局
Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine
时间窗: Course 1 (first 28 days)
Evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The highest dose with none or one DLT observed in six patients will be declared as MTD. To ensure the toxicity at the MTD is acceptable, additional 6 patients will be accrued at the MTD.
次要结局
- Pharmacokinetics and pharmacodynamics of both perifosine and 7-hydroxystaurosporine(Baseline and at weeks 1, 5, and 9)
- Progression free survival(The time between the study entry and the first date that relapse or progressive disease is objectively documented, or death from any cause occurs)
- Disease specific survival and survival Rate(1 year)
- Response rate, determined by improvement of blast cell count, degree of marrow infiltration by tumor cells, and improvement in peripheral blood count(Baseline, at the end of course 1 (day 21-28), and any time that disease progression is suspected)
- Overall survival(From time of enrollment onto this study to the time of death)