Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 2
- 主要终点
- Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide
研究概览
简要总结
This phase I trial is studying the side effects and best dose of vorinostat when given together with cytarabine and etoposide in treating patients with relapsed or refractory acute leukemia or myelodysplastic syndromes or myeloproliferative disorders. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with cytarabine and etoposide may kill more cancer cells.
详细描述
OBJECTIVES:
I. Determine the feasibility, tolerability, and toxicities, in terms of the maximum tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or transforming myelodysplastic syndromes or myeloproliferative disorders.
II. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves outcome, in terms of complete response rate, duration of response, and overall survival, in these patients.
III. Determine the effects of SAHA on induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal mucosa cells, using pre-SAHA and on SAHA treatment samples).
IV. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
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 or cytologically confirmed diagnosis of 1 of the following:
- •Relapsed or refractory acute myeloid leukemia (AML)
- •Patients with acute promyelocytic leukemia t(15;17) must have failed prior tretinoin and arsenic trioxide-containing regimen
- •Must be refractory to both agents with absence of durable hematologic response OR relapsed after a complete response duration of < 6 months
- •Relapsed or refractory acute lymphoblastic leukemia
- •Chronic myelogenous leukemia in accelerated or blastic phase
- •Must be refractory to treatment with imatinib mesylate or dasatinib
- •Disease progression despite continued treatment with imatinib mesylate or dasatinib
- •Patients in accelerated or blastic phase are eligible if unable to tolerate imatinib mesylate provided their disease has progressed on dasatinib or if unable to tolerate dasatinib
- •AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or myeloproliferative disorders (MPD)
- •Secondary or therapy-related AML
- •No active CNS leukemia
- •Leukostasis OR leukemic blast count > 50,000/mm³ allowed provided patient is treated with emergency leukapheresis or hydroxyurea to reduce leukemic blast count to < 30,000/mm³
- •ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- •Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •AST and ALT ≤ 2.5 times ULN
- •Creatinine ≤ 2.0 mg/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •No history of cytarabine-related neurotoxicity
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in the study
- •No other uncontrolled illness, including, but not limited to, any of the following:
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia
- •Psychiatric illness or social situation that would preclude compliance with study requirements
- •Infection allowed provided patient is receiving active treatment
- •No HIV positivity
- •See Disease Characteristics
- •Recovered from prior therapy
- •Persistent alopecia, fingernail discoloration, or hematologic abnormalities (primarily related to underlying disease) > 4 weeks after last course of chemotherapy or radiotherapy does not exclude patient
- •At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
- •No more than 3 prior courses of induction/reinduction chemotherapy, including induction and consolidation therapy or induction therapy after any bone marrow transplantation or similar procedure
- •Prior low-dose azacitidine, growth factors, cytokines, thalidomide, interferon, or imatinib mesylate for treatment of preceding MDS/MPD do not count as prior induction/reinduction therapy
- •At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas [e.g., carmustine] or mitomycin C) or radiotherapy
- •At least 24 hours since prior hydroxyurea
- •At least 2 weeks since prior imatinib mesylate, hematopoietic growth factors, and biological agents
- •At least 4 weeks since prior autologous stem cell transplantation
- •Prior allogeneic stem cell transplantation allowed if all of the following criteria are met:
- •At least 90 days since prior transplant
- •No evidence of graft-vs-host disease
- •At least 2 weeks since prior immunosuppressive therapy
- •No other concurrent anticancer agents or therapies
- •No other concurrent investigational agents
- •Concurrent hydroxyurea or leukapheresis allowed on days 1-10 of study treatment to control rising leukemic blasts (blasts > 30,000/mm³) or leukostasis
排除标准
- 未提供
研究组 & 干预措施
Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
干预措施: vorinostat (Drug)
Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
干预措施: cytarabine (Drug)
Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
干预措施: etoposide (Drug)
Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide
时间窗: Course 1
Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
次要结局
- Response rate(Baseline, day 4-7 of course 1, and after each course)
- Progression-free survival(At 30 days after completion of study treatment and continued follow up visits)
- Disease-specific survival(At 30 days after completion of study treatment and continued follow up visits)
- One-year survival(At 1 year)
- Overall survival(At 30 days after completion of study treatment and continued follow up visits)
- Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis(Baseline and days 4-7 of course 1)
- Alterations in cell cycle phase(Baseline and days 4-7 of course 1)
- Expression of MDR proteins at MTD of SAHA(Baseline and days 4-7 of course 1)