A Phase 1 Study of Vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in Combination With Decitabine in Patients With Advanced Solid Tumors, Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia in Blast Crisis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 4
- 主要终点
- Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
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 decitabine in treating patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.
Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 decitabine may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. Establish the maximum tolerated dose and recommended phase II dose of vorinostat in conjunction with decitabine in patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis.
SECONDARY OBJECTIVES:
I. Identify the minimal effective dose of vorinostat in conjunction with decitabine that will lead to DNA demethylation, histone acetylation, and gene reactivation with tolerable toxicity in these patients.
II. Determine the pharmacokinetic profiles of vorinostat and decitabine in these patients. Correlate pharmacokinetic profiles of vorinostat and decitabine with toxicity and biological activity in these patients.
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:
- •Confirmed relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia in blast crisis (CML-BC)
- •Patients with acute promyelocytic leukemia who have relapsed while on tretinoin allowed
- •Patients with previously untreated AML who refuse induction chemotherapy allowed
- •Patients who are not candidates for aggressive management (those that have medical conditions that prevent the administration of standard curative chemotherapy or those who require an allogeneic bone marrow transplantation for curative therapy but lack an appropriate donor) are allowed
- •Histologically or cytologically confirmed relapsed or refractory non-Hodgkin's lymphoma (NHL)
- •Histologically confirmed solid tumor that is metastatic or unresectable or for which standard curative or palliative measures do not exist or are no longer effective
- •Clinically or radiologically documented disease
- •Patients whose only evidence of disease is tumor marker elevation are not eligible
- •Patients with AML, ALL, or CML-BC who have cerebral spinal fluid involvement may be included
- •May be treated with intrathecal cytarabine and/or methotrexate prior to and/or during the study
- •No known brain metastases in patients with solid tumors or NHL
- •ECOG performance status 0-2
- •Karnofsky 60-100%
- •Life expectancy > 12 weeks for patients with solid tumors (including non-Hodgkin's lymphoma) and 6 weeks for patients with hematological malignancies
- •Patients with solid tumors (including NHL) must also have normal marrow function as defined below:
- •Leukocytes ≥ 3,000/mm^3
- •Absolute neutrophil count ≥ 1,500/mm^3
- •Platelets ≥ 100,000/mm^3
- •Creatinine ≤ 150 μmol/L
- •Creatinine clearance ≥ 60 mL/min
- •Bilirubin normal
- •AST/ALT ≤ 2.5 times upper limit of normal (ULN)
- •Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control or abstinence) prior to study entry and for the duration of study participation
- •Not pregnant or nursing
- •Negative pregnancy test
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
- •Able to take oral medications
- •Patients who have a clinical or radiological diagnosis of bowel obstruction are ineligible
- •No ongoing or active infection
- •No symptomatic congestive heart failure
- •No unstable angina pectoris
- •No cardiac arrhythmia
- •No psychiatric illness/social situations that would limit compliance with study requirements
- •No other uncontrolled intercurrent illness
- •No limitation on the number or types of prior therapy
- •At least 3 weeks since prior radiotherapy, chemotherapy (6 weeks for nitrosoureas or mitomycin C), or molecularly targeted agents
- •Exceptions may be made for low-dose, non-myelosuppressive radiotherapy
- •At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
- •Must have recovered from prior therapy
- •Patients with hematological malignancies may receive hydroxyurea until 24 hours prior to starting study medications
- •Previous surgery is permitted provided that wound healing has occurred
- •No prior decitabine
- •No other concurrent investigational agents
- •No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
- •No HIV-positive patients receiving combination antiretroviral therapy
- •No concurrent prophylactic hematopoietic growth factors (e.g. filgrastim [G-CSF], sargramostim [GM-CSF], thrombopoietin, or epoetin alfa)
- •Hematopoietic growth factors colony stimulating factors for the treatment of cytopenia may be permitted at the discretion of the principal investigator
排除标准
- 未提供
研究组 & 干预措施
Treatment (enzyme inhibitor, chemotherapy)
Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5.
干预措施: vorinostat (Drug)
Treatment (enzyme inhibitor, chemotherapy)
Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5.
干预措施: decitabine (Drug)
结局指标
主要结局
Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
时间窗: Course 1
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
次要结局
- Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia)(Baseline and between days 3-10)
- Pharmacokinetics of vorinostat in conjunction with decitabine(Days 1-15)
- Antitumor activity(Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL)
- Methylation status of gene promoter regions and gene expression(Baseline and between days 3-10)
- Altered response of leukemic cells to PPAr and RAR ligands(Baseline and between days 3-8)