A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 84
- 试验地点
- 1
- 主要终点
- MEPD of valproic acid in combination with decitabine
研究概览
简要总结
This phase I trial is studying the side effects and best dose of decitabine and valproic acid in treating patients with refractory or relapsed acute myeloid leukemia or previously treated chronic lymphocytic leukemia or small lymphocytic leukemia. Drugs used in chemotherapy, such as decitabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Valproic acid may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Combining decitabine with valproic acid may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. Determine the minimally effective pharmacological dose (MEPD) of decitabine in patients with refractory or relapsed acute myeloid leukemia or with previously treated chronic lymphocytic lymphoma or small lymphocytic lymphoma.
II. Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD of decitabine in these patients.
III. Determine the MEPD of valproic acid in combination with decitabine in these patients.
IV. Determine the qualitative and quantitative toxic effects of decitabine alone and in combination with valproic acid, in terms of organ specificity, time course, predictability, and reversibility 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
- •Patients with AML (Stratum I) or CLL/SLL (Stratum II) will be enrolled
- •Patients in stratum I will have one of the following:
- •Primary refractory or relapsed (in 1 year or less) disease and not a candidate for potentially curative therapy
- •Untreated AML patients who are not candidates for chemotherapy
- •Patients in stratum I must have a normal WBC (=< 10 x 10^9/L) or a WBC =< 40 x 10^9/L that is stable for 1 week (this may be sustained with hydroxyurea prior to starting therapy and during the first 4 days of therapy if clinically indicated)
- •Patients in stratum II will have received at least one prior therapy for CLL/SLL that has included a purine analog; patients in stratum II with a history of severe autoimmune disease or requiring therapy with chronic corticosteroids or who have any other specific relative contraindications to receive a purine analog and, therefore, have received another form of therapy that include alkylating agents will be eligible to participate
- •Performance status - ECOG 0-2
- •At least 12 weeks life expectancy
- •Stratum II:
- •No uncontrolled autoimmune hemolytic anemia
- •No idiopathic thrombocytopenia purpura
- •Bilirubin =< 1.5 mg/dL
- •ALT and AST =< 2 times upper limit of normal
- •Creatinine =< 2.0 mg/dL
- •No active infection requiring IV antibiotics
- •HIV negative
- •No other severe medical condition that would preclude study participation
- •No psychiatric condition that would preclude study compliance
- •No history of seizures
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •More than 14 days since prior chemotherapy (except hydroxyurea)
- •No prior FR901228 (depsipeptide) for step 2 of this study
- •No other concurrent chemotherapy
- •No concurrent corticosteroids for antiemetic therapy
- •No concurrent hormonal therapy except for the following:
- •Steroids for treatment of adrenal failure or septic shock
- •Insulin for diabetes
- •Tamoxifen or equivalent for breast cancer prevention or adjuvant therapy
- •Estrogens or progestins for gynecologic indications
- •More than 14 days since prior radiotherapy
- •No concurrent palliative radiotherapy
- •No concurrent anticonvulsant medication, including valproic acid
排除标准
- 未提供
研究组 & 干预措施
Treatment (decitabine, valproic acid)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the MEPD is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences DLT.
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid 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 DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.
干预措施: decitabine (Drug)
Treatment (decitabine, valproic acid)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the MEPD is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences DLT.
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid 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 DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.
干预措施: valproic acid (Drug)
Treatment (decitabine, valproic acid)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the MEPD is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences DLT.
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid 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 DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (decitabine, valproic acid)
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the MEPD is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences DLT.
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid 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 DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months 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
MEPD of valproic acid in combination with decitabine
时间窗: Up to 29 days
Qualitative and quantitative toxicities of single agent decitabine alone and in combination with valproic acid in regard to organ specificity, time course, predictability, and reversibility
时间窗: Up to 24 months
MTD of the combination of valproic acid with the MEPD of decitabine
时间窗: Up to 21 days
MEPD of single agent decitabine
时间窗: 10 days
次要结局
未报告次要终点