A Phase I Study of Suberoylanilide Hydroxamic Acid (Vorinostat) in Combination With 5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX) in Patients With Colorectal Cancer and Other Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of vorinostat
研究概览
简要总结
This phase I trial is studying the side effects and best dose of suberoylanilide hydroxamic acid when given together with fluorouracil, leucovorin, and oxaliplatin in treating patients with progressive metastatic or unresectable colorectal cancer or solid tumor. Drugs used in chemotherapy, such as suberoylanilide hydroxamic acid, fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Suberoylanilide hydroxamic acid may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose of suberoylanilide hydroxamic acid when administered with fluorouracil, leucovorin calcium, and oxaliplatin in patients with progressive metastatic or unresectable colorectal cancer or other solid tumors.
SECONDARY OBJECTIVES:
I. Determine the toxicity of this regimen in these patients. II. Determine the pharmacokinetics of oxaliplatin, fluorouracil, and suberoylanilide hydroxamic acid in these patients.
OUTLINE: This is a dose-escalation study of suberoylanilide hydroxamic acid (SAHA).
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 confirmed colorectal cancer
- •Metastatic or unresectable disease OR diagnosis of solid tumor
- •No known brain metastases
- •ECOG 0-1 OR Karnofsky 70-100%
- •Life expectancy > 12 weeks
- •Absolute neutrophil count ≥ 1,500/mm^3
- •WBC ≥ 3,000/mm^3
- •Platelet count ≥ 100,000/mm^3
- •Bilirubin normal
- •AST and ALT ≤ 3 times upper limit of normal
- •Creatinine normal OR creatinine clearance ≥ 60 mL/min
- •No symptomatic congestive heart failure
- •No unstable angina pectoris
- •No cardiac arrhythmia
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during and for 3 months after study participation
- •No ongoing or active infection
- •No neuropathy > grade 1
- •No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs
- •No psychiatric illness or social situation that would preclude study compliance
- •No psychiatric illness or social situation that would preclude study compliance
- •No other uncontrolled illness
- •Prior bevacizumab and/or cetuximab allowed
- •No concurrent routine or prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
- •More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
- •More than 4 weeks since prior radiotherapy
- •Recovered from prior therapy
- •At least 2 weeks since prior valproic acid
- •No concurrent combination anti-retroviral therapy for HIV-positive patients
- •No other concurrent investigational agents
- •No other concurrent anticancer therapy
排除标准
- 未提供
研究组 & 干预措施
Treatment (vorinostat, mFOLFOX)
Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (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. A total of 10 patients are treated at the MTD.
干预措施: oxaliplatin (Drug)
Treatment (vorinostat, mFOLFOX)
Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (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. A total of 10 patients are treated at the MTD.
干预措施: leucovorin calcium (Drug)
Treatment (vorinostat, mFOLFOX)
Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (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. A total of 10 patients are treated at the MTD.
干预措施: vorinostat (Drug)
Treatment (vorinostat, mFOLFOX)
Patients receive oral SAHA once or twice daily on days 1-3. Patients also receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 4 followed by fluorouracil IV over 46 hours on days 4-5. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (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. A total of 10 patients are treated at the MTD.
干预措施: fluorouracil (Drug)
结局指标
主要结局
Maximum tolerated dose of vorinostat
时间窗: 2 weeks
Graded according to the NCI CTCAE.
Grade 3, 4, or 5 adverse events graded using the NCI CTCAE version 4.0
时间窗: Up to 30 days after completion of study treatment
次要结局
- Response, evaluated using the new international criteria proposed by the RECIST committee(Up to 4 weeks after completion of study treatment)
- Gene expression studies for evidence of up-regulation or down-regulation, obtained from microarray testing and changes in expression patterns of TS(Up to 4 weeks after completion of study treatment)
- DPD activity(Up to 8 days after the first dose of vorinostat (course 1))
- Pharmacokinetic analysis for vorinostat and 5-FU(Days 1 and 15)