Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 11
- 主要终点
- Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 1)
研究概览
简要总结
This phase I trial is studying the side effects and best dose of vorinostat in treating patients with metastatic or unresectable solid tumors or lymphoma and liver dysfunction. (closed for accrual as of 04/05/2010) Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Vorinostat may have different effects in patients who have changes in their liver function.
详细描述
PRIMARY OBJECTIVES:
I. Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.
II. Establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe).
SECONDARY OBJECTIVES:
I. Document the non-DLTs associated with administration of vorinostat in patients with hepatic dysfunction.
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 solid malignancy or lymphoma that is metastatic or unresectable
- •Patients with a liver mass, elevated α-fetoprotein level (≥ 500 ng/mL), and positive serology for hepatitis consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis
- •Standard curative or palliative measures do not exist or are no longer effective
- •Patients who have not received any prior therapy for malignancy are also eligible if they are ineligible for standard therapy due to hepatic dysfunction
- •Patients with abnormal liver function will be eligible
- •No distinction will be made between liver dysfunction due to metastases and liver dysfunction due to other causes
- •Patients with biliary obstruction for which a shunt has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of vorinostat (SAHA) and liver function has stabilized
- •Two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function
- •No evidence of biliary sepsis
- •Patients with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to study enrollment
- •Patients with known brain metastases should have had brain irradiation (whole brain or gamma knife) more than 4 weeks before starting protocol treatment
- •Patients with unstable or untreated (non-irradiated) brain metastases should be excluded
- •ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
- •Life expectancy > 3 months
- •Absolute neutrophil count > 1,500/mm^3
- •Platelets ≥ 100,000/mm^3
- •Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min
- •Not pregnant or nursing
- •Fertile patients must use effective contraception
- •HIV-positive patients without an AIDS-defining diagnosis who are not receiving agents with the potential for pharmacokinetic interactions with vorinostat may be eligible
- •Able to take oral medications on a continuous basis
- •No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •No active hemolysis
- •More than 3 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
- •Patients who have been treated with agents that persist in the body for longer than 4 to 6 weeks (such as suramin) are ineligible during the elimination period for those agents
- •More than 14 days since prior major surgery
- •No prior vorinostat
- •At least 2 weeks since prior valproic acid or other histone deacetylase inhibitors
- •More than 4 weeks since other prior investigational agents
- •No concurrent combination antiretroviral therapy for HIV-positive patients
- •No concurrent therapy with enzyme-inducing anticonvulsants
- •No concurrent prophylactic granulocyte growth factors during the first cycle of therapy
- •No other concurrent investigational or commercial agents or therapies
排除标准
- 未提供
研究组 & 干预措施
Treatment (enzyme inhibitor therapy)
Vorinostat (SAHA) will be administered as a single oral dose on day -6 for all patients. Blood samples are obtained periodically on day -6 for pharmacokinetic studies.
One week later (day 1), the first course of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment course will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: vorinostat (Drug)
Treatment (enzyme inhibitor therapy)
Vorinostat (SAHA) will be administered as a single oral dose on day -6 for all patients. Blood samples are obtained periodically on day -6 for pharmacokinetic studies.
One week later (day 1), the first course of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment course will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
结局指标
主要结局
Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 1)
时间窗: Days -6 and 1 of course 1
The Wilcoxon test will be used for PK data. Concentrations of vorinostat and 2 metabolites (vorinostat glucuronide and 4-anilino-4-oxobutanoic acid) will be quantitated with a liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed and validated in our laboratory. Plasma concentration versus time data for vorinostat and metabolites will be analyzed non-compartmentally using the LaGrange function as implemented by the Lagran computer program.
MTD of vorinostat based on incidence of DLT
时间窗: Up to 21 days
The MTD is the highest dose at which no more than one instance of DLT is observed (among 6 patients treated). The MTDs determined in this study represent a simple summary of the relationship between the dose of vorinostat that can be administered with acceptable toxicity and a patient's level of liver dysfunction. Treatment-related events occurring during the first course of treatment are considered DLTs.
次要结局
- Child-Pugh classification and liver function test results(At baseline)
- Toxicity profile of vorinostat(Up to 4 weeks after completion of treatment)
- Clinical response rate(Up to 4 weeks after completion of treatment)