Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
概览
- 阶段
- 1 期
- 干预措施
- vorinostat
- 疾病 / 适应症
- Adult Grade III Lymphomatoid Granulomatosis
- 发起方
- National Cancer Institute (NCI)
- 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)
- 状态
- 已完成
- 最后更新
- 12年前
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. II. Determine the association of the Child-Pugh classification of hepatic dysfunction with the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat administration. III. Document any antitumor activity associated with vorinostat treatment in patients enrolled on this study. OUTLINE: This is a parallel-group, dose-escalation study. Patients are stratified according to level of hepatic dysfunction (normal vs mild vs moderate vs severe). (closed for accrual as of 04/05/2010) PART I: 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. PART II: 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. Dose escalation will proceed within each hepatic dysfunction group (except in the normal group). Only dose-limiting toxicities (DLTs) that occur during the first cycle of treatment will be used to guide dose escalation. The maximum tolerated dose (MTD) is the highest dose at which no more than one instance of DLT is observed (among 6 patients treated). Once the MTD has been determined for a given hepatic dysfunction group, a maximum of 12 patients will be accrued to this dose level. After completion of study treatment, patients are followed for 4 weeks.
研究者
入排标准
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
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
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
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)