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Vorinostat, Irinotecan, Fluorouracil, and Leucovorin in Treating Patients With Advanced Upper Gastrointestinal Cancer

2013年6月26日 更新者：Roswell Park Cancer Institute

Phase I Study of Vorinostat [Suberoylanilide Hydroxamic Acid (VORINOSTAT)] With Irinotecan, 5-Fluorouracil (5-FU) and Leucovorin (FOLFIRI) for Advanced Upper Gastrointestinal Cancers

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as irinotecan, fluorouracil, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when given together with irinotecan, fluorouracil, and leucovorin in treating patients with advanced upper gastrointestinal cancer.

研究概览

地位

完全的

条件

干预/治疗

详细说明

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of vorinostat (SAHA) when administered continuously with standard doses of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with advanced upper gastrointestinal cancer.
  • Determine the MTD and RPTD of SAHA when administered intermittently with standard doses of FOLFIRI in these patients.

Secondary

  • Describe the toxicity of the SAHA and FOLFIRI combination.
  • Explore the effects of SAHA and FOLFIRI combination on TGF-β expression.
  • Explore the alteration of survivin expression by the SAHA and FOLFIRI combination.
  • Describe the effect of FOLFIRI on the pharmacokinetics of SAHA.
  • Describe the effect of SAHA on the pharmacokinetics of irinotecan.
  • Describe the response rate, progression-free survival, and overall survival of patients treated with this regimen.

OUTLINE: Patients receive irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2 (FOLFIRI). Patients also receive oral vorinostat (SAHA) according to 1 of the following dosing regimens outlined below, depending upon time of study entry:

  • Determination of maximum tolerated dose (MTD) for continuous SAHA dosing: Patients receive SAHA once daily on days 2-14 of course 1 and then on days 1-14 of all subsequent courses.
  • Evaluation of SAHA pharmacokinetics at MTD for continuous dose SAHA: Patients receive SAHA on day -7 (before beginning course 1) and then once daily on days 1-14 at the MTD.
  • Determination of MTD for intermittent SAHA: Patients receive SAHA once daily on days 1-7 at the MTD determined for continuous SAHA dosing. Patients receive escalating doses of SAHA until the MTD of intermittent SAHA is determined.

Treatment with FOLFIRI and vorinostat repeats every 2 weeks for 24 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo tumor tissue and blood sample collection periodically for pharmacokinetic and correlative studies. Tumor tissue samples are assessed for TGF-β expression by immunohistochemical methods and by reverse transcriptase-polymerase chain reaction for mRNA expression. Immunohistochemistry and immunoenzymatic techniques are performed to study survivin expression before beginning treatment and after completion of course 1. Pharmacokinetic studies for irinotecan, SN38, and SN38G are obtained on days 1 (before SAHA) and 15 (after SAHA). Blood is also collected for analysis of UGT1A1 polymorphism. Other patients undergo blood collection on days -7 (before FOLFIRI) and 2 (with FOLFIRI) for vorinostat Pharmacokinetic studies. Samples are analyzed by liquid chromatography-mass spectrometry.

After completion of study treatment, patients are followed for 4 weeks.

研究类型

介入性

注册 (实际的)

23

阶段

  • 阶段1

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习地点

  • 美国
    • New York
      • Buffalo、New York、美国、14263-0001
        • Roswell Park Cancer Institute

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

18年 及以上 (成人、年长者)

接受健康志愿者

不

有资格学习的性别

全部

描述

DISEASE CHARACTERISTICS:

  • Histologically confirmed upper gastrointestinal tract cancer, including any of the following:

    • Esophageal cancer (adenocarcinoma or squamous cell carcinoma)
    • Gastric cancer (adenocarcinoma or squamous cell carcinoma)
    • Hepatocellular carcinoma
  • Locally advanced, inoperable disease or metastatic disease
  • No uncontrolled brain metastases

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-1 (Karnofsky PS ≥ 70%)
  • Life expectancy > 12 weeks
  • Platelet count ≥ 100,000/mcL
  • Absolute neutrophil count ≥ 1,500/mcL
  • Leukocytes ≥ 3,000/mcL
  • Total bilirubin ≤ 1.5 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to understand and willing to sign a written informed consent document
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in the study

  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Uncontrolled hypertension
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study requirements
  • No coagulopathy or bleeding disorder
  • No known UGT1A1 polymorphism

PRIOR CONCURRENT THERAPY:

  • No more than 1 prior chemotherapy for metastatic disease
  • No prior histone deacetylase inhibitors
  • No concurrent prophylactic hematologic growth factors
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No concurrent valproic acid
  • No other concurrent investigational therapy
  • Concurrent therapeutic anticoagulation therapy is allowed

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：不适用
  • 介入模型：单组作业
  • 屏蔽：无（打开标签）

研究衡量的是什么？

主要结果指标

结果测量
大体时间
Maximum tolerated dose (MTD) of vorinostat (SAHA) when administered continuously and intermittently with standard doses of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI)
大体时间：4 weeks
4 weeks
Recommended phase II dose (RPTD) of SAHA when administered continuously and intermittently with standard doses of FOLFIRI
大体时间：4 weeks
4 weeks

次要结果测量

结果测量
大体时间
Toxicity of the SAHA and FOLFIRI combination
大体时间：Baseline and after 2 weeks of Treatment
Baseline and after 2 weeks of Treatment
Effects of SAHA and FOLFIRI combination on TGF-β signaling and survivin expression
大体时间：Every 6 months
Every 6 months
Response rate
大体时间：Every 6 months
Every 6 months
Progression-free survival
大体时间：Every 6 months
Every 6 months
Overall survival
大体时间：Every 3 months for 5 years
Every 3 months for 5 years

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Roswell Park Cancer Institute

合作者

Merck Sharp & Dohme LLC

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始

2006年11月1日

初级完成 (实际的)

2012年10月1日

研究完成 (实际的)

2013年6月1日

研究注册日期

首次提交

2007年9月27日

首先提交符合 QC 标准的

2007年9月27日

首次发布 (估计)

2007年9月28日

研究记录更新

最后更新发布 (估计)

2013年6月28日

上次提交的符合 QC 标准的更新

2013年6月26日

最后验证

2013年6月1日

更多信息

与本研究相关的术语

关键字

其他相关的 MeSH 术语

其他研究编号

  • CDR0000564857
  • RPCI-I-78806

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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