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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00537121
Recruitment Status : Completed
First Posted : September 28, 2007
Last Update Posted : June 28, 2013
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Esophageal Cancer Gastric Cancer Liver Cancer Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: vorinostat Other: pharmacological study Phase 1

Detailed Description:



  • 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.


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Vorinostat [Suberoylanilide Hydroxamic Acid (VORINOSTAT)] With Irinotecan, 5-Fluorouracil (5-FU) and Leucovorin (FOLFIRI) for Advanced Upper Gastrointestinal Cancers
Study Start Date : November 2006
Actual Primary Completion Date : October 2012
Actual Study Completion Date : June 2013

Intervention Details:
  • Drug: fluorouracil
    Given IV
  • Drug: irinotecan hydrochloride
    Given IV
  • Drug: leucovorin calcium
    Given IV
  • Drug: vorinostat
    Taken Orally
  • Other: pharmacological study
    Correlative Study

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of vorinostat (SAHA) when administered continuously and intermittently with standard doses of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) [ Time Frame: 4 weeks ]
  2. Recommended phase II dose (RPTD) of SAHA when administered continuously and intermittently with standard doses of FOLFIRI [ Time Frame: 4 weeks ]

Secondary Outcome Measures :
  1. Toxicity of the SAHA and FOLFIRI combination [ Time Frame: Baseline and after 2 weeks of Treatment ]
  2. Effects of SAHA and FOLFIRI combination on TGF-β signaling and survivin expression [ Time Frame: Every 6 months ]
  3. Response rate [ Time Frame: Every 6 months ]
  4. Progression-free survival [ Time Frame: Every 6 months ]
  5. Overall survival [ Time Frame: Every 3 months for 5 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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


  • 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


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00537121

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United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263-0001
Sponsors and Collaborators
Roswell Park Cancer Institute
Merck Sharp & Dohme Corp.
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Principal Investigator: Nikhil Khushalani, MD Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute Identifier: NCT00537121     History of Changes
Other Study ID Numbers: CDR0000564857
First Posted: September 28, 2007    Key Record Dates
Last Update Posted: June 28, 2013
Last Verified: June 2013

Keywords provided by Roswell Park Cancer Institute:
recurrent gastric cancer
stage IV gastric cancer
recurrent esophageal cancer
stage IV esophageal cancer
adenocarcinoma of the esophagus
adenocarcinoma of the stomach
squamous cell carcinoma of the esophagus
adult primary hepatocellular carcinoma
stage III gastric cancer
stage III esophageal cancer
advanced adult primary liver cancer
localized unresectable adult primary liver cancer
recurrent adult primary liver cancer

Additional relevant MeSH terms:
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Stomach Neoplasms
Esophageal Neoplasms
Liver Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Liver Diseases
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Protective Agents