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

Phase 1
18 Years
Not Enrolling
Esophageal Cancer, Gastric Cancer, Liver Cancer

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Trial Information

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



- 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.

Inclusion Criteria


- Histologically confirmed upper gastrointestinal tract cancer, including any of the

- 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

- 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

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of vorinostat (SAHA) when administered continuously and intermittently with standard doses of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI)

Outcome Time Frame:

4 weeks

Safety Issue:


Principal Investigator

Nikhil Khushalani, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

November 2006

Completion Date:

June 2013

Related Keywords:

  • Esophageal Cancer
  • Gastric Cancer
  • Liver Cancer
  • 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
  • Esophageal Diseases
  • Esophageal Neoplasms
  • Liver Neoplasms
  • Stomach Neoplasms
  • Gastrointestinal Neoplasms



Roswell Park Cancer InstituteBuffalo, New York  14263