• 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 ] [ Designated as safety issue: Yes ]
  
• Recommended phase II dose (RPTD) of SAHA when administered continuously and intermittently with standard doses of FOLFIRI [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  

• Toxicity of the SAHA and FOLFIRI combination [ Time Frame: Baseline and after 2 weeks of Treatment ] [ Designated as safety issue: Yes ]
  
• Effects of SAHA and FOLFIRI combination on TGF-β signaling and survivin expression [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
  
• Response rate [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
  
• Progression-free survival [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
  
• Overall survival [ Time Frame: Every 3 months for 5 years ] [ Designated as safety issue: No ]
  

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

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.