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

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.