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

Roswell Park Comprehensive Cancer Center

Status and phase

Completed

Phase 1

Conditions

Gastric Cancer

Esophageal Cancer

Liver Cancer

Treatments

Drug: fluorouracil

Drug: vorinostat

Drug: leucovorin calcium

Other: pharmacological study

Drug: irinotecan hydrochloride

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00537121

RPCI-I-78806

CDR0000564857

Details and patient eligibility

About

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.

Full description

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.

Enrollment

23 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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