Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Active	Over 18	NCI	RPCI-I-78806 I 78806, NCT00537121

Objectives

Primary

1. 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.
2. Determine the MTD and RPTD of SAHA when administered intermittently with standard doses of FOLFIRI in these patients.

Secondary

1. Describe the toxicity of the SAHA and FOLFIRI combination.
2. Explore the effects of SAHA and FOLFIRI combination on TGF-β expression.
3. Explore the alteration of survivin expression by the SAHA and FOLFIRI combination.
4. Describe the effect of FOLFIRI on the pharmacokinetics of SAHA.
5. Describe the effect of SAHA on the pharmacokinetics of irinotecan.
6. Describe the response rate, progression-free survival, and overall survival of patients treated with this regimen.

Entry 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

Prior/Concurrent Therapy:

• 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

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

Expected Enrollment

Outcomes

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

Toxicity of the SAHA and FOLFIRI combination
Effects of SAHA and FOLFIRI combination on TGF-β signaling and survivin expression
Response rate
Progression-free survival
Overall survival

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.

Trial Contact Information

Trial Lead Organizations

Roswell Park Cancer Institute

Nikhil Khushalani, MD, Principal investigator		Ph: 716-845-3852; 800-685-6825

U.S.A.
New York
	Buffalo
	Roswell Park Cancer Institute
		Nikhil Khushalani, MD	Ph:  716-845-7614

Registry Information
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
Trial Start Date		2006-11-24
Trial Completion Date		2010-12-20 (estimated)
Registered in ClinicalTrials.gov		NCT00537121
Date Submitted to PDQ		2007-08-27
Information Last Verified		2009-10-22
NCI Grant/Contract Number		CA16056

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