Deze pagina is automatisch vertaald en de nauwkeurigheid van de vertaling kan niet worden gegarandeerd. Raadpleeg de Engelse versie voor een brontekst.

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

26 juni 2013 bijgewerkt door: Roswell Park Cancer Institute

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

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.

Studie Overzicht

Toestand

Voltooid

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

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.

Studietype

Ingrijpend

Inschrijving (Werkelijk)

Fase

Fase 1

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

Verenigde Staten
- New York
  - Buffalo, New York, Verenigde Staten, 14263-0001
    - Roswell Park Cancer Institute

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar en ouder (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Primair doel: Behandeling
Toewijzing: NVT
Interventioneel model: Opdracht voor een enkele groep
Masker: Geen (open label)

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat	Tijdsspanne
Maximum tolerated dose (MTD) of vorinostat (SAHA) when administered continuously and intermittently with standard doses of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) Tijdsspanne: 4 weeks	4 weeks
Recommended phase II dose (RPTD) of SAHA when administered continuously and intermittently with standard doses of FOLFIRI Tijdsspanne: 4 weeks	4 weeks

Secundaire uitkomstmaten

Uitkomstmaat	Tijdsspanne
Toxicity of the SAHA and FOLFIRI combination Tijdsspanne: Baseline and after 2 weeks of Treatment	Baseline and after 2 weeks of Treatment
Effects of SAHA and FOLFIRI combination on TGF-β signaling and survivin expression Tijdsspanne: Every 6 months	Every 6 months
Response rate Tijdsspanne: Every 6 months	Every 6 months
Progression-free survival Tijdsspanne: Every 6 months	Every 6 months
Overall survival Tijdsspanne: Every 3 months for 5 years	Every 3 months for 5 years

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Roswell Park Cancer Institute

Medewerkers

Merck Sharp & Dohme LLC

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 november 2006

Primaire voltooiing (Werkelijk)

1 oktober 2012

Studie voltooiing (Werkelijk)

1 juni 2013

Studieregistratiedata

Eerst ingediend

27 september 2007

Eerst ingediend dat voldeed aan de QC-criteria

27 september 2007

Eerst geplaatst (Schatting)

28 september 2007

Updates van studierecords

Laatste update geplaatst (Schatting)

28 juni 2013

Laatste update ingediend die voldeed aan QC-criteria

26 juni 2013

Laatst geverifieerd