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

26. juni 2013 oppdatert av: 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.

Studieoversikt

Status

Fullført

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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

Intervensjonell

Registrering (Faktiske)

23

Fase

  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • New York
      • Buffalo, New York, Forente stater, 14263-0001
        • Roswell Park Cancer Institute

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Intervensjonsmodell: Enkeltgruppeoppdrag
  • Masking: Ingen (Open Label)

Hva måler studien?

Primære resultatmål

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

Sekundære resultatmål

Resultatmål
Tidsramme
Toxicity of the SAHA and FOLFIRI combination
Tidsramme: 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
Tidsramme: Every 6 months
Every 6 months
Response rate
Tidsramme: Every 6 months
Every 6 months
Progression-free survival
Tidsramme: Every 6 months
Every 6 months
Overall survival
Tidsramme: Every 3 months for 5 years
Every 3 months for 5 years

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Roswell Park Cancer Institute

Samarbeidspartnere

Merck Sharp & Dohme LLC

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. november 2006

Primær fullføring (Faktiske)

1. oktober 2012

Studiet fullført (Faktiske)

1. juni 2013

Datoer for studieregistrering

Først innsendt

27. september 2007

Først innsendt som oppfylte QC-kriteriene

27. september 2007

Først lagt ut (Anslag)

28. september 2007

Oppdateringer av studieposter

Sist oppdatering lagt ut (Anslag)

28. juni 2013

Siste oppdatering sendt inn som oppfylte QC-kriteriene

26. juni 2013

Sist bekreftet

1. juni 2013

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • CDR0000564857
  • RPCI-I-78806

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