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Vorinostat in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma and Liver Dysfunction
This study has been completed.

First Received on July 10, 2007.   Last Updated on February 19, 2012   History of Changes
Sponsor: University of Pittsburgh
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00499811
  Purpose

RATIONALE: Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Vorinostat may have different effects in patients who have changes in their liver function.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat in treating patients with metastatic or unresectable solid tumors or lymphoma and liver dysfunction. (closed for accrual as of 04/05/2010)


Condition Intervention Phase
Brain and Central Nervous System Tumors
Lymphoma
Small Intestine Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: vorinostat
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Pharmacokinetic variables corresponding to the disposition of vorinostat (SAHA) [ Designated as safety issue: No ]
  • Maximum tolerated dose and dose-limiting toxicity of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe) [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Toxicity profile of vorinostat [ Designated as safety issue: Yes ]
  • Clinical response rate [ Designated as safety issue: No ]
  • Child-Pugh classification and liver function test results [ Designated as safety issue: No ]

Estimated Enrollment: 118
Study Start Date: June 2007
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.
  • Establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe).

Secondary

  • Document the non-DLTs associated with administration of vorinostat in patients with hepatic dysfunction.
  • Determine the association of the Child-Pugh classification of hepatic dysfunction with the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat administration.
  • Document any antitumor activity associated with vorinostat treatment in patients enrolled on this study.

OUTLINE: This is a parallel-group, dose-escalation study. Patients are stratified according to level of hepatic dysfunction (normal vs mild vs moderate vs severe).(closed for accrual as of 04/05/2010)

  • Part I: Vorinostat (SAHA) will be administered as a single oral dose on day -6 for all patients.

Blood samples are obtained periodically on day -6 for pharmacokinetic studies.

  • Part II: One week later (day 1), the first cycle of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment cycle will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

Dose escalation will proceed within each hepatic dysfunction group (except in the normal group). Only dose-limiting toxicities (DLTs) that occur during the first cycle of treatment will be used to guide dose escalation. The maximum tolerated dose (MTD) is the highest dose at which no more than one instance of DLT is observed (among 6 patients treated). Once the MTD has been determined for a given hepatic dysfunction group, a maximum of 12 patients will be accrued to this dose level.

After completion of study treatment, patients are followed for 4 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable

    • Patients with a liver mass, elevated α-fetoprotein level (≥ 500 ng/mL), and positive serology for hepatitis consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis
  • Standard curative or palliative measures do not exist or are no longer effective

    • Patients who have not received any prior therapy for malignancy are also eligible if they are ineligible for standard therapy due to hepatic dysfunction
  • Patients with abnormal liver function will be eligible

    • No distinction will be made between liver dysfunction due to metastases and liver dysfunction due to other causes
    • Patients with biliary obstruction for which a shunt has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of vorinostat (SAHA) and liver function has stabilized

      • Two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function
    • No evidence of biliary sepsis
  • Patients with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to study enrollment

    • Patients with known brain metastases should have had brain irradiation (whole brain or gamma knife) more than 4 weeks before starting protocol treatment
    • Patients with unstable or untreated (non-irradiated) brain metastases should be excluded

PATIENT CHARACTERISTICS:

  • ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
  • Life expectancy > 3 months
  • Absolute neutrophil count > 1,500/mm^3
  • Platelets ≥ 100,000/mm^3
  • Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • HIV-positive patients without an AIDS-defining diagnosis who are not receiving agents with the potential for pharmacokinetic interactions with vorinostat may be eligible
  • Able to take oral medications on a continuous basis
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • No active hemolysis

PRIOR CONCURRENT THERAPY:

  • More than 3 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered

    • Patients who have been treated with agents that persist in the body for longer than 4 to 6 weeks (such as suramin) are ineligible during the elimination period for those agents
  • More than 14 days since prior major surgery
  • No prior vorinostat
  • At least 2 weeks since prior valproic acid or other histone deacetylase inhibitors
  • More than 4 weeks since other prior investigational agents
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No concurrent therapy with enzyme-inducing anticonvulsants
  • No concurrent prophylactic granulocyte growth factors during the first cycle of therapy
  • No other concurrent investigational or commercial agents or therapies
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00499811

Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles, California, United States, 90089-9181
City of Hope Medical Group
Pasadena, California, United States, 91105
University of California Davis Cancer Center
Sacramento, California, United States, 95817
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
NCI - Medical Oncology Branch
Bethesda, Maryland, United States, 20892
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201-1379
United States, New York
Albert Einstein Cancer Center at Albert Einstein College of Medicine
Bronx, New York, United States, 10461
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106-5065
United States, Pennsylvania
Penn State Cancer Institute at Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
UPMC Cancer Centers
Pittsburgh, Pennsylvania, United States, 15232
United States, Texas
Institute for Drug Development
San Antonio, Texas, United States, 78245-3217
United States, Wisconsin
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
Madison, Wisconsin, United States, 53792-6164
Sponsors and Collaborators
University of Pittsburgh
Investigators
Study Chair: Suresh Ramalingam, MD University of Pittsburgh
Principal Investigator: Shivaani Kummar, MD NCI - Medical Oncology Branch
  More Information

Additional Information:
Publications:
Egorin MJ, Kummar S, Sarantopoulos J, et al.: Phase I study of vorinostat for patients with advanced solid tumors and hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI #8057). [Abstract] J Clin Oncol 28 (Suppl 15): A-2545, 2010.
Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, Holleran J, Lin Y, Beumer JH, Harvey RD, Ivy SP, Belani CP, Egorin MJ. Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol. 2010 Oct 10;28(29):4507-12. Epub 2010 Sep 13.

ClinicalTrials.gov Identifier: NCT00499811     History of Changes
Other Study ID Numbers: CDR0000555102, PCI-07013, PCI-UPCI 07-013, NCI-07-C-0228
Study First Received: July 10, 2007
Last Updated: February 19, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
unspecified adult solid tumor, protocol specific
recurrent adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
stage III adult Hodgkin lymphoma
recurrent adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
stage III adult T-cell leukemia/lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
cutaneous B-cell non-Hodgkin lymphoma
recurrent mycosis fungoides/Sezary syndrome
stage IV mycosis fungoides/Sezary syndrome
stage III mycosis fungoides/Sezary syndrome
recurrent cutaneous T-cell non-Hodgkin lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage III adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma
stage III grade 1 follicular lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Nervous System Neoplasms
Lymphoma, Large-Cell, Immunoblastic
Central Nervous System Neoplasms
Liver Diseases
Duodenal Neoplasms
Ileal Neoplasms
Jejunal Neoplasms
Neoplasms
Intestinal Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Nervous System Diseases
Digestive System Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Gastrointestinal Diseases
Duodenal Diseases
Intestinal Diseases
Ileal Diseases
Jejunal Diseases
Vorinostat
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 24, 2012