Vorinostat in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma and Liver Dysfunction

February 21, 2014 updated by: National Cancer Institute (NCI)

Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction

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) 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.

II. 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 OBJECTIVES:

I. Document the non-DLTs associated with administration of vorinostat in patients with hepatic dysfunction.

II. Determine the association of the Child-Pugh classification of hepatic dysfunction with the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat administration.

III. 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 course of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment course 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.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91010
        • City of Hope Medical Center
      • Los Angeles, California, United States, 90033
        • University of Southern California
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University/Winship Cancer Institute
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Wayne State University-Karmanos Cancer Institute
    • New York
      • Bronx, New York, United States, 10467-2490
        • Montefiore Medical Center
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033-0850
        • Penn State Milton S Hershey Medical Center
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh
    • West Virginia
      • Morgantown, West Virginia, United States, 26506
        • West Virginia University Healthcare
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Hospital and Clinics

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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
  • 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

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (enzyme inhibitor therapy)

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.

One week later (day 1), the first course of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment course will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: vorinostat
Given orally
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 1)
Time Frame: Days -6 and 1 of course 1
The Wilcoxon test will be used for PK data. Concentrations of vorinostat and 2 metabolites (vorinostat glucuronide and 4-anilino-4-oxobutanoic acid) will be quantitated with a liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed and validated in our laboratory. Plasma concentration versus time data for vorinostat and metabolites will be analyzed non-compartmentally using the LaGrange function as implemented by the Lagran computer program.
Days -6 and 1 of course 1
MTD of vorinostat based on incidence of DLT
Time Frame: Up to 21 days
The MTD is the highest dose at which no more than one instance of DLT is observed (among 6 patients treated). The MTDs determined in this study represent a simple summary of the relationship between the dose of vorinostat that can be administered with acceptable toxicity and a patient's level of liver dysfunction. Treatment-related events occurring during the first course of treatment are considered DLTs.
Up to 21 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity profile of vorinostat
Time Frame: Up to 4 weeks after completion of treatment
Toxicities will be graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category, grade. Tabulations will be separate for each liver dysfunction group, and may also be separate for each dose level within a group, if appropriate. For grade 3-4 toxicity, analyses will utilize Fisher's exact test.
Up to 4 weeks after completion of treatment
Clinical response rate
Time Frame: Up to 4 weeks after completion of treatment
Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.
Up to 4 weeks after completion of treatment
Child-Pugh classification and liver function test results
Time Frame: At baseline
The Child-Pugh Classification and its association with toxicity and PK data will be studies in an exploratory analysis. For grade 3-4 toxicity, analyses will utilize Fisher's exact test; for PK data, the Wilcoxon test will be used. In addition, the correlation between the level(s) of liver dysfunction (bilirubin and/or synthetic (albumin), hepatocellular (bilirubin, ALT, AST) and/or ductal (gamma-GT, alkaline phosphatase) parameters and alterations in the PK of vorinostat will be evaluated with Spearman's test
At baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Suresh Ramalingam, University of Pittsburgh

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2007

Primary Completion (Actual)

August 1, 2011

Study Registration Dates

First Submitted

July 10, 2007

First Submitted That Met QC Criteria

July 10, 2007

First Posted (Estimate)

July 11, 2007

Study Record Updates

Last Update Posted (Estimate)

February 24, 2014

Last Update Submitted That Met QC Criteria

February 21, 2014

Last Verified

October 1, 2011

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00272 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U01CA099168 (U.S. NIH Grant/Contract)
  • U01CA062505 (U.S. NIH Grant/Contract)
  • U01CA062491 (U.S. NIH Grant/Contract)
  • U01CA062487 (U.S. NIH Grant/Contract)
  • N01CM62208 (U.S. NIH Grant/Contract)
  • P30CA047904 (U.S. NIH Grant/Contract)
  • NCI-07-C-0228
  • CDR0000555102
  • PCI-UPCI 07-013
  • UPCI 07-013 (Other Identifier: University of Pittsburgh)
  • 8057 (Other Identifier: CTEP)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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