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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:

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.

  • 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.
  • 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.


    • Original Primary Outcome:

    • Pharmacokinetic variables corresponding to the disposition of vorinostat (SAHA)
    • Maximum tolerated dose and dose-limiting toxicity of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe)


    Current Secondary Outcome:

    • 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.
    • 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.
    • 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


    Original Secondary Outcome:

    • Toxicity profile of vorinostat
    • Clinical response rate
    • Child-Pugh classification and liver function test results


    Information By: National Cancer Institute (NCI)

    Dates:
    Date Received: July 10, 2007
    Date Started: June 2007
    Date Completion:
    Last Updated: February 21, 2014
    Last Verified: October 2011