Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
I. Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with
metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic
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).
I. Document the non-DLTs associated with administration of vorinostat in patients with
II. Determine the association of the Child-Pugh classification of hepatic dysfunction with
the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 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
University of Pittsburgh
United States: Food and Drug Administration
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|Montefiore Medical Center||Bronx, New York 10467-2490|
|City of Hope Medical Center||Duarte, California 91010|
|University of Pittsburgh||Pittsburgh, Pennsylvania 15261|
|National Institutes of Health||Bethesda, Maryland 20892|
|Case Western Reserve University||Cleveland, Ohio 44106|
|Emory University||Atlanta, Georgia 30322|
|Wayne State University||Detroit, Michigan 48202|
|University of Southern California||Los Angeles, California 90033|
|Penn State Milton S Hershey Medical Center||Hershey, Pennsylvania 17033|
|West Virginia University||Morgantown, West Virginia 26506|