A Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
- Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs are frequently deregulated
in cancer cells, leading to an increase in deacetylation and the silencing of genes
that normally control cell cycle arrest and apoptosis.
- Belinostat has growth inhibitory activity in several malignancies in vitro and in vivo,
both as a single agent and in combination with chemotherapeutic agents. Several Phase I
and II clinical trials have been conducted to date in patients with solid tumor and
hematologic malignancies; belinostat has been generally well tolerated.
- Belinostat is metabolized in the liver and therefore, the safety and dosing of
belinostat needs to be established in patients with varying degrees of hepatic
- Establish the safety and tolerability of belinostat given on days 1-5 of 21-day cycles
to patients with varying degrees of liver dysfunction.
- Define the maximum tolerated dose (MTD) and recommended dose of belinostat given on
days 1-5 of 21-day cycles to patients with varying degrees of liver dysfunction.
- Evaluate the pharmacokinetics (PK) of one dose of belinostat (400 mg/m(2)) in patients
with varying degrees of liver dysfunction.
- Obtain preliminary evidence of anti-tumor activity at tolerable doses of belinostat in
patients with varying degrees of liver dysfunction.
- Determine polymorphisms in the UGT1A1 28 allele and correlate these with the observed
toxicities and the PK of belinostat in patients with varying degrees of liver
- Measure direct versus indirect bilirubin levels and correlate these with observed
toxicities, PK, and UGT1A1 polymorphisms.
-Adults with solid tumors or lymphomas whose disease has progressed after standard therapy
or who have no acceptable standard treatment options. Patients with normal and varying
degrees of hepatic dysfunction (mild, moderate, and severe) are eligible.
-Patients will be divided into 4 cohorts based on their level of liver dysfunction.
Belinostat will be administered IV over 30 minutes. On day -7 (Cycle 1 only), all patients
will receive a single dose of 400 mg/m(2) belinostat. On days 1-5 of each cycle, patients
will receive belinostat at a dose dependent on the level of hepatic dysfunction (see below).
The total length of Cycle 1 will be 28 days; all other cycles will be 21 days. No more than
12 patients with normal hepatic function will be accrued.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Establish safety and tolerability of belinostat given on days 1-5 of 21-day cycles to patients with varying degrees of liver dysfunction.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|Albert Einstein College of Medicine||Bronx, New York 10461|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|City of Hope National Medical Center||Los Angeles, California 91010|
|University of Colorado||Denver, Colorado 80217|
|Institute for Drug Development||San Antonio, Texas 78245-3217|
|Case Western Reserve University||Cleveland, Ohio 44106|
|Emory University||Atlanta, Georgia 30322|
|Moffitt Cancer Center||Tampa, Florida 33612|
|USC Norris Cancer Center||Los Angeles, California 90033|
|Karmanos Cancer Institute||Detroit, Michigan 48201|
|University of California, Davis||Sacramento, California 95818|
|Penn State Hershey Cancer Institute||Hershey, Pennsylvania 17033|
|Pittsburgh Clinical Research||Pittsburgh, Pennsylvania 15215|