- 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 dysfunction.
- 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 dysfunction.
- Measure direct versus indirect bilirubin levels and correlate these with observed toxicities, PK, and UGT1A1 polymorphisms.
-Adults with histologically confirmed 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.