Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction

Background:

- 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.

Objectives:

- Establish the safety and tolerability of belinostat given on days 1 through 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 through 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.

- Measure direct versus indirect bilirubin levels and correlate these with observed
toxicities, PK.

Eligibility:

-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.

Study Design:

-Patients will be divided into 4 dose escalation cohorts based on their level of liver
dysfunction. Belinostat will be administered intravenously (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
through 5 of each cycle, patients will receive belinostat at a dose dependent on the level of
hepatic dysfunction and dose level. Mild, moderate, and severe liver dysfunction cohorts will
begin on dose level 1; patients with normal hepatic function will not have their dose
escalated (see below). The total length of Cycle 1 will be 28 days; all other cycles will be
21 days. No more than 12 evaluable patients with normal hepatic function will be accrued.

INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed (at original diagnosis or
subsequent recurrence or progression) solid tumor or lymphoma that is metastatic,
unresectable, progressive, or recurrent, and for which standard curative or palliative
measures do not exist or are no longer effective.

- No radiation, major surgery, chemotherapy or biologic therapy within 4 weeks prior to
entering the study (6 weeks for nitrosoureas or mitomycin C); greater than or equal to
2 weeks since any prior administration of study drug in an exploratory Investigational
New Drug (IND)/Phase 0 study. (also referred to as an "early Phase I study" or
"pre-Phase I study" where a sub-therapeutic dose of drug is administered) at the
Principal Investigator's (PI's) discretion. Patients must have recovered to at least
eligibility levels due to adverse events and/or toxicity of prior chemotherapy or
biologic therapy.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of belinostat in patients < 18 years of age, children
are excluded from this study but will be eligible for future pediatric Phase I
single-agent trials.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
(Karnofsky greater than or equal to 60 percent.

- Life expectancy of greater than 3 months.

- Patients must have acceptable renal and marrow function as defined below:

leukocytes greater than or equal to 3,000/mcL

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or equal to 100,000/mcL

serum creatinine within normal institutional limits OR creatinine clearance greater than or
equal to 60 mL/min for patients with creatinine levels above institutional normal, as
determined by a measured 24-hour creatinine clearance Baseline evaluations should be
conducted within 7 days of treatment start date.

- Patients with abnormal liver function will be eligible. Patients with active hemolysis
should be excluded. 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 stent has been placed are eligible,
provided the stent has been in place for at least 10 days prior to the first dose of
belinostat and the 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. There should be 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 enrollment. Patients with known brain metastases should have had brain
irradiation (whole brain or gamma knife) more than 4 weeks before starting the
protocol. Note that patients should have had their steroids tapered to low dose (i.e.,
< 1.5 mg of dexamethasone/day).

- The effects of belinostat on the developing human fetus are unknown. For this reason
and because histone deacetylase (HDAC) inhibitors are known to be teratogenic, women
of child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

- Prior therapy with belinostat.

- Patients may not be receiving any other investigational agents.

- Patients with history of allergic reactions attributed to compounds of similar
chemical or biologic composition to belinostat, including hydroxamate compounds or
arginine.

- Patients should not have taken valproic acid, another HDAC inhibitor, for at least 2
weeks prior to enrollment.

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, or psychiatric illness/social situations that would limit
compliance with study requirements.

- Pregnant women are excluded from this study because belinostat is an HDAC inhibitor
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with belinostat, breastfeeding should be discontinued if the
mother is treated with belinostat.

- Human Immunodeficiency Virus (HIV) positive patients who are not on retroviral therapy
will not be excluded from cohort 1, the normal liver function cohort. HIV positive
patients who are not on retroviral therapy will be excluded from cohorts 2-4 because
of confounding effects from potential complications from HIV and opportunistic
infections.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for the increased risk of liver dysfunction from the antiretroviral
therapies themselves and because of potential pharmacokinetics (PK) interactions with
belinostat. Appropriate studies will be undertaken in these groups of patients when
indicated.

- Patients with significant cardiovascular disease (New York Heart Association Class III
or IV cardiac disease), symptomatic congestive heart failure, myocardial infarction
within the past 6 months, unstable angina, unstable arrhythmia or a need for
anti-arrhythmic therapy (use of frequency adjusting medication for atrial fibrillation
is allowed, if stable medication for at least last month prior to initiation of
belinostat treatment and medication not listed as causing Torsades de Points), or
evidence of acute ischemia on electrocardiogram (ECG). Marked baseline prolongation of
Q wave, T wave (QT)/Corrected QT Interval (QTc) interval, e.g., repeated demonstration
of a QTc interval > 450 msec; Long QT Syndrome; the required use of concomitant
medication that may cause Torsades de Pointes.