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A Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction

Phase 1
18 Years
Open (Enrolling)
Neoplasms, Lymphomas

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Trial Information

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.

Study Design:

-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.

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 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 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.

- 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


- -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

- 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

- 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 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


- 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

- 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.

- 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 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 ECG. Marked baseline prolongation of QT/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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Establish safety and tolerability of belinostat given on days 1-5 of 21-day cycles to patients with varying degrees of liver dysfunction.

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Neoplasms
  • Lymphomas
  • Histone Deacetylase Inhibitor
  • Liver Dysfunction
  • Pharmacokinetics
  • UGT1A1 Polymorphisms
  • Solid Tumor
  • Cancer
  • Lymphoma
  • Neoplasms
  • Lymphoma
  • Liver Diseases



Albert Einstein College of MedicineBronx, New York  10461
National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
City of Hope National Medical CenterLos Angeles, California  91010
University of ColoradoDenver, Colorado  80217
Institute for Drug DevelopmentSan Antonio, Texas  78245-3217
Case Western Reserve UniversityCleveland, Ohio  44106
Emory UniversityAtlanta, Georgia  30322
Moffitt Cancer CenterTampa, Florida  33612
USC Norris Cancer CenterLos Angeles, California  90033
Karmanos Cancer InstituteDetroit, Michigan  48201
University of California, DavisSacramento, California  95818
Penn State Hershey Cancer InstituteHershey, Pennsylvania  17033
Pittsburgh Clinical ResearchPittsburgh, Pennsylvania  15215