Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
Condition: Neoplasms; Lymphomas
MeSH terms: Lymphoma
Intervention: Belinostat
Intervention description: Belinostat was administered intravenously (IV) over 30 minutes on days 1 through 5 of a 21-day cycle. All patients were administered a single dose of 400 mg/m(2) of belinostat on Cycle 1 Day -7 for pharmacokinetic analysis (the total length of Cycle 1 was 28 days).
Intervention MeSH terms: Belinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 110 Years
Healthy volunteers: No
Keywords: Histone Deacetylase Inhibitor; Liver Dysfunction; Pharmacokinetics; UGT1A1 Polymorphisms; Solid Tumor; Cancer; Lymphoma

Summary:

      Background:

      - Belinostat is an experimental cancer treatment drug that works by helping to turn on genes
      that limit cell growth and survival of cancer cells. These genes are often switched off in
      tumors. Belinostat has been given to patients with different types of cancer to measure its
      safety and effectiveness, but it has not been given in a formal trial to cancer patients who
      have abnormal liver function. Because belinostat is processed by the liver, its safety and
      effectiveness needs to be established in individuals who have abnormal liver function.
      Researchers are interested in comparing the effects of belinostat as a cancer treatment drug
      in individuals with normal and abnormal liver function.

      Objectives:

        -  To test the safety and effectiveness of belinostat in individuals who have solid tumors
           and lymphomas and who also have abnormal liver function.

        -  To compare the results of belinostat treatment in individuals with normal and abnormal
           liver function.

      Eligibility:

        -  Individuals at least 18 years of age who have been diagnosed with solid tumors or
           lymphomas that have not responded to standard treatment.

        -  Individuals with normal liver function and varying degrees of abnormal liver function
           (mild, moderate, severe) are eligible.

      Design:

        -  Participants will be screened with a full medical history and physical examination, as
           well as blood and urine tests, and tumor imaging studies. Participants will then be
           divided into study groups based on their liver function.

        -  Participants will receive belinostat in cycles of treatment. Except for cycle 1, all
           cycles will last 21 days. Cycle 1 will last 28 days. For cycle 1 only, participants will
           receive a single dose of belinostat 1 week before the regular 21-day treatment cycle
           starts.

        -  In each cycle, participants will receive belinostat once a day for 5 days, and will be
           asked to keep a medication diary to record any side effects.

        -  Participants will have regular clinic visits with blood and urine sample collection and
           imaging studies to evaluate the cancer's response to treatment.

        -  Participants may continue to take belinostat for as long as the cancer responds to the
           treatment.
    

Eligibility criteria:

        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.