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0C-11-1 Ph1-66 Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients with Varying Degrees of Hepatic Dysfunction

Description

Belinostat looks promising for the treatment of patients with cancer, having activity in several tumor types as a single therapy and in combination. Exploring appropriate dosing for patients with varying degrees of abnormal liver function would benefit patients with many diseases. Belinostat is broken down in the liver and is also excreted primarily through the liver. Therefore, belinostat dosing in patients with abnormal liver function will be explored in this phase I clinical trial to establish dosing guidelines. The primary objectives of this study in patients with varying degrees of liver function are to establish safety and tolerability of belinostat given on days 15 of 21-day cycles, define the maximum tolerated dose (MTD) and recommended dose of belinostat given on days 15 of 21-day cycles, and to evaluate the drug levels (pharmacokinetics (PK)) of one dose of belinostat (400 mg/m2).Patients will be divided into four groups according to their liver function: normal liver function (Cohort 1), mild abnormal liver function (Cohort 2), moderate abnormal liver function (Cohort 3), and severe abnormal liver function (Cohort 4). Patients will have screening tests/procedures done to see if they are eligible for the study. Once they are deemed eligible, they will be assigned to one of the cohorts. Participants will be given belinostat through a vein in their arm for 30 minutes. They will take the study drug on Days 1-5 during each 21 day cycle, except for cycle 1. On Day -7, cycle 1, participants will receive an extra dose of belinostat and have PK blood draws done at the Clinical Trials Unit. During each cycle, they will have a physical exam, vital signs, assessment of performance status, blood draws, assessment of their tumor with radiographic scans, monitoring for compliance to treatment and monitoring for side effects. Patients will continue the treatment until their disease worsens, they cannot tolerate the side effects, they are physically unable to continue, at the decision of the study doctor, or they decide to withdraw from the study. Participants will be followed for 30 days after the last dose is given or until one of the following occurs: they enroll on another study (phase 0 or early phase I), they receive standard of care, or death, whichever comes first. The follow-up will consist of a phone call between Days 27-30 after the last dose to evaluate side effects that were ongoing and any new events that might be related to the therapy. Unacceptable side effects related to the study drug that have not resolved by Day 30 post-treatment will be followed through twice weekly phone calls until they stabilize or resolve. Participants will be removed from study for one of the following reasons: completed 30-day followup period, side effects are unresolved but stabilized, they enroll on another study (phase 0 or early phase I), or receive standard of care. The study uses a 3+3 design. A minimum of 2 and a maximum of 6 participants will be accrued in each abnormal liver function Cohort (2-4) at each dose level, and 12 patients will be entered at the recommended dose level in Cohort 1. MTD will not be established for the normal cohort as that is already known. Three additional patients will be accrued to the MTD levels (following establishment of MTD for that cohort in the first 6 patients at that dose level) for each abnormal liver function cohort to allow additional information to be gained at these levels. Some patients may need to be replaced if they are not evaluable based on protocol guidelines. As long as < 33% of the patients treated at a given dose level experience a dose limiting side effect, that dose level will be considered the MTD.

Phase

Phase 1 - a new treatment that has not been tested, and researchers are looking for the best way to administer the treatment and how much can be given safely. Phase I trials are usually offered only to patients with advanced disease who would not be helped by other known treatments. Some patients are helped by these treatments, although in this early stage physicians don’t really know if the treatment will be effective.

Inclusion and Exclusion 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 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 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.

  • 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.
  • 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 Pointes.

Sites

  • California

    • City of Hope National Medical Center, Duarte, California, 91010
  • Texas

    • Institute for Drug Development, San Antonio, Texas, 78229
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