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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01273155
Collaborator
(none)
72
Enrollment
7
Locations
7
Arms
81.5
Actual Duration (Months)
10.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
72 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I Pharmacokinetic Study of Belinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
Actual Study Start Date :
Jan 10, 2011
Actual Primary Completion Date :
Oct 25, 2017
Actual Study Completion Date :
Oct 25, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Normal Function-Belinostat 1000 mg/m(2)

Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN.

Drug: Belinostat
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).
Other Names:
  • Beleodaq

    		•
    Experimental: Mild Dysfunction-Belinostat 750 mg/m(2)

    Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN.

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•
    Experimental: Mild Dysfunction-Belinostat 1000 mg/m(2)

    Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN.

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•
    Experimental: Moderate Dysfunction-Belinostat 500 mg/m(2)

    Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST).

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•
    Experimental: Moderate Dysfunction-Belinostat 750 mg/m(2)

    Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST).

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•
    Experimental: Severe Dysfunction-Belinostat 250 mg/m(2)

    Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•
    Experimental: Severe Dysfunction-Belinostat 350 mg/m(2)

    Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST).

    Drug: Belinostat
    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).
    Other Names:
  • Beleodaq

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Dose Limiting Toxicity (DLTs) [First cycle of therapy, 28 days.]

      A DLT was defined as an adverse event deemed possibly, probably, or definitely related to administration of study drugs and met the following criteria: grade≥3 non-hematological toxicity (except grade ≥3 diarrhea, nausea, vomiting responsive to supportive therapy);grade≥3 rise in creatinine (except grade 3 able to be corrected to grade 1 or baseline with intravenous fluids within 24hrs); grade≥3 electrolyte toxicities (except those able to be corrected to grade 1 or baseline within 48hrs); grade 4 thrombocytopenia; grade 4 neutropenia for >5 days or febrile neutropenia; any neurotoxicity grade≥2 not reversible to grade 1 or baseline within 2wks; or any delay in treatment by ≥2wks due to treatment-related toxicity. Worsening liver function, as defined by a rise in serum bilirubin not related to tumor progression, was considered a DLT if a patient with mild dysfunction became severe for 1wk, or if a patient in either the moderate/severe groups had a >1.5x increase in bilirubin for 1 wk.

    2. Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction [First cycle of therapy, 28 days]

      In order to maintain consistent dosing across the hepatic dysfunction groups, the dose recommended for cohorts with greater liver dysfunction could be no greater than the dose for cohorts of lesser dysfunction. In other words, it was assumed that a particular group would not tolerate a dose not tolerated by a group with lesser dysfunction and conversely, will tolerate a dose tolerated by a group with greater dysfunction. If a higher dose was tolerated in a group of greater dysfunction, but not in the group of lesser dysfunction, the lower dose would be recommended for both groups. The highest dose to be explored was no greater than the recommended dose for patients with normal liver function.

    3. Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug [From Cycle 1 Day -7 up to 12 (21-day) cycles]

      The number of participants experiencing each adverse event by liver function cohort at each dose level. The grade refers to the severity of the Adverse Event. Grade 1 Mild; Grade 2 Moderate; Grade 3 Severe or medically significant but not immediately life-threatening; Grade 4 Life-threatening consequences; Grade 5 Death related to adverse event.

    4. Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) [Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Maximum plasma concentrations (Cmax) for belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.

    5. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) [Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after start of infusion; and 5, 10, 15, 60, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for belinostat and four metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.

    6. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) of Belinostat [Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) for Belinostat glucuronide, a Belinostat Metabolite on Cycle 1 Day-7 as a function of degree of liver dysfunction.

    7. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) [Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Half-life Period (t1/2) of belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver function.

    8. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) [Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Clearance (CL) of Belinostat on Cycle 1 Day-7 as a function of degree of liver dysfunction

    9. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) [Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Belinostat Apparent volume of distribution at steady state (Vss) on Cycle 1 Day-7 as a function of degree of liver dysfunction.

    10. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Maximum Plasma Concentrations (Cmax) for the Belinostat Metabolic Pathway [Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Metabolic ratios of Maximum Plasma Concentrations (Cmax), reported as a geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.

    11. Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for the Belinostat Metabolic Pathway [Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.]

      Metabolic ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf), reported as geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.

    Secondary Outcome Measures

    1. Best Response [at baseline and every two 21-day cycles of treatment, up to 12 cycles]

      Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles of treatment based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per RECIST v1.1 Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum diameters; Stable Disease (SD), neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for Progression of Disease (PD), taking as reference the smallest sum diameters while on study; PD, >=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and an absolute increase of at least 5mm or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    2. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). [From Cycle 1 Day -7 up to 12 (21-day) cycles.]

      Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 110 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of California, Davis Davis California United States 95616
    2 City of Hope National Medical Center Duarte California United States 91010
    3 USC Norris Cancer Center Los Angeles California United States 90033
    4 Emory University Atlanta Georgia United States 30322-1102
    5 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892
    6 Karmanos Cancer Institute Detroit Michigan United States 48201
    7 Albert Einstein College of Medicine Bronx New York United States 10461

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Naoko Takebe, M.D., Ph.D., National Cancer Institute (NCI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01273155
    Other Study ID Numbers:
    • 110060
    • 11-C-0060
    First Posted:
    Jan 10, 2011
    Last Update Posted:
    Mar 26, 2019
    Last Verified:
    Mar 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    Histone Deacetylase Inhibitor
    Liver Dysfunction
    Pharmacokinetics
    UGT1A1 Polymorphisms
    Solid Tumor
    Cancer
    Lymphoma
    Additional relevant MeSH terms:
    Lymphoma
    Belinostat

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Period Title: Overall Study
    STARTED 14 12 18 5 5 10 8
    COMPLETED 12 8 6 4 3 5 2
    NOT COMPLETED 2 4 12 1 2 5 6

    Baseline Characteristics

    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction Total
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Total of all reporting groups
    Overall Participants 14 30 10 18 72
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    7
    50%
    22
    73.3%
    6
    60%
    12
    66.7%
    47
    65.3%
    >=65 years
    7
    50%
    8
    26.7%
    4
    40%
    6
    33.3%
    25
    34.7%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    65
    59
    63.5
    57.5
    61
    Sex: Female, Male (Count of Participants)
    Female
    6
    42.9%
    11
    36.7%
    3
    30%
    8
    44.4%
    28
    38.9%
    Male
    8
    57.1%
    19
    63.3%
    7
    70%
    10
    55.6%
    44
    61.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    7.1%
    1
    3.3%
    1
    10%
    3
    16.7%
    6
    8.3%
    Not Hispanic or Latino
    13
    92.9%
    29
    96.7%
    9
    90%
    15
    83.3%
    66
    91.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    2
    6.7%
    0
    0%
    1
    5.6%
    3
    4.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    4
    28.6%
    8
    26.7%
    2
    20%
    2
    11.1%
    16
    22.2%
    White
    10
    71.4%
    19
    63.3%
    8
    80%
    15
    83.3%
    52
    72.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    1
    3.3%
    0
    0%
    0
    0%
    1
    1.4%
    Region of Enrollment (participants) [Number]
    United States
    14
    100%
    30
    100%
    10
    100%
    18
    100%
    72
    100%
    Eastern Cooperative Oncology Group Performance Status (Count of Participants)
    Grade 0
    4
    28.6%
    2
    6.7%
    3
    30%
    1
    5.6%
    10
    13.9%
    Grade 1
    9
    64.3%
    26
    86.7%
    5
    50%
    13
    72.2%
    53
    73.6%
    Grade 2
    1
    7.1%
    2
    6.7%
    2
    20%
    4
    22.2%
    9
    12.5%

    Outcome Measures

    1. Primary Outcome
    Title Dose Limiting Toxicity (DLTs)
    Description A DLT was defined as an adverse event deemed possibly, probably, or definitely related to administration of study drugs and met the following criteria: grade≥3 non-hematological toxicity (except grade ≥3 diarrhea, nausea, vomiting responsive to supportive therapy);grade≥3 rise in creatinine (except grade 3 able to be corrected to grade 1 or baseline with intravenous fluids within 24hrs); grade≥3 electrolyte toxicities (except those able to be corrected to grade 1 or baseline within 48hrs); grade 4 thrombocytopenia; grade 4 neutropenia for >5 days or febrile neutropenia; any neurotoxicity grade≥2 not reversible to grade 1 or baseline within 2wks; or any delay in treatment by ≥2wks due to treatment-related toxicity. Worsening liver function, as defined by a rise in serum bilirubin not related to tumor progression, was considered a DLT if a patient with mild dysfunction became severe for 1wk, or if a patient in either the moderate/severe groups had a >1.5x increase in bilirubin for 1 wk.
    Time Frame First cycle of therapy, 28 days.

    Outcome Measure Data

    Analysis Population Description
    Forty patients were evaluable for dose-limiting toxicity; others came off study prior to the end of Cycle 1 and were not evaluable.
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 12 8 6 4 3 5 2
    Number [Toxicities]
    0
    0
    0
    0
    0
    0
    0
    2. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction
    Description In order to maintain consistent dosing across the hepatic dysfunction groups, the dose recommended for cohorts with greater liver dysfunction could be no greater than the dose for cohorts of lesser dysfunction. In other words, it was assumed that a particular group would not tolerate a dose not tolerated by a group with lesser dysfunction and conversely, will tolerate a dose tolerated by a group with greater dysfunction. If a higher dose was tolerated in a group of greater dysfunction, but not in the group of lesser dysfunction, the lower dose would be recommended for both groups. The highest dose to be explored was no greater than the recommended dose for patients with normal liver function.
    Time Frame First cycle of therapy, 28 days

    Outcome Measure Data

    Analysis Population Description
    Normal liver function patients were not eligible for dose escalation. Twenty-eight patients were evaluable for MTD; others came off study prior to the end of Cycle 1 and were not evaluable.
    Arm/Group Title Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 7 7
    Number [mg/m(2)]
    1000
    NA
    NA
    3. Primary Outcome
    Title Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug
    Description The number of participants experiencing each adverse event by liver function cohort at each dose level. The grade refers to the severity of the Adverse Event. Grade 1 Mild; Grade 2 Moderate; Grade 3 Severe or medically significant but not immediately life-threatening; Grade 4 Life-threatening consequences; Grade 5 Death related to adverse event.
    Time Frame From Cycle 1 Day -7 up to 12 (21-day) cycles

    Outcome Measure Data

    Analysis Population Description
    Total number of evaluable patients per cohort on the indicated dose level; only patients who received study drug were evaluable for assessment of toxicity (some patients were assigned to a dose level but did not receive study drug and are therefore not included).
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 10 15 5 6 9 5
    Grade 2 Anemia
    1
    7.1%
    1
    3.3%
    3
    30%
    0
    0%
    1
    1.4%
    0
    NaN
    1
    NaN
    Grade 3 Anemia
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Anorexia
    1
    7.1%
    0
    0%
    1
    10%
    1
    5.6%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Dyspepsia
    0
    0%
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Dyspnea
    1
    7.1%
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Edema (limbs)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    0
    NaN
    Grade 2 Fatigue
    2
    14.3%
    1
    3.3%
    2
    20%
    1
    5.6%
    1
    1.4%
    1
    NaN
    0
    NaN
    Grade 3 Fatigue
    1
    7.1%
    1
    3.3%
    2
    20%
    0
    0%
    2
    2.8%
    0
    NaN
    0
    NaN
    Grade 2 Hypertension
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Hypophosphatemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    0
    NaN
    Grade 3 Hypophosphatemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 2 Infusion related reaction
    1
    7.1%
    1
    3.3%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 infusion site extravasation
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 INR Increased
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 5 Lung Infection
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Lymphocyte count decreased
    1
    7.1%
    0
    0%
    4
    40%
    1
    5.6%
    1
    1.4%
    0
    NaN
    1
    NaN
    Grade 3 Lymphocyte count decreased
    3
    21.4%
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Nausea
    3
    21.4%
    0
    0%
    3
    30%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 3 Pain in extremity
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Peripheral nerve infection
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Phlebitis
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Rash maculo-papular
    0
    0%
    1
    3.3%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 3 Syncope
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Vomiting
    1
    7.1%
    1
    3.3%
    1
    10%
    0
    0%
    0
    0%
    1
    NaN
    0
    NaN
    Grade 3 Vomiting
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Weight loss
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 White blood cell decreased
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Abdominal distension
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 3 Alanine aminotransferase increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.8%
    0
    NaN
    0
    NaN
    Grade 3 Ascites
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 3 Aspartate aminotransferase increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.8%
    0
    NaN
    0
    NaN
    Grade 2 Blood bilirubin increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 3 Blood bilirubin increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.8%
    0
    NaN
    0
    NaN
    Grade 4 Blood bilirubin increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    1
    NaN
    Grade 2 Chills
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Constipation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 2 Diarrhea
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Fever
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 3 Generalized muscle weakness
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    Grade 2 Infections and infestations - Other
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Malaise
    0
    0%
    0
    0%
    1
    10%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Grade 2 Platelet count decreased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    NaN
    0
    NaN
    4. Primary Outcome
    Title Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax)
    Description Maximum plasma concentrations (Cmax) for belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinistat on Cycle 1 Day-7 and had blood samples successfully collected at the specified timepoints for PK analysis. There were 3 patients with Mild Liver Dysfunction who were not evaluable for Belinostat Cmax.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Belinostat
    21.9
    (8.7)
    26.6
    (9.5)
    22.1
    (5.7)
    25.0
    (7.4)
    Belinostat glucuronide
    80.8
    (27.3)
    90.8
    (19.2)
    67.2
    (33.6)
    72.8
    (28.2)
    Methyl belinostat
    2.10
    (0.94)
    2.99
    (1.15)
    3.26
    (0.75)
    3.35
    (0.90)
    M21
    1.26
    (0.75)
    1.79
    (0.70)
    1.64
    (0.32)
    1.93
    (0.59)
    M24
    2.56
    (0.77)
    2.35
    (0.96)
    1.82
    (0.65)
    1.88
    (0.96)
    M26
    1.68
    (0.71)
    1.80
    (0.64)
    1.83
    (0.52)
    2.24
    (1.65)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat
    Statistical Test of Hypothesis p-Value 0.327
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.096
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat glucuronide
    Statistical Test of Hypothesis p-Value 0.063
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.178
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Methyl belinostat
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.382
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M21
    Statistical Test of Hypothesis p-Value 0.009
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.253
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.278
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26
    Statistical Test of Hypothesis p-Value 0.312
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.098
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf)
    Description Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for belinostat and four metabolites on Cycle 1 Day -7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after start of infusion; and 5, 10, 15, 60, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinostat on Cycle 1 day -7 and had blood samples successfully collected at the specified timepoints for PK analysis. One patient with Mild Liver Dysfunction was not evaluated for Belinostat AUC0-inf.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Belinostat
    719
    (265)
    859
    (270)
    834
    (217)
    1012
    (408)
    Methyl belinostat
    354
    (305)
    483
    (163)
    829
    (471)
    930
    (797)
    M21
    647
    (884)
    840
    (589)
    1058
    (398)
    1295
    (600)
    M24
    1009
    (555)
    916
    (450)
    885
    (514)
    970
    (693)
    M26
    361
    (193)
    396
    (164)
    600
    (292)
    740
    (576)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat
    Statistical Test of Hypothesis p-Value 0.025
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.215
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Methyl belinostat
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.426
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M21
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.337
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24
    Statistical Test of Hypothesis p-Value 0.524
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.061
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.246
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) of Belinostat
    Description Area Under the Plasma Concentration Time Curve Extrapolated to Infinity(AUC0-inf) for Belinostat glucuronide, a Belinostat Metabolite on Cycle 1 Day-7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinostat on Cycle 1 Day -7 and had blood samples successfully collected at the specified timepoints for PK analysis.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Mean (Standard Deviation) [mg*min/mL]
    15.1
    (10.4)
    18.4
    (5.9)
    18.4
    (13.4)
    23.4
    (25.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.548
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.057
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2)
    Description Half-life Period (t1/2) of belinostat and five metabolites on Cycle 1 Day -7 as a function of degree of liver function.
    Time Frame Cycle 1 Day -7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinostat on Cycle 1 Day -7 and had blood samples successfully collected at the specified timepoints for PK analysis.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Belinostat
    118
    (90)
    127
    (57)
    144
    (86)
    157
    (118)
    Belinostat glucuronide
    280
    (55)
    246
    (59)
    238
    (128)
    267
    (134)
    Methyl belinostat
    79.6
    (38.9)
    80.3
    (19.1)
    136.1
    (96.0)
    133
    (98)
    M21
    305
    (337)
    460
    (324)
    486
    (191)
    485
    (205)
    M24
    264
    (106)
    253
    (97)
    223
    (119)
    260
    (133)
    M26
    131
    (115)
    151
    (194)
    177
    (95)
    153
    (83)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat
    Statistical Test of Hypothesis p-Value 0.340
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.091
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat glucuronide
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.216
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Methyl belinostat
    Statistical Test of Hypothesis p-Value 0.005
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.268
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M21
    Statistical Test of Hypothesis p-Value 0.011
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.242
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24
    Statistical Test of Hypothesis p-Value 0.231
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.114
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26
    Statistical Test of Hypothesis p-Value 0.021
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.220
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL)
    Description Clearance (CL) of Belinostat on Cycle 1 Day-7 as a function of degree of liver dysfunction
    Time Frame Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinistat on Cycle 1 Day-7 and had blood samples successfully collected at the specified timepoints for PK analysis.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Mean (Standard Deviation) [mL/min/m^2]
    661
    (346)
    542
    (214)
    505
    (114)
    444
    (137)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.216
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss)
    Description Belinostat Apparent volume of distribution at steady state (Vss) on Cycle 1 Day-7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinistat on Cycle 1 Day-7 and had blood samples successfully collected at the specified timepoints for PK analysis.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Mean (Standard Deviation) [L/m^2]
    30.1
    (16.1)
    25.7
    (17.4)
    38.1
    (40.4)
    29.6
    (15.4)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.531
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.060
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Maximum Plasma Concentrations (Cmax) for the Belinostat Metabolic Pathway
    Description Metabolic ratios of Maximum Plasma Concentrations (Cmax), reported as a geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinistat on Cycle 1 Day-7 and had blood samples successfully collected at the specified timepoints for PK analysis. There were 3 patients with Mild Liver Dysfunction who were not evaluable for Belinostat Cmax.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Belinostat glucuronide/belinostat
    3.78
    (1.47)
    3.57
    (1.47)
    2.88
    (1.54)
    2.85
    (1.51)
    Methyl belinostat/belinostat
    0.0948
    (1.53)
    0.112
    (1.52)
    0.149
    (1.54)
    0.134
    (1.38)
    M21/belinostat
    0.0522
    (1.69)
    0.0642
    (1.50)
    0.0768
    (1.54)
    0.0759
    (1.43)
    M24/belinostat
    0.117
    (1.36)
    0.0870
    (1.61)
    0.0738
    (1.46)
    0.0710
    (1.84)
    M26/belinostat
    0.0752
    (1.48)
    0.0666
    (1.44)
    0.0824
    (1.57)
    0.0806
    (1.64)
    M24/M26
    1.56
    (1.46)
    1.32
    (1.50)
    0.895
    (1.88)
    0.611
    (1.66)
    M26/M21
    1.44
    (1.88)
    0.96
    (1.62)
    1.07
    (1.50)
    1.06
    (1.84)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat glucuronide/belinostat
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.224
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Methyl belinostat/belinostat
    Statistical Test of Hypothesis p-Value 0.011
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.295
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M21/belinostat
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.335
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24/belinostat
    Statistical Test of Hypothesis p-Value 0.037
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.240
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26/belinostat
    Statistical Test of Hypothesis p-Value 0.275
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.127
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24/M26
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.308
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26/M21
    Statistical Test of Hypothesis p-Value 0.095
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.159
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Primary Outcome
    Title Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Metabolic Ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf) for the Belinostat Metabolic Pathway
    Description Metabolic ratios of Area Under the Plasma Concentration Time Curve Extrapolated to Infinity (AUC0-inf), reported as geometric mean (geometric standard deviation), for the belinostat metabolic pathway on Cycle 1 Day-7 as a function of degree of liver dysfunction.
    Time Frame Cycle 1 Day-7 prior to infusion; 15 and 25 minutes after the start of infusion; and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 8, and 24 hours after the end of infusion.

    Outcome Measure Data

    Analysis Population Description
    The number of patients in a given cohort that received Belinistat on Cycle 1 Day-7 and had blood samples successfully collected at the specified timepoints for PK analysis. One patient with Mild Liver Dysfunction was not evaluable for Belinostat AUC0-inf.
    Arm/Group Title Normal Function Mild Dysfunction Moderate Dysfunction Severe Dysfunction
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 25 10 15
    Belinostat glucuronide/belinostat
    18.7
    (1.63)
    21.8
    (1.63)
    18.1
    (1.86)
    17.7
    (1.91)
    Methyl belinostat/belinostat
    0.422
    (1.56)
    0.574
    (1.53)
    0.892
    (1.65)
    0.759
    (1.65)
    M21/belinostat
    0.901
    (3.64)
    0.783
    (2.30)
    1.24
    (1.85)
    1.13
    (2.13)
    M24/belinostat
    1.24
    (1.55)
    1.01
    (1.74)
    0.916
    (1.62)
    0.825
    (1.96)
    M26/belinostat
    0.452
    (1.50)
    0.423
    (1.49)
    0.666
    (1.63)
    0.611
    (1.66)
    M24/M26
    2.74
    (1.72)
    2.35
    (1.59)
    1.38
    (1.91)
    1.35
    (2.38)
    M26/M21
    1.15
    (4.14)
    0.531
    (2.26)
    0.539
    (1.59)
    0.541
    (2.63)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Belinostat glucuronide/belinostat
    Statistical Test of Hypothesis p-Value 0.568
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.055
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments Methyl belinostat/belinostat
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.380
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M21/belinostat
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.315
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24/belinostat
    Statistical Test of Hypothesis p-Value 0.037
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.205
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26/belinostat
    Statistical Test of Hypothesis p-Value 0.033
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value 0.218
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M24/M26
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.309
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Normal Function-Belinostat 1000 mg/m(2), Mild Dysfunction-Belinostat 750 mg/m(2), Mild Dysfunction-Belinostat 1000 mg/m(2), Moderate Dysfunction-Belinostat 500 mg/m(2)
    Comments Effects of liver dysfunction on PK parameter values were evaluated with SPSS 22.0 for Windows (SPSS Inc., Chicago, IL), using the Jonckheere-Terpstra and Kendall's Tau test. Data were considered significantly different when p<0.05.
    Type of Statistical Test Other
    Comments M26/M21
    Statistical Test of Hypothesis p-Value 0.032
    Comments
    Method Jonckheere-Terpstra
    Comments
    Method of Estimation Estimation Parameter Kendall's Tau
    Estimated Value -0.205
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Best Response
    Description Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles of treatment based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per RECIST v1.1 Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum diameters; Stable Disease (SD), neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for Progression of Disease (PD), taking as reference the smallest sum diameters while on study; PD, >=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and an absolute increase of at least 5mm or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
    Time Frame at baseline and every two 21-day cycles of treatment, up to 12 cycles

    Outcome Measure Data

    Analysis Population Description
    Patients were considered evaluable for response if they received at least one cycle of therapy and had their disease re-evaluated with a restaging scan, or exhibited objective disease progression prior ot the end of Cycle 1 but after receiving all Cycle 1 doses.
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 9 8 4 3 6 3
    Partial Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Stable Disease
    6
    42.9%
    3
    10%
    1
    10%
    2
    11.1%
    1
    1.4%
    0
    NaN
    0
    NaN
    Progressive Disease
    8
    57.1%
    6
    20%
    7
    70%
    2
    11.1%
    2
    2.8%
    6
    NaN
    3
    NaN
    13. Secondary Outcome
    Title Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0).
    Description Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
    Time Frame From Cycle 1 Day -7 up to 12 (21-day) cycles.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    Measure Participants 14 12 18 5 5 10 8
    Count of Participants [Participants]
    14
    100%
    11
    36.7%
    14
    140%
    5
    27.8%
    4
    5.6%
    9
    NaN
    6
    NaN

    Adverse Events

    Time Frame From Cycle 1 Day -7 up to 12 (21-day) cycles.
    Adverse Event Reporting Description
    Arm/Group Title Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Arm/Group Description Normal Liver Function was defined as bilirubin ≤Upper Limit of Normal (ULN) and aspartate aminotransferase (AST) ≤ ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Mild Liver Dysfunction was defined as bilirubin >Upper Limit of Normal (ULN) but ≤1.5 x ULN and/or aspartate aminotransferase (AST) > ULN. Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Moderate Liver Dysfunction was defined as bilirubin >1.5 to ≤ 3 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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). Severe Liver Dysfunction was defined as bilirubin >3 but ≤ 10 x ULN and any aspartate aminotransferase (AST). Belinostat: 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).
    All Cause Mortality
    Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/14 (0%) 1/12 (8.3%) 3/18 (16.7%) 1/5 (20%) 1/5 (20%) 6/10 (60%) 4/8 (50%)
    Serious Adverse Events
    Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/14 (35.7%) 6/12 (50%) 7/18 (38.9%) 4/5 (80%) 3/5 (60%) 7/10 (70%) 4/8 (50%)
    Blood and lymphatic system disorders
    Anemia 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Blood and lymphatic system disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Cardiac disorders
    Cardiac arrest 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Myocardial infarction 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 5 0/10 (0%) 0 0/8 (0%) 0
    Gastrointestinal disorders
    Ascites 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Constipation 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 0
    Gastric hemorrhage 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 0
    Gastrointestinal disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Ileus 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Nausea 1/14 (7.1%) 1 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Upper gastrointestinal hemorrhage 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Vomiting 1/14 (7.1%) 1 1/12 (8.3%) 1 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 1
    General disorders
    Chills 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Fatigue 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 5 1/10 (10%) 1 0/8 (0%) 0
    Fever 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Multi-organ failure 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Infections and infestations
    Catheter related infection 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 2 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Device related infection 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hepatic infection 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Infections and infestations - Other, specify 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Lung infection 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 0
    Sepsis 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Upper respiratory infection 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications - Other, specify 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Investigations
    Blood bilirubin increased 0/14 (0%) 0 1/12 (8.3%) 1 1/18 (5.6%) 2 1/5 (20%) 3 0/5 (0%) 0 3/10 (30%) 3 0/8 (0%) 0
    Creatinine increased 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    INR increased 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Metabolism and nutrition disorders
    Anorexia 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Dehydration 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hyperkalemia 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 1/14 (7.1%) 1 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Generalized muscle weakness 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 5 0/10 (0%) 0 0/8 (0%) 0
    Musculoskeletal and connective tissue disorder - Other, specify 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 0/14 (0%) 0 1/12 (8.3%) 1 3/18 (16.7%) 5 0/5 (0%) 0 0/5 (0%) 0 5/10 (50%) 6 3/8 (37.5%) 3
    Nervous system disorders
    Encephalopathy 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Syncope 1/14 (7.1%) 4 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Psychiatric disorders
    Confusion 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Epistaxis 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypoxia 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Pleural effusion 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Vascular disorders
    Hypotension 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Other (Not Including Serious) Adverse Events
    Normal Function-Belinostat 1000 mg/m(2) Mild Dysfunction-Belinostat 750 mg/m(2) Mild Dysfunction-Belinostat 1000 mg/m(2) Moderate Dysfunction-Belinostat 500 mg/m(2) Moderate Dysfunction-Belinostat 750 mg/m(2) Severe Dysfunction-Belinostat 250 mg/m(2) Severe Dysfunction-Belinostat 350 mg/m(2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 14/14 (100%) 11/12 (91.7%) 14/18 (77.8%) 5/5 (100%) 4/5 (80%) 9/10 (90%) 6/8 (75%)
    Blood and lymphatic system disorders
    Anemia 6/14 (42.9%) 71 4/12 (33.3%) 7 5/18 (27.8%) 24 5/5 (100%) 27 2/5 (40%) 3 4/10 (40%) 7 4/8 (50%) 6
    Cardiac disorders
    Atrioventricular block first degree 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Palpitations 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Sinus bradycardia 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Sinus tachycardia 2/14 (14.3%) 4 2/12 (16.7%) 2 3/18 (16.7%) 4 2/5 (40%) 3 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Supraventricular tachycardia 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Eye disorders
    Eye disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 1/5 (20%) 5 0/10 (0%) 0 1/8 (12.5%) 1
    Gastrointestinal disorders
    Abdominal distension 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 1/5 (20%) 3 0/10 (0%) 0 2/8 (25%) 2
    Abdominal pain 2/14 (14.3%) 5 1/12 (8.3%) 1 1/18 (5.6%) 1 2/5 (40%) 4 2/5 (40%) 3 0/10 (0%) 0 2/8 (25%) 2
    Ascites 0/14 (0%) 0 2/12 (16.7%) 2 0/18 (0%) 0 1/5 (20%) 2 1/5 (20%) 3 3/10 (30%) 5 0/8 (0%) 0
    Bloating 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Constipation 1/14 (7.1%) 14 1/12 (8.3%) 1 2/18 (11.1%) 4 1/5 (20%) 2 3/5 (60%) 9 1/10 (10%) 4 1/8 (12.5%) 2
    Diarrhea 2/14 (14.3%) 6 2/12 (16.7%) 4 2/18 (11.1%) 4 5/5 (100%) 5 1/5 (20%) 1 3/10 (30%) 3 1/8 (12.5%) 1
    Dry mouth 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 0
    Dyspepsia 1/14 (7.1%) 28 3/12 (25%) 11 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Dysphagia 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Esophageal hemorrhage 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 1 0/8 (0%) 0
    Flatulence 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Gastroesophageal reflux disease 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hemorrhoidal hemorrhage 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 1/5 (20%) 8 0/10 (0%) 0 0/8 (0%) 0
    Mucositis oral 0/14 (0%) 0 0/12 (0%) 0 2/18 (11.1%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Nausea 10/14 (71.4%) 50 7/12 (58.3%) 33 8/18 (44.4%) 15 5/5 (100%) 13 3/5 (60%) 8 3/10 (30%) 3 3/8 (37.5%) 3
    Rectal pain 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Small intestinal obstruction 1/14 (7.1%) 4 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Vomiting 7/14 (50%) 16 6/12 (50%) 24 7/18 (38.9%) 18 2/5 (40%) 4 2/5 (40%) 4 4/10 (40%) 5 0/8 (0%) 5
    General disorders
    Chills 0/14 (0%) 0 3/12 (25%) 10 1/18 (5.6%) 1 2/5 (40%) 2 1/5 (20%) 2 0/10 (0%) 0 1/8 (12.5%) 1
    Edema limbs 0/14 (0%) 0 1/12 (8.3%) 1 2/18 (11.1%) 2 1/5 (20%) 1 2/5 (40%) 5 4/10 (40%) 8 2/8 (25%) 2
    Edema trunk 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Fatigue 8/14 (57.1%) 106 4/12 (33.3%) 11 7/18 (38.9%) 14 2/5 (40%) 3 3/5 (60%) 7 2/10 (20%) 3 2/8 (25%) 3
    Fever 2/14 (14.3%) 3 3/12 (25%) 11 2/18 (11.1%) 4 3/5 (60%) 16 1/5 (20%) 2 1/10 (10%) 1 1/8 (12.5%) 2
    Flu like symptoms 1/14 (7.1%) 2 1/12 (8.3%) 8 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Infusion related reaction 1/14 (7.1%) 7 1/12 (8.3%) 1 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Infusion site extravasation 1/14 (7.1%) 7 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Injection site reaction 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Malaise 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pain 2/14 (14.3%) 55 1/12 (8.3%) 1 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 2/8 (25%) 2
    Hepatobiliary disorders
    Hepatic failure 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Hepatobiliary disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 3
    Immune system disorders
    Allergic reaction 0/14 (0%) 0 1/12 (8.3%) 2 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Infections and infestations
    Infections and infestations - Other, specify 2/14 (14.3%) 14 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Mucosal infection 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 2/5 (40%) 7 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Peripheral nerve infection 1/14 (7.1%) 1 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pharyngitis 0/14 (0%) 0 1/12 (8.3%) 3 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Phlebitis 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Sinusitis 1/14 (7.1%) 7 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Skin infection 2/14 (14.3%) 4 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Upper respiratory infection 0/14 (0%) 0 1/12 (8.3%) 3 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urinary tract infection 0/14 (0%) 0 1/12 (8.3%) 2 0/18 (0%) 0 1/5 (20%) 2 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Injury, poisoning and procedural complications
    Bruising 1/14 (7.1%) 2 1/12 (8.3%) 8 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Fall 1/14 (7.1%) 12 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 1/5 (20%) 2 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Alanine aminotransferase increased 1/14 (7.1%) 2 6/12 (50%) 19 4/18 (22.2%) 8 3/5 (60%) 6 2/5 (40%) 14 0/10 (0%) 0 3/8 (37.5%) 4
    Alkaline phosphatase increased 1/14 (7.1%) 4 3/12 (25%) 7 9/18 (50%) 17 2/5 (40%) 4 2/5 (40%) 3 3/10 (30%) 5 1/8 (12.5%) 1
    Aspartate aminotransferase increased 2/14 (14.3%) 6 7/12 (58.3%) 27 6/18 (33.3%) 17 2/5 (40%) 4 3/5 (60%) 8 3/10 (30%) 7 4/8 (50%) 7
    Blood bilirubin increased 0/14 (0%) 0 6/12 (50%) 12 9/18 (50%) 18 5/5 (100%) 17 3/5 (60%) 14 4/10 (40%) 10 2/8 (25%) 3
    Creatinine increased 2/14 (14.3%) 6 1/12 (8.3%) 1 3/18 (16.7%) 5 2/5 (40%) 3 1/5 (20%) 3 0/10 (0%) 0 2/8 (25%) 5
    Electrocardiogram QT corrected interval prolonged 2/14 (14.3%) 15 2/12 (16.7%) 2 3/18 (16.7%) 6 2/5 (40%) 3 0/5 (0%) 0 1/10 (10%) 2 0/8 (0%) 0
    INR increased 1/14 (7.1%) 4 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 3 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Lymphocyte count decreased 6/14 (42.9%) 25 3/12 (25%) 4 6/18 (33.3%) 26 5/5 (100%) 11 0/5 (0%) 0 2/10 (20%) 3 3/8 (37.5%) 3
    Lymphocyte count increased 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Neutrophil count decreased 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Platelet count decreased 1/14 (7.1%) 2 6/12 (50%) 24 2/18 (11.1%) 4 2/5 (40%) 2 1/5 (20%) 5 2/10 (20%) 2 0/8 (0%) 2
    Weight loss 1/14 (7.1%) 24 0/12 (0%) 0 1/18 (5.6%) 3 2/5 (40%) 8 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    White blood cell decreased 2/14 (14.3%) 15 0/12 (0%) 0 2/18 (11.1%) 4 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Metabolism and nutrition disorders
    Anorexia 3/14 (21.4%) 43 1/12 (8.3%) 1 6/18 (33.3%) 14 3/5 (60%) 7 2/5 (40%) 6 1/10 (10%) 1 2/8 (25%) 2
    Dehydration 1/14 (7.1%) 1 1/12 (8.3%) 1 0/18 (0%) 0 1/5 (20%) 1 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Glucose intolerance 0/14 (0%) 0 1/12 (8.3%) 16 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypercalcemia 0/14 (0%) 0 2/12 (16.7%) 4 2/18 (11.1%) 4 1/5 (20%) 2 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hyperglycemia 2/14 (14.3%) 74 1/12 (8.3%) 16 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Hyperkalemia 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Hypermagnesemia 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypernatremia 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hyperuricemia 1/14 (7.1%) 2 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypoalbuminemia 4/14 (28.6%) 32 4/12 (33.3%) 7 8/18 (44.4%) 29 1/5 (20%) 1 2/5 (40%) 3 3/10 (30%) 7 1/8 (12.5%) 2
    Hypocalcemia 1/14 (7.1%) 1 1/12 (8.3%) 3 3/18 (16.7%) 4 1/5 (20%) 3 2/5 (40%) 3 1/10 (10%) 2 1/8 (12.5%) 1
    Hypoglycemia 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Hypokalemia 3/14 (21.4%) 5 6/12 (50%) 8 5/18 (27.8%) 9 3/5 (60%) 9 1/5 (20%) 2 2/10 (20%) 6 1/8 (12.5%) 3
    Hypomagnesemia 1/14 (7.1%) 2 2/12 (16.7%) 9 2/18 (11.1%) 8 0/5 (0%) 0 2/5 (40%) 7 0/10 (0%) 7 1/8 (12.5%) 2
    Hyponatremia 4/14 (28.6%) 26 4/12 (33.3%) 6 5/18 (27.8%) 11 3/5 (60%) 12 1/5 (20%) 3 3/10 (30%) 4 3/8 (37.5%) 6
    Hypophosphatemia 2/14 (14.3%) 2 4/12 (33.3%) 27 2/18 (11.1%) 2 3/5 (60%) 6 3/5 (60%) 14 3/10 (30%) 7 2/8 (25%) 2
    Metabolism and nutrition disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 2/14 (14.3%) 5 1/12 (8.3%) 1 0/18 (0%) 0 1/5 (20%) 6 1/5 (20%) 2 1/10 (10%) 2 0/8 (0%) 0
    Bone pain 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 2 0/8 (0%) 0
    Chest wall pain 1/14 (7.1%) 12 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Generalized muscle weakness 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 3 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Muscle weakness lower limb 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Musculoskeletal and connective tissue disorder - Other, specify 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Myalgia 1/14 (7.1%) 3 1/12 (8.3%) 8 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Neck pain 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 6 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pain in extremity 1/14 (7.1%) 24 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 2/14 (14.3%) 5 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Nervous system disorders
    Cognitive disturbance 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Dizziness 3/14 (21.4%) 13 0/12 (0%) 0 2/18 (11.1%) 3 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Dysesthesia 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Dysgeusia 0/14 (0%) 0 1/12 (8.3%) 1 1/18 (5.6%) 2 1/5 (20%) 1 0/5 (0%) 0 1/10 (10%) 2 0/8 (0%) 0
    Encephalopathy 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Extrapyramidal disorder 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Headache 2/14 (14.3%) 3 2/12 (16.7%) 2 2/18 (11.1%) 2 0/5 (0%) 2 1/5 (20%) 1 1/10 (10%) 1 0/8 (0%) 0
    Lethargy 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Paresthesia 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Peripheral sensory neuropathy 0/14 (0%) 0 1/12 (8.3%) 1 1/18 (5.6%) 3 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 2 0/8 (0%) 0
    Somnolence 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Tremor 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Psychiatric disorders
    Anxiety 2/14 (14.3%) 14 1/12 (8.3%) 8 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 1/8 (12.5%) 1
    Confusion 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 3 0/10 (0%) 0 0/8 (0%) 0
    Depression 0/14 (0%) 0 1/12 (8.3%) 1 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Insomnia 2/14 (14.3%) 9 2/12 (16.7%) 9 2/18 (11.1%) 2 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 1/8 (12.5%) 1
    Psychiatric disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 66 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Renal and urinary disorders
    Hematuria 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Proteinuria 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 1/5 (20%) 1 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Renal and urinary disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urinary frequency 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urinary incontinence 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urinary tract pain 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urinary urgency 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 1/14 (7.1%) 7 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Cough 1/14 (7.1%) 2 0/12 (0%) 0 2/18 (11.1%) 2 1/5 (20%) 2 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Dyspnea 1/14 (7.1%) 24 1/12 (8.3%) 1 3/18 (16.7%) 5 1/5 (20%) 2 1/5 (20%) 1 0/10 (0%) 0 2/8 (25%) 2
    Epistaxis 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 9 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hiccups 1/14 (7.1%) 24 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypoxia 0/14 (0%) 0 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pleural effusion 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Postnasal drip 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Productive cough 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Sore throat 1/14 (7.1%) 12 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 0/8 (0%) 0
    Wheezing 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 1/8 (12.5%) 1
    Skin and subcutaneous tissue disorders
    Dry skin 0/14 (0%) 0 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 1/10 (10%) 2 0/8 (0%) 0
    Erythema multiforme 2/14 (14.3%) 23 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hyperhidrosis 1/14 (7.1%) 1 0/12 (0%) 0 1/18 (5.6%) 1 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pain of skin 1/14 (7.1%) 7 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Papulopustular rash 0/14 (0%) 0 1/12 (8.3%) 2 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Pruritus 1/14 (7.1%) 6 2/12 (16.7%) 2 0/18 (0%) 0 2/5 (40%) 4 0/5 (0%) 0 0/10 (0%) 0 2/8 (25%) 2
    Rash acneiform 0/14 (0%) 0 0/12 (0%) 0 1/18 (5.6%) 2 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Rash maculo-papular 1/14 (7.1%) 2 1/12 (8.3%) 1 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Skin and subcutaneous tissue disorders - Other, specify 0/14 (0%) 0 0/12 (0%) 0 2/18 (11.1%) 3 0/5 (0%) 0 1/5 (20%) 1 0/10 (0%) 0 1/8 (12.5%) 1
    Skin induration 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Urticaria 0/14 (0%) 0 1/12 (8.3%) 8 0/18 (0%) 0 0/5 (0%) 0 1/5 (20%) 8 0/10 (0%) 0 0/8 (0%) 0
    Vascular disorders
    Flushing 1/14 (7.1%) 4 3/12 (25%) 12 1/18 (5.6%) 1 0/5 (0%) 0 1/5 (20%) 2 0/10 (0%) 0 0/8 (0%) 0
    Hot flashes 0/14 (0%) 0 0/12 (0%) 0 3/18 (16.7%) 6 0/5 (0%) 0 0/5 (0%) 0 0/10 (0%) 0 0/8 (0%) 0
    Hypertension 3/14 (21.4%) 12 1/12 (8.3%) 1 2/18 (11.1%) 11 3/5 (60%) 15 1/5 (20%) 3 0/10 (0%) 0 3/8 (37.5%) 5
    Hypotension 1/14 (7.1%) 2 0/12 (0%) 0 0/18 (0%) 0 1/5 (20%) 1 2/5 (40%) 3 0/10 (0%) 0 1/8 (12.5%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Naoko Takebe, M.D., Ph.D.
    Organization National Cancer Institute
    Phone 240-781-3398
    Email Takeben@mail.nih.gov
    Responsible Party:
    Naoko Takebe, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01273155
    Other Study ID Numbers:
    • 110060
    • 11-C-0060
    First Posted:
    Jan 10, 2011
    Last Update Posted:
    Mar 26, 2019
    Last Verified:
    Mar 1, 2019