Lymphomas, Neoplasms
Conditions
Keywords
Histone Deacetylase Inhibitor, Liver Dysfunction, Pharmacokinetics, UGT1A1 Polymorphisms, Solid Tumor, Cancer, Lymphoma
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.
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.
Interventions
DRUGBelinostat
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).
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 110 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Function 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). | 14 |
| Mild Dysfunction 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). | 30 |
| Moderate Dysfunction 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). | 10 |
| Severe Dysfunction 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). | 18 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Change in liver function/no longer eval. | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Died during Cycle 1 | 0 | 0 | 1 | 1 | 0 | 2 | 2 |
| Overall Study | Off study prior to C1/due to toxicity | 0 | 0 | 2 | 0 | 0 | 0 | 1 |
| Overall Study | Off study trmt prior to end of C1/PD | 2 | 3 | 8 | 0 | 0 | 2 | 3 |
| Overall Study | Withdrew during C1/refused further trmt | 0 | 0 | 1 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Normal Function | Mild Dysfunction | Moderate Dysfunction | Severe Dysfunction | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 8 Participants | 4 Participants | 6 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 22 Participants | 6 Participants | 12 Participants | 47 Participants |
| Age, Continuous | 65 years | 59 years | 63.5 years | 57.5 years | 61 years |
| Eastern Cooperative Oncology Group Performance Status Grade 0 | 4 Participants | 2 Participants | 3 Participants | 1 Participants | 10 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1 | 9 Participants | 26 Participants | 5 Participants | 13 Participants | 53 Participants |
| Eastern Cooperative Oncology Group Performance Status Grade 2 | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 29 Participants | 9 Participants | 15 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 2 Participants | 2 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 19 Participants | 8 Participants | 15 Participants | 52 Participants |
| Region of Enrollment United States | 14 participants | 30 participants | 10 participants | 18 participants | 72 participants |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 3 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Male | 8 Participants | 19 Participants | 7 Participants | 10 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 1 / 12 | 3 / 18 | 1 / 5 | 1 / 5 | 6 / 10 | 4 / 8 |
| other Total, other adverse events | 14 / 14 | 11 / 12 | 14 / 18 | 5 / 5 | 4 / 5 | 9 / 10 | 6 / 8 |
| serious Total, serious adverse events | 5 / 14 | 6 / 12 | 7 / 18 | 4 / 5 | 3 / 5 | 7 / 10 | 4 / 8 |
Outcome results
Primary
Dose Limiting Toxicity (DLTs)
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.
Population: Forty patients were evaluable for dose-limiting toxicity; others came off study prior to the end of Cycle 1 and were not evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Dose Limiting Toxicity (DLTs) | 0 Toxicities |
Primary
Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction | 1000 mg/m(2) |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction | NA mg/m(2) |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Maximum Tolerated Dose (MTD) of Belinostat According to Degree of Liver Dysfunction | NA mg/m(2) |
Primary
Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 3 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 3 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 1 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 2 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 1 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 1 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 1 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 1 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 1 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 4 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 3 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 2 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 3 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 2 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 1 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 1 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 1 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 1 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 1 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 1 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Fatigue | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Generalized muscle weakness | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Blood bilirubin increased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Weight loss | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 INR Increased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Vomiting | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Alanine aminotransferase increased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 infusion site extravasation | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fatigue | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 4 Blood bilirubin increased | 1 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Vomiting | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Anemia | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Syncope | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Abdominal distension | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspnea | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infections and infestations - Other | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Chills | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Rash maculo-papular | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Infusion related reaction | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Phlebitis | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anorexia | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Hypophosphatemia | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Anemia | 1 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Constipation | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Peripheral nerve infection | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Dyspepsia | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Pain in extremity | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 White blood cell decreased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Malaise | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypophosphatemia | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Diarrhea | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Nausea | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Aspartate aminotransferase increased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Lymphocyte count decreased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Hypertension | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 3 Ascites | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Fever | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Lymphocyte count decreased | 1 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Blood bilirubin increased | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 5 Lung Infection | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Edema (limbs) | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants Experiencing Adverse Events Considered to be at Least Possibly Related to the Study Drug | Grade 2 Platelet count decreased | 0 Participants |
Primary
Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax)
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat | 21.9 µg/mL | Standard Deviation 8.7 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat glucuronide | 80.8 µg/mL | Standard Deviation 27.3 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Methyl belinostat | 2.10 µg/mL | Standard Deviation 0.94 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M21 | 1.26 µg/mL | Standard Deviation 0.75 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M24 | 2.56 µg/mL | Standard Deviation 0.77 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M26 | 1.68 µg/mL | Standard Deviation 0.71 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M26 | 1.80 µg/mL | Standard Deviation 0.64 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M21 | 1.79 µg/mL | Standard Deviation 0.7 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat | 26.6 µg/mL | Standard Deviation 9.5 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Methyl belinostat | 2.99 µg/mL | Standard Deviation 1.15 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat glucuronide | 90.8 µg/mL | Standard Deviation 19.2 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M24 | 2.35 µg/mL | Standard Deviation 0.96 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat glucuronide | 67.2 µg/mL | Standard Deviation 33.6 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Methyl belinostat | 3.26 µg/mL | Standard Deviation 0.75 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M21 | 1.64 µg/mL | Standard Deviation 0.32 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M26 | 1.83 µg/mL | Standard Deviation 0.52 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M24 | 1.82 µg/mL | Standard Deviation 0.65 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat | 22.1 µg/mL | Standard Deviation 5.7 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M24 | 1.88 µg/mL | Standard Deviation 0.96 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M26 | 2.24 µg/mL | Standard Deviation 1.65 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat glucuronide | 72.8 µg/mL | Standard Deviation 28.2 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | M21 | 1.93 µg/mL | Standard Deviation 0.59 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Belinostat | 25.0 µg/mL | Standard Deviation 7.4 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of a Single-dose Belinostat (400 mg/m^2)) According to Degree of Liver Dysfunction: Maximum Plasma Concentrations (Cmax) | Methyl belinostat | 3.35 µg/mL | Standard Deviation 0.9 |
Comparison: 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.p-value: 0.327Jonckheere-Terpstra
Comparison: 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.p-value: 0.063Jonckheere-Terpstra
Comparison: 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.p-value: <0.001Jonckheere-Terpstra
Comparison: 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.p-value: 0.009Jonckheere-Terpstra
Comparison: 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.p-value: 0.004Jonckheere-Terpstra
Comparison: 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.p-value: 0.312Jonckheere-Terpstra
Primary
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)
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | 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) | M24 | 1009 µg*min/mL | Standard Deviation 555 |
| Normal Function-Belinostat 1000 mg/m(2) | 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) | Methyl belinostat | 354 µg*min/mL | Standard Deviation 305 |
| Normal Function-Belinostat 1000 mg/m(2) | 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) | M26 | 361 µg*min/mL | Standard Deviation 193 |
| Normal Function-Belinostat 1000 mg/m(2) | 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) | M21 | 647 µg*min/mL | Standard Deviation 884 |
| Normal Function-Belinostat 1000 mg/m(2) | 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) | Belinostat | 719 µg*min/mL | Standard Deviation 265 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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) | M21 | 840 µg*min/mL | Standard Deviation 589 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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) | M24 | 916 µg*min/mL | Standard Deviation 450 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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) | M26 | 396 µg*min/mL | Standard Deviation 164 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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) | Methyl belinostat | 483 µg*min/mL | Standard Deviation 163 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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) | Belinostat | 859 µg*min/mL | Standard Deviation 270 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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) | M21 | 1058 µg*min/mL | Standard Deviation 398 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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) | Belinostat | 834 µg*min/mL | Standard Deviation 217 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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) | Methyl belinostat | 829 µg*min/mL | Standard Deviation 471 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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) | M24 | 885 µg*min/mL | Standard Deviation 514 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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) | M26 | 600 µg*min/mL | Standard Deviation 292 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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) | M24 | 970 µg*min/mL | Standard Deviation 693 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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) | Methyl belinostat | 930 µg*min/mL | Standard Deviation 797 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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) | Belinostat | 1012 µg*min/mL | Standard Deviation 408 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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) | M21 | 1295 µg*min/mL | Standard Deviation 600 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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) | M26 | 740 µg*min/mL | Standard Deviation 576 |
Comparison: 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.p-value: 0.025Jonckheere-Terpstra
Comparison: 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.p-value: <0.001Jonckheere-Terpstra
Comparison: 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.p-value: <0.001Jonckheere-Terpstra
Comparison: 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.p-value: 0.524Jonckheere-Terpstra
Comparison: 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.p-value: 0.01Jonckheere-Terpstra
Primary
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
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | 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 | 15.1 mg*min/mL | Standard Deviation 10.4 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | 18.4 mg*min/mL | Standard Deviation 5.9 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | 18.4 mg*min/mL | Standard Deviation 13.4 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | 23.4 mg*min/mL | Standard Deviation 25.6 |
Comparison: 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.p-value: 0.548Jonckheere-Terpstra
Primary
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL)
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) | 661 mL/min/m^2 | Standard Deviation 346 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) | 542 mL/min/m^2 | Standard Deviation 214 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) | 505 mL/min/m^2 | Standard Deviation 114 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Clearance (CL) | 444 mL/min/m^2 | Standard Deviation 137 |
Comparison: 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.p-value: 0.023Jonckheere-Terpstra
Primary
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2)
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M24 | 264 min | Standard Deviation 106 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat | 118 min | Standard Deviation 90 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat glucuronide | 280 min | Standard Deviation 55 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Methyl belinostat | 79.6 min | Standard Deviation 38.9 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M21 | 305 min | Standard Deviation 337 |
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M26 | 131 min | Standard Deviation 115 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat glucuronide | 246 min | Standard Deviation 59 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Methyl belinostat | 80.3 min | Standard Deviation 19.1 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M21 | 460 min | Standard Deviation 324 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M24 | 253 min | Standard Deviation 97 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat | 127 min | Standard Deviation 57 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M26 | 151 min | Standard Deviation 194 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M21 | 486 min | Standard Deviation 191 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat | 144 min | Standard Deviation 86 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M26 | 177 min | Standard Deviation 95 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat glucuronide | 238 min | Standard Deviation 128 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Methyl belinostat | 136.1 min | Standard Deviation 96 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M24 | 223 min | Standard Deviation 119 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Methyl belinostat | 133 min | Standard Deviation 98 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat | 157 min | Standard Deviation 118 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M21 | 485 min | Standard Deviation 205 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M24 | 260 min | Standard Deviation 133 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | Belinostat glucuronide | 267 min | Standard Deviation 134 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Half-Life (t1/2) | M26 | 153 min | Standard Deviation 83 |
Comparison: 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.p-value: 0.34Jonckheere-Terpstra
Comparison: 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.p-value: 0.023Jonckheere-Terpstra
Comparison: 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.p-value: 0.005Jonckheere-Terpstra
Comparison: 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.p-value: 0.011Jonckheere-Terpstra
Comparison: 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.p-value: 0.231Jonckheere-Terpstra
Comparison: 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.p-value: 0.021Jonckheere-Terpstra
Primary
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
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 18.7 ratio | Standard Deviation 1.63 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M24/M26 | 2.74 ratio | Standard Deviation 1.72 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M26/belinostat | 0.452 ratio | Standard Deviation 1.5 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.422 ratio | Standard Deviation 1.56 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M26/M21 | 1.15 ratio | Standard Deviation 4.14 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M21/belinostat | 0.901 ratio | Standard Deviation 3.64 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M24/belinostat | 1.24 ratio | Standard Deviation 1.55 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M24/M26 | 2.35 ratio | Standard Deviation 1.59 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M24/belinostat | 1.01 ratio | Standard Deviation 1.74 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M21/belinostat | 0.783 ratio | Standard Deviation 2.3 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M26/belinostat | 0.423 ratio | Standard Deviation 1.49 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M26/M21 | 0.531 ratio | Standard Deviation 2.26 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.574 ratio | Standard Deviation 1.53 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 21.8 ratio | Standard Deviation 1.63 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M24/belinostat | 0.916 ratio | Standard Deviation 1.62 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 18.1 ratio | Standard Deviation 1.86 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.892 ratio | Standard Deviation 1.65 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M21/belinostat | 1.24 ratio | Standard Deviation 1.85 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M26/belinostat | 0.666 ratio | Standard Deviation 1.63 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M24/M26 | 1.38 ratio | Standard Deviation 1.91 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M26/M21 | 0.539 ratio | Standard Deviation 1.59 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M21/belinostat | 1.13 ratio | Standard Deviation 2.13 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M26/M21 | 0.541 ratio | Standard Deviation 2.63 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M24/M26 | 1.35 ratio | Standard Deviation 2.38 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.759 ratio | Standard Deviation 1.65 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 17.7 ratio | Standard Deviation 1.91 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M26/belinostat | 0.611 ratio | Standard Deviation 1.66 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M24/belinostat | 0.825 ratio | Standard Deviation 1.96 |
Comparison: 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.p-value: 0.568Jonckheere-Terpstra
Comparison: 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.p-value: <0.001Jonckheere-Terpstra
Comparison: 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.p-value: 0.001Jonckheere-Terpstra
Comparison: 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.p-value: 0.037Jonckheere-Terpstra
Comparison: 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.p-value: 0.033Jonckheere-Terpstra
Comparison: 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.p-value: 0.001Jonckheere-Terpstra
Comparison: 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.p-value: 0.032Jonckheere-Terpstra
Primary
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
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 3.78 ratio | Standard Deviation 1.47 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M24/M26 | 1.56 ratio | Standard Deviation 1.46 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M26/belinostat | 0.0752 ratio | Standard Deviation 1.48 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.0948 ratio | Standard Deviation 1.53 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M26/M21 | 1.44 ratio | Standard Deviation 1.88 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M21/belinostat | 0.0522 ratio | Standard Deviation 1.69 |
| Normal Function-Belinostat 1000 mg/m(2) | 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 | M24/belinostat | 0.117 ratio | Standard Deviation 1.36 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M24/M26 | 1.32 ratio | Standard Deviation 1.5 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M24/belinostat | 0.0870 ratio | Standard Deviation 1.61 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M21/belinostat | 0.0642 ratio | Standard Deviation 1.5 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M26/belinostat | 0.0666 ratio | Standard Deviation 1.44 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | M26/M21 | 0.96 ratio | Standard Deviation 1.62 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.112 ratio | Standard Deviation 1.52 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 3.57 ratio | Standard Deviation 1.47 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M24/belinostat | 0.0738 ratio | Standard Deviation 1.46 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 2.88 ratio | Standard Deviation 1.54 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.149 ratio | Standard Deviation 1.54 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M21/belinostat | 0.0768 ratio | Standard Deviation 1.54 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M26/belinostat | 0.0824 ratio | Standard Deviation 1.57 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M24/M26 | 0.895 ratio | Standard Deviation 1.88 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | 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 | M26/M21 | 1.07 ratio | Standard Deviation 1.5 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M21/belinostat | 0.0759 ratio | Standard Deviation 1.43 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M26/M21 | 1.06 ratio | Standard Deviation 1.84 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M24/M26 | 0.611 ratio | Standard Deviation 1.66 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | Methyl belinostat/belinostat | 0.134 ratio | Standard Deviation 1.38 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | Belinostat glucuronide/belinostat | 2.85 ratio | Standard Deviation 1.51 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M26/belinostat | 0.0806 ratio | Standard Deviation 1.64 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | 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 | M24/belinostat | 0.0710 ratio | Standard Deviation 1.84 |
Comparison: 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.p-value: 0.023Jonckheere-Terpstra
Comparison: 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.p-value: 0.011Jonckheere-Terpstra
Comparison: 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.p-value: 0.004Jonckheere-Terpstra
Comparison: 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.p-value: 0.037Jonckheere-Terpstra
Comparison: 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.p-value: 0.275Jonckheere-Terpstra
Comparison: 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.p-value: 0.002Jonckheere-Terpstra
Comparison: 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.p-value: 0.095Jonckheere-Terpstra
Primary
Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss)
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) | 30.1 L/m^2 | Standard Deviation 16.1 |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) | 25.7 L/m^2 | Standard Deviation 17.4 |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) | 38.1 L/m^2 | Standard Deviation 40.4 |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Pharmacokinetics (PK) of Single-dose Belinostat (400 mg/m^2) According to Degree of Liver Dysfunction: Volume of Distribution at Steady State (Vss) | 29.6 L/m^2 | Standard Deviation 15.4 |
Comparison: 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.p-value: 0.531Jonckheere-Terpstra
Secondary
Best Response
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Best Response | Progressive Disease | 8 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Best Response | Stable Disease | 6 Participants |
| Normal Function-Belinostat 1000 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Best Response | Stable Disease | 3 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Best Response | Progressive Disease | 6 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Best Response | Stable Disease | 1 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Best Response | Progressive Disease | 7 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Best Response | Stable Disease | 2 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Best Response | Progressive Disease | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Best Response | Progressive Disease | 2 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Best Response | Stable Disease | 1 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Best Response | Progressive Disease | 6 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Best Response | Stable Disease | 0 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Best Response | Partial Response | 0 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Best Response | Progressive Disease | 3 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Best Response | Stable Disease | 0 Participants |
Secondary
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0).
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Function-Belinostat 1000 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 14 Participants |
| Mild Dysfunction-Belinostat 750 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 11 Participants |
| Mild Dysfunction-Belinostat 1000 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 14 Participants |
| Moderate Dysfunction-Belinostat 500 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 5 Participants |
| Moderate Dysfunction-Belinostat 750 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 4 Participants |
| Severe Dysfunction-Belinostat 250 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 9 Participants |
| Severe Dysfunction-Belinostat 350 mg/m(2) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | 6 Participants |