To Evaluate Safety and Pharmacokinetics of Belinostat in Patients Who Have Mild, Moderate and Severe Renal Impairment.

Study Overview
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Brief Summary
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A phase I, open-label, nonrandomized study to determine the PK profile of belinostat in patients with relapsed/refractory solid tumors or hematological malignancies in patients with renal impairment. Eligible patients will be assigned to 1 of 4 cohorts (A, B, C or D) based on their level of renal function (normal, mild, moderate, or severe renal impairment) and receive belinostat dose A for normal or mild renal impairment, and dose B for moderate or severe renal impairment.

Detailed Description
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Study Design: A phase I, open-label, nonrandomized study to determine safety and pharmacokinetics of belinostat in patients with relapsed/refractory solid tumors or hematological malignancies and to determine the PK profiles in patients with renal impairment. Eligible patients will be assigned to 1 of 4 cohorts (A, B, C or D) based on their level of renal function (normal, mild, moderate, or severe renal impairment) and receive belinostat dose A for normal or mild renal impairment, and dose B for moderate or severe renal impairment. Enrollment into all cohorts will occur simultaneously rather than sequentially except in the following instance: Before any patient is enrolled in Cohort D, safety will be assessed for at least 1 patient in Cohort C through the end of Cycle 6. If the patient in Cohort C experiences a toxicity that is at least Grade 3 in severity, Cohort D will proceed at a reduced starting dose. Belinostat will be administered via a 30-minute intravenous (IV) infusion once daily on Days 1 to 5 of a 21-day cycle (for up to 6 cycles). Clinical safety will be monitored in each patient, and up to two dose reductions from the starting dose (not less than 250mg/m^2) is allowed based on pre-defined criteria. If a patient cannot tolerate the reduced dose due to Grade 3 or 4 toxicity, belinostat administration must be discontinued. Dose escalation is not allowed. Blood samples for PK analysis will be collected from Day 1 to Day 3, and urine samples for PK analysis will be collected from Day 1 to Day 4.

Official Title
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An Open-label, Nonrandomized, Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Belinostat in Patients With Relapsed/Refractory Solid Tumors or Hematological Malignancies Who Have Mild, Moderate, and Severe Renal Impairment

Conditions
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Relapsed/Refractory Solid Tumors/Hematological Malignancies

Intervention / Treatment
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* Drug: Belinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is diagnosed with advanced solid tumors or advanced hematological malignancy that is relapsed/refractory, for which no standard salvage therapy exists. Patient must have received at least 1 prior therapy for the current malignancy and has recovered from any toxicity of the prior therapy at screening. Patient has either normal or impaired renal functions. Patient has adequate hematological and hepatic functions. Exclusion Criteria: Patient has acute or progressive renal impairment related to disease or any other cause (eg, toxicity, obstructive uropathy due to retroperitoneal disease, proteinuria, nephrotic syndrome), or requires dialysis. Patient has acute HBV or HCV Patient has known human immunodeficiency virus (HIV) positive diagnosis. Patient has had previous exposure to belinostat.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Normal Renal function, Belinostat IV, Dose A | Drug: Belinostat<br>* Belinostat will be administered once daily on days 1 to 5 of a 21-day cycle (up to 6 cycles) via 30-min. IV infusion.<br>* Other names: Beleodaq;|
| Experimental: Cohort B<br>Mild Impairment, Belinostat IV, Dose A | Drug: Belinostat<br>* Belinostat will be administered once daily on days 1 to 5 of a 21-day cycle (up to 6 cycles) via 30-min. IV infusion.<br>* Other names: Beleodaq;|
| Experimental: Cohort C<br>Moderate Impairment, Belinostat IV, Dose B | Drug: Belinostat<br>* Belinostat will be administered once daily on days 1 to 5 of a 21-day cycle (up to 6 cycles) via 30-min. IV infusion.<br>* Other names: Beleodaq;|
| Experimental: Cohort D<br>Severe Impairment, Belinostat IV, Dose B | Drug: Belinostat<br>* Belinostat will be administered once daily on days 1 to 5 of a 21-day cycle (up to 6 cycles) via 30-min. IV infusion.<br>* Other names: Beleodaq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish pharmacokinetic (PK) profile of belinostat from Area under the Curve (AUC) parameters in patients based on renal impairments in cohorts A,B, C, & D | Area under the plasma drug concentration vs. time curve (AUC) at time 0 to tn will be determined based on specified time points of plasma sample collection from Day 1 to Day 3 of belinostat administration | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat from Volume of Distribution (Vdss) parameters in patients based on renal impairments in cohorts A,B, C, & D | Volume of Distribution (Vdss) proportionality of drug confined to the plasma vs proportion distributed to other tissues will be determined based on total dose of the drug over specified time points of plasma sample collection from Day 1 to Day 3 of belinostat administration | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat from Total Body Clearance (CLtot) parameters in patients based on renal impairments in cohorts A,B, C, & D | Total Body Clearance (CLtot) of the drug will be determined by the specified time points of in the Urine PK sample collection from Day 1 to Day 4 of belinostat administration. | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat from Fraction Excreted (Fe) Unchanged parameters in patients based on renal impairments in cohorts A,B, C, & D | Fraction of the drug that is excreted unchanged (Fe) in the urine will be determined by dividing renal clearance over the total renal clearance based on Urine PK samples collection from specified time points in Day 1 to Day 4 of belinostat administration. | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat from Non Renal Clearance (CLnonren) parameters in patients based on renal impairments in cohorts A,B, C, & D | Non renal clearance (CLnonren) of the drug will be determined by total clearance minus renal clearance based on Urine PK sample collections from specified time points in Day 1 to Day 4 of belinostat administration | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat from peak concentration (Cmax) parameters in patients based on renal impairments in cohorts A,B, C, & D | Peak Concentration (Cmax) rate of absorption will be determined as the highest observed concentration in a concentration-time profile of Plasma PK sample collection from Day 1 to Day 3 of belinostat administration | 26 weeks | 
| Establish pharmacokinetic (PK) profile of belinostat half-life (t1/2) parameters in patients based on renal impairments in cohorts A,B, C, & D | Half-life (t1/2 ) of the drug will be determined by by volume of distribution (Vdss) over clearance (Cl) based on specified time points of plasma sample collection from Day 1 to Day 3 of belinostat administration | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and percentage of patients with any TEAEs by SOC (System Organ Class) and Preferred Term (PT) | safety analysis of patients with onset of treatment emergent related events from Grade 1-5 of the most common TEAE: nausea, fatigue,pyrexia, anemia, vomiting, thrombocytopenia, dypsnea, neutropenia and hypokalemia | First dose of study drug until 30 days after last dose | 
| Number and percentage of patients with any SAEs by SOC (System Organ Class) and Preferred Term (PT) | safety analysis of patients with serious adverse events includes pneumonia, pyrexia, infection,anemia, deep vein thrombosis, blood creatinine increase, multi-organ failure, and pulmonary embolism | First dose of study drug until 30 days after last dose | 
| Number and percentage of patients with any TEAEs related to belinostat by SOC (System Organ Class) and Preferred Term (PT) | safety analysis of patients with new onset of treatment emergent adverse event related to study drug based on pyrexia, thrombocytopenia and blood creatinine increase | First dose of study drug until 30 days after last dose | 
| Number and percentage of patients with any TEAEs causing discontinuation of the study by SOC (System Organ Class ) and PT (Preferred Term) | safety analysis of patients who discontinued treatment based on anemia, fatigue, febrile neutropenia, pneumonia, & multi-organ failure | First dose of study drug until 30 days after last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed/refractory solid tumors, beleodaq, renal impairment, belinostat, hematological malignancies