Establish the PK of Belinostat in Patients With Wild-type, Heterozygous, and Homozygous UGT1A1*28 Genotypes

Study Overview
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Brief Summary
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This is a Phase 1, open-label, nonrandomized study to determine the PK profiles of belinostat in patients with relapsed/refractory solid tumors or hematological malignancies who have heterozygous and homozygous UGT1A1*28 genotypes and wild-type UGT1A1 gene. Enrolled patients will be assigned to 1 of 3 cohorts (A, B, or C) based on their UGT1A1 genotype

Detailed Description
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This is a Phase 1, open-label, nonrandomized study to determine the PK profiles of belinostat in patients with relapsed/refractory solid tumors or hematological malignancies who have heterozygous and homozygous UGT1A1*28 genotypes and wild-type UGT1A1 gene. Enrolled patients will be assigned to 1 of 3 cohorts (A, B, or C) based on their UGT1A1 genotype Enrollment into all cohorts will occur simultaneously rather than sequentially. Belinostat will be administered via a 30-minute infusion once daily from Day 1 to Day 5 of one 21-day cycle. Clinical safety will be monitored in each patient. 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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Open-label, Nonrandomized, Phase 1 Study Evaluating Safety and Pharmacokinetics of Belinostat in Patients With Relapsed/Refractory Solid Tumors or Hematological Malignancies in Wild-Type, Heterozygous, and Homozygous UGT1A1*28 Genotypes

Conditions
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Solid Tumors, Hematological Malignancies

Intervention / Treatment
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* Drug: Belinostat IV


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 systemic therapy for the current malignancy and has recovered from any toxicity of the prior therapy at screening. Patient has adequate hematological and hepatic functions. Exclusion Criteria: Patient is taking UGT1A1 inhibitors (eg, atazanavir, gemfibrozil, indinavir, ketoconazole, sorafenib) at screening. Patient has HBV or HCV Patient has a known HIV positive diagnosis. Patient has congestive heart failure Class III/IV 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: Wild Type UGT1A1<br>Cohort A: Open for Enrollment Wild Type UGT1A1, Belinostat IV | Drug: Belinostat IV<br>* Cohort A: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort B: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort C: Belinostat 750mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion.<br>* Other names: Beleodaq;|
| Experimental: Heterozygous UGT1A1*28<br>Cohort B: Closed For Enrollment Heterozygous UGT1A1, Belinostat IV | Drug: Belinostat IV<br>* Cohort A: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort B: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort C: Belinostat 750mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion.<br>* Other names: Beleodaq;|
| Experimental: Homozygous UGT1A1*28<br>Cohort C: Open For Enrollment Homozygous UGT1A1, Belinostat IV | Drug: Belinostat IV<br>* Cohort A: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort B: Belinostat 1000mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion. Cohort C: Belinostat 750mg will be administered once daily on days 1 through 5 of one 21-day cycle via 30-minute IV infusion.<br>* Other names: Beleodaq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma and urine concentrations of belinostat will be measured | PK will be measured for area under the time-concentration curve (AUC), steady state volume of distribution (Vdss),PK will be measured for total body clearance (CLtot),PK will be measured for fraction excreted unchanged (fe), PK will be measured for renal clearance (CLren), PK will be measured for non-renal clearance (CLnonren), PK will be measured for peak concentration (Cmax),and half-life (t1/2) | 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess overall incidence of treatment emergent adverse events (TEAEs) using CTCAE version 4.03 | Assess Safety of belinostat in patients with wild type, heterozygous, and homozygousUGT1A1*28 genotypes | 26 Weeks | 
| Assess any adverse events (AEs) (changes in physical exam or laboratory findings related to study medication dosing | Assess Safety of belinostat in patients with wild type, heterozygous, and homozygousUGT1A1*28 genotypes | 26 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UGT1A1*28, Belinostat, beleodaq, wild type genotypes, heterozygous genotypes, homozygous genotypes