Pharmacokinetic Study of BKM120 in Subjects With Hepatic Impairment

Study Overview
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Brief Summary
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To assess pharamcokinetics, safety and tolerability of a single oral dose of BKM120 in subjects with mild, moderate and severe hepatic impairment

Official Title
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A Phase I, Multicenter, Open-label, Single-dose, Parallel Group Study to Assess the Pharmacokinetics of BKM120 in Subjects With Mild, Moderate and Severe Hepatic Impairmen

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects should be in good health (except for additional/ specific inclusion criteria related to hepatic impaired subjects) as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests of no significance at screening Subjects must weigh at least 45 kg to participate in this study, and must have a body mass index (BMI) from (18.5-35.0 kg/m2) Subjects must be able to communicate well with the investigator, to understand the requirements of the study and agree to use strict contraception for 16 weeks after the last BKM120 dose ---Additional inclusion criteria Group 1 - control healthy subjects Subjects should be matched to the hepatic impaired subjects of group 2 in gender, age (± 10 years), weight (± 20%), and BMI (±5%) ---Additional inclusion criteria Group 2 - hepatic impaired subjects Subjects with physical signs consistent with stable hepatic impairment Child-Pugh Clinical Assessment Score consistent with degree of hepatic impairment (mild , moderate or severe) Subjects must be free of significant medical disorders unrelated to the subject's hepatic disorder as judged by the investigator. Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L Platelet count ≥ 50 x 109 /L serum creatinine ≤ 1.5 x ULN Exclusion Criteria: Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for the hepatic impaired subjects who due to their liver disease may be affected by significant medical problems which require frequent hospitalizations. Invasive systemic fungal infections need to be fully resolved prior to study entry Use of tobacco products within 2 weeks prior to dosing or during the study. Consumption of alcohol within 2 days prior to dosing or during the study Subjects with known ongoing alcohol and or/drug abuse within 1 month prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and/or at baseline Subjects not willing to avoid certain study prohibited food, drink, over the counter medicines and supplements Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. Medical history of cardiac disease and/or clinically significant ECG abnormalities. History of clinically significant hematologic, renal, endocrinologic, pulmonary cardiovascular, hepatic, or allergic disease medically documented Medical history of relevant psychiatric disorders Subjects with Diabetes Mellitus or subjects with glucose levels out of normal range as judge by the investigator History of immunodeficiency diseases, including Human Immunodeficiency Virus (HIV), as confirmed by (HIV-1, HIV-2) test Additional exclusion criteria Group 1 (matched healthy control subjects) History or presence of liver disease or liver injury as indicated by an abnormal liver function profile A positive Hepatitis C test or a positive Hepatitis B surface antigen (HBsAg) Additional exclusion criteria Group 2- hepatic impaired subjects Subjects with clinically significant abnormal findings, not consistent with clinical disease, upon physical examination, ECG or laboratory evaluation Any evidence of progressive liver disease (within the last 4 weeks prior to the screening visit) as indicated by liver transaminases, alkaline phosphatase and GGT or a ≥ 50% worsening of serum bilirubin or prothrombin time Total bilirubin > 6mg/dl Subject has ascites requiring intervention

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mild Hepatic Impaired Group<br>Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - mildly hepatically impaired | Drug: BKM120<br> <br> |
| Experimental: Moderate Hepatic Impaired group<br>Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - moderately hepatically impaired | Drug: BKM120<br> <br> |
| Experimental: Severe Hepatic Impaired Group<br>Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - Severely hepatically impaired | Drug: BKM120<br> <br> |
| Experimental: Control Group<br>Matching healthy control subjects who do not have hepatic impairment and are matched to the hepatic impaired subjects by sex, age, gender and BMI | Drug: BKM120<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of pharmacokinctis (PK) parameter Tmax | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter TMax (time to maximum concentration) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter Cmax | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CMax (maximum concentration) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter AUC-t | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-t (Area under the curve at specified timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter AUC-last | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-last (Area under the curve at last timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter AUC-inf | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-inf (Area under the curve to time infinity) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter CL/F | infMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CL/F (clearance) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter Vz/F | FMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter Vz/F (Volume distribution) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 
| Plasma concentration of PK parameter terminal T 1/2 | Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter terminal T 1/2 (terminal half-life) | predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events severity | Severtiy of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120 | From baseline day-1 to 30 days post dose | 
| Change from baseline in laboratory parameters | Change from baseline in hematological and biochemical laboratory parameters | From baseline day-1 to 30 days post dose | 
| Change from baseline in ECG parameters | Change from baseline in ECG parameters | From baseline day-1 to 30 days post dose | 
| Change from baseline between PK parameters and total bilirubin, prothrombin time or INR and serum albumin | Relationship between PK parameters and baseline hepatic function parameters | From baseline day-1 to 15 days post dose | 
| measurement of plasma binding | Determination of the free fraction of BKM120 in plasmaexpressed weher relevant in terms of unbound drug concentration | From baseline day-1 to 15 days post dose | 
| Adverse events frequency | Frequency of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120 | From baseline day-1 to 30 days post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic impairment, Clinical pharmacology study, Volunteer study