Evaluation of Hepatic Function Impairment on the Pharmacokinetics of LEE011

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetics (PK), safety and tolerability of a single oral dose of LEE011 in subjects with varying degrees of impaired hepatic function (based on Child-Pugh classification) as compared to demographically-matched control subjects with normal hepatic function.

Official Title
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A Phase I, Open Label, Multi-center, Parallel Cohort, Single Dose Study to Evaluate the Pharmacokinetics of LEE011 in Healthy Subjects With Normal Hepatic Function and Subjects With Impaired Hepatic Function.

Conditions
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Normal Hepatic Function, Impaired Hepatic Function

Intervention / Treatment
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* Drug: LEE011


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Subjects: Male or female (sterile or postmenopausal) subjects between 18-75 (both inclusive) years of age and healthy as determined by absence of clinically significant deviation from normal in medical history, physical examination, vital signs, electrocardiograms, and clinical laboratory determinations. Subjects must have a BMI between 18 kg/m2 and 36 kg/m2 and weight at least 50 kg and no more than 120 kg. Other than hepatic impairment, subjects must be in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, (except for additional inclusion criteria described below). Subjects in Child-Pugh A, B and C cohorts: Additional inclusion criteria Child-Pugh Clinical Assessment Score consistent with degree of hepatic impairment No change in hepatic status at least one month prior to dosing (i.e. worsening of Child-Pugh score). Exclusion Criteria: All Subjects: Subject has received a liver transplant at any time in the past and is on immunosuppressant therapy. History or presence of impaired cardiac function Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism or excretion of drugs Administration of CYP3A4/5 inhibitors or inducers or CYP3A4 substrates with narrow therapeutic windows Administration of medications that prolong the QT interval History of immunodeficiency diseases, including HIV, as confirmed by (HIV-1, HIV-2) test. Participation in another clinical trial within 4 weeks prior to the study drug administration. Subjects with normal hepatic function: Additional exclusion criteria A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. Subjects in Child-Pugh A, B and C cohorts: Additional exclusion criteria Clinical evidence of severe ascites (e.g. requiring regular tapping). Bilirubin > 6 mg/dL

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Hepatic Function<br>Normal hepatic function; matched demography to hepatic impairment cohorts | Drug: LEE011<br>* 400 mg<br>* Other names: Ribociclib;|
| Experimental: Mild Hepatic Impairment<br>Child-Pugh Classification A (score 5-6) | Drug: LEE011<br>* 400 mg<br>* Other names: Ribociclib;|
| Experimental: Moderate Hepatic Impairment<br>Child-Pugh Classification B (score 7-9) | Drug: LEE011<br>* 400 mg<br>* Other names: Ribociclib;|
| Experimental: Severe Hepatic Impairment<br>Child-Pugh Classification C (score 10-15) | Drug: LEE011<br>* 400 mg<br>* Other names: Ribociclib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Pharmacokinetic (PK) profile of a single oral dose of LEE011 in subjects with impaired hepatic function as compared to healthy subjects with normal hepatic function. | PK profile includes the following parameters Tmax, Cmax, AUClast, AUCinf, T1/2, CL/F, Vz/F. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events (AEs) | Safety profile of a single dose of LEE011 in healthy subjects and subjects with varying degrees of hepatic function includes changes observed in physical examination, changes in vital signs, changes in electrocardiograms (ECGs), abnormal laboratory results. | From consent to 28 days post-dose |