INC280 in Healthy Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function

Study Overview
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Brief Summary
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This is a phase I, multi-center, open-label, single oral dose, parallel group study to evaluate the pharmacokinetics and safety of INC280 in non-cancer subjects with impaired hepatic function and non-cancer subjects with normal hepatic function.The study population will be healthy male and postmenopausal or sterile female subjects who meet all of the inclusion and none of the exclusion criteria. Subjects will be assigned to groups according to their hepatic function: normal (Group 1), mild (Group 2), moderate (Group 3), and severe (Group 4) impairment. This study consists of a two-staged design with interim analysis. In Stage 1, subjects in Groups 1, 2 and 3 will be enrolled. Upon completion of Stage 1, an interim analysis will be conducted. Depending on the results of the analysis, either the study will conclude with no further enrollment or Stage 2 will commence with enrollment of Group 4. A minimum of 6 evaluable subjects per group will be enrolled.Once enrolled in the study, participants will be confined to the facility for 4 days, given a single dose of INC280 and monitored for pharmacokinetic and safety assessments.

Official Title
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An Open Label, Single-dose, Multi-center, Parallel-group, Two-staged Study to Evaluate Pharmacokinetics of Oral cMET Inhibitor INC280 in Non-Cancer Subjects With Impaired Hepatic Function and Non-Cancer Subjects With Normal Hepatic Function

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: INC280


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (all groups): Female subjects must be postmenopausal or sterile Good health, as determined by absence of clinically significant findings in medical history, physical examination, vital signs, and ECGs, unless it is consistent with known clinical disease for hepatic impairment subjects Adequate organ function and normal laboratory tests, unless it is consistent with known clinical disease for hepatic impairment subjects Body Mass Index (BMI) of 18- 36 kg/m2, with body weight ≥ 50 kg Inclusion Criteria (hepatic impairment groups): Confirmed liver disease Stable comorbidities are allowed as long as generally considered healthy Subjects with hepatic impairment must meet the following laboratory values: Aspartate transaminase (AST) ≤ 5 x ULN Alanine transaminase (ALT) ≤ 5 x ULN Total bilirubin ≤ 3 x ULN (≤ 5 x XULN for subjects with severe hepatic impairment [group 4]) Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min Platelets > 50 x 10^9/L. Subjects with severe hepatic impairment can be enrolled if platelet count > 40 x 10^9/L Exclusion Criteria (all groups): History or presence of clinically significant ECG abnormalities or clinically significant cardiovascular disease Immunocompromised subjects, including HIV Use of drugs known to affect CYP3A4 Use of QT-prolonging drugs Use of any other drugs, unless they are required to treat the hepatic impairment subject's disease Use of proton pump inhibitors (PPI) medications within 7 days prior to dosing and during the current study until last day of confinement Exclusion Criteria (normal hepatic function group): A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result Exclusion Criteria (hepatic impairment groups): Active Grade 3 or 4 hepatic encephalopathy within 4 weeks of study entry Clinical evidence of severe ascites Ascites requiring paracentesis within 3 weeks prior to dosing Other protocol-defined inclusion/exclusion criteria may apply.

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>Subjects with normal hepatic function | Drug: INC280<br>* Single 200 mg dose INC280<br>|
| Experimental: Mild hepatic impairment<br>Subjects with mild hepatic impairment | Drug: INC280<br>* Single 200 mg dose INC280<br>|
| Experimental: Moderate hepatic impairment<br>Subjects with moderate hepatic impairment | Drug: INC280<br>* Single 200 mg dose INC280<br>|
| Experimental: Severe hepatic impairment<br>Subjects with severe hepatic impairment | Drug: INC280<br>* Single 200 mg dose INC280<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| AUCinf of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| Cmax of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| Tmax of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| T1/2 of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| CL/F of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 
| Vz/F of INC280 | INC280 pharmacokinetic parameters | Up to 72 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events based on the CTCAE v4.03 grade (severity) and frequency, and other safety data (e.g., ECG, laboratory results) | Safety | Up to 30 days | 
| Unbound fraction and AUClast based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and AUCinf based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and Cmax based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and Tmax based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and T1/2 based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and CL/F based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 
| Unbound fraction and Vz/F based on unbound concentration in plasma | To assess the plasma protein binding of INC280 | 3 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatic impairment,, INC280,, Oral cMET Inhibitor,, Non-Cancer