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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02474537

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

6.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Impairment	Drug: INC280	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 12, 2015

Actual Primary Completion Date :

Aug 14, 2017

Actual Study Completion Date :

Sep 12, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Normal hepatic function Subjects with normal hepatic function	Drug: INC280 Single 200 mg dose INC280
Experimental: Mild hepatic impairment Subjects with mild hepatic impairment	Drug: INC280 Single 200 mg dose INC280
Experimental: Moderate hepatic impairment Subjects with moderate hepatic impairment	Drug: INC280 Single 200 mg dose INC280
Experimental: Severe hepatic impairment Subjects with severe hepatic impairment	Drug: INC280 Single 200 mg dose INC280

Outcome Measures

Primary Outcome Measures

AUClast of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
AUCinf of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
Cmax of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
Tmax of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
T1/2 of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
CL/F of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters
Vz/F of INC280 [Up to 72 hours post-dose]
INC280 pharmacokinetic parameters

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Miller School of Medicine Clinical Resea Oncology	Miami	Florida	United States	33136
2	Clinical Pharmacology of Miami, LLC.	Miami	Florida	United States	33142
3	Orlando Clinical Research Center	Orlando	Florida	United States	32086
4	DaVita Clinical Research	Minneapolis	Minnesota	United States	55404
5	Duke University Medical Center Oncology	Durham	North Carolina	United States	27710