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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: INC280

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine Clinical Resea Oncology
    • Miami, Florida, United States, 33142
      • Clinical Pharmacology of Miami, LLC.
    • Orlando, Florida, United States, 32086
      • Orlando Clinical Research Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • DaVita Clinical Research
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: NovartisPharmaceuticals, NovartisPharmaceuticals

Publications and helpful links

General Publications

• Chen X, Cui X, Pognan N, Quinlan M, Kapoor S, Rahmanzadeh G, Giovannini M, Marbury TC. Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study. Br J Clin Pharmacol. 2022 Jan;88(1):91-102. doi: 10.1111/bcp.14929. Epub 2021 Jun 18.

Helpful Links

• Results for CINC280A2106 can be found on the Novartis Clinical Trial Results website

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2015
• Primary Completion (Actual): August 14, 2017
• Study Completion (Actual): September 12, 2017

Study Registration Dates

• First Submitted: June 9, 2015
• First Submitted That Met QC Criteria: June 16, 2015
• First Posted (Estimate): June 17, 2015

Study Record Updates

• Last Update Posted (Actual): December 10, 2020
• Last Update Submitted That Met QC Criteria: December 8, 2020
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Non-Cancer; hepatic impairment,; INC280,; Oral cMET Inhibitor,
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: CINC280A2106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No