Clinical trial NCT02474537: INC280 in Healthy Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: hepatic impairment,
INC280,
Oral cMET Inhibitor,
Non-Cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-06-17
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: AUClast of INC280
timeFrame: Up to 72 hours post-dose
measure: AUCinf of INC280
timeFrame: Up to 72 hours post-dose
measure: Cmax of INC280
timeFrame: Up to 72 hours post-dose
measure: Tmax of INC280
timeFrame: Up to 72 hours post-dose
measure: T1/2 of INC280
timeFrame: Up to 72 hours post-dose
measure: CL/F of INC280
timeFrame: Up to 72 hours post-dose
measure: Vz/F of INC280
timeFrame: Up to 72 hours post-dose
Secondary outcomes:
measure: Adverse events based on the CTCAE v4.03 grade (severity) and frequency, and other safety data (e.g., ECG, laboratory results)
timeFrame: Up to 30 days
measure: Unbound fraction and AUClast based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and AUCinf based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and Cmax based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and Tmax based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and T1/2 based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and CL/F based on unbound concentration in plasma
timeFrame: 3 hours post-dose
measure: Unbound fraction and Vz/F based on unbound concentration in plasma
timeFrame: 3 hours post-dose
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Miller School of Medicine Clinical Resea Oncology
state: Florida
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, LLC.
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: Minneapolis
country: United States
facility: DaVita Clinical Research
state: Minnesota
city: Durham
country: United States
facility: Duke University Medical Center Oncology
state: North Carolina
Study officials:
affiliation: NovartisPharmaceuticals
name: NovartisPharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.