A Safety Study of Tucatinib in Healthy and Hepatically-Impaired Subjects

Study Overview
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Brief Summary
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The investigators are doing this study to find out if tucatinib is safe for patients with liver problems. This study will look at participants with mild, moderate, and severe liver problems. For each participant with liver problems who takes part, a matching healthy participant who is of similar age, similar body mass index (BMI), and of the same sex will also take part. The study will look at how the drug affects healthy participants compared to participants with liver problems.

Detailed Description
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This study is being conducted to provide information to develop dosing recommendations for tucatinib in subjects with hepatic impairment. The current study will be carried out in subjects with hepatic impairment according to 3 different Child-Pugh (CP) categories (Mild, Moderate, and Severe impairment), and in matched-control healthy subjects. The minimum number of matched-control healthy subjects will be enrolled in order to ensure that each hepatically-impaired subject has a healthy match. Each matched-control healthy subject will be enrolled following the enrollment of a Mild and/or Moderate and/or Severe hepatic impairment subject and will be matched by age (+/- 10 years), by BMI (+/- 20%), and by sex to the enrolled hepatic impairment subject(s). Each healthy subject may be matched with up to 1 subject within each hepatic impairment group. Based on these criteria, with 3 cohorts of 8 hepatically-impaired subjects enrolled in the study, the number of healthy control subjects required to be enrolled will be at least 8 and not more than 24.

Official Title
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An Open-label, Non-randomized, Single-dose, Parallel-group, Safety, Tolerability, and Pharmacokinetic Study of Tucatinib Administered at 300 mg in Fasted, Hepatically-impaired Male and Female Subjects and Fasted Matched-control Healthy Subjects

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In good general health, except for additional inclusion criteria related to subjects with hepatic impairment Within body mass index (BMI) range of 18 to 37 kg/m^2 (inclusive) Males capable of fathering a child must agree to use contraception from check in through 90 days after dose administration Females must be of nonchildbearing potential Able to understand and provide written informed consent Able to comply with all study procedures, including the 3-night stay at the clinical site and follow-up phone call Healthy subjects only: matched to subjects with Mild and/or Moderate and/or Severe hepatic impairment in sex, age (+/- 10 years), and BMI (+/- 20%). Hepatic impairment subjects only: considered to have Mild, Moderate, or Severe hepatic impairment that has been clinically stable for at least 1 month Hepatic impairment patients only: currently on stable medication regimen Exclusion Criteria: Subjects with at-rest vital signs outside of the following ranges: heart rate (40 to 120 bpm), systolic blood pressure (90 to 150 mmHg), diastolic blood pressure (40 to 95 mmHg) Clinically significant abnormal laboratory values or physical examination findings Evidence/history of long QT syndrome Use of drugs/substances known to be inhibitors or inducers of CYP3A4 or CYP2C8 enzyme within 30 days Consumption of foods or beverages containing poppy seeds, grapefruit, or Seville oranges within 7 days of check-in Consumption of alcohol-, citric acid-, caffeine-, or xanthine-containing foods or beverages within 48 hours prior to check in Subjects with known alcohol and/or drug abuse within 1 month prior to check in History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance History of congenital nonhemolytic hyperbilirubinemia History of stomach or intestinal surgery that would potentially alter absorption and/or excretion of orally administered drugs Prior doses of tucatinib Prior dose of any investigational drug within the past 30 days or 5 half-lives

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 |
| --- | --- |
| Active Comparator: Group 1: Healthy<br>Match-controlled healthy subjects with normal hepatic function | Drug: Tucatinib<br>* 300mg oral single dose<br>|
| Experimental: Group 2: Mild Hepatic Impairment<br>Subjects with Mild hepatic impairment (Child-Pugh Class A, score of 5 or 6) | Drug: Tucatinib<br>* 300mg oral single dose<br>|
| Experimental: Group 3: Moderate Hepatic Impairment<br>Subjects with Moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9) | Drug: Tucatinib<br>* 300mg oral single dose<br>|
| Experimental: Group 4: Severe Hepatic Impairment<br>Subjects with Severe hepatic impairment (Child-Pugh Class C, score of 10 to 14) | Drug: Tucatinib<br>* 300mg oral single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) | Pharmacokinetic (PK) endpoint of tucatinib | Up to 48 hours | 
| Time of maximum observed concentration (Tmax) | PK endpoint of tucatinib | Up to 48 hours | 
| Area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC[0-t]) | PK endpoint of tucatinib | Up to 48 hours | 
| AUC from time 0 to infinity (AUC[0-inf]) | PK endpoint of tucatinib | Up to 48 hours | 
| Percentage extrapolation for AUC (%AUCextrap) | PK endpoint of tucatinib | 48 hours | 
| Apparent terminal elimination rate constant (λz) | PK endpoint of tucatinib | Up to 48 hours | 
| Apparent terminal elimination half-life (t½) | PK endpoint of tucatinib | Up to 48 hours | 
| Apparent total clearance | PK endpoint of tucatinib | Up to 48 hours | 
| Apparent volume of distribution during the terminal phase | PK endpoint of tucatinib | Up to 48 hours | 
| Mean residence time (MRT) | PK endpoint of tucatinib | Up to 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | PK endpoint of ONT-993 | Up to 48 hours | 
| Tmax | PK endpoint of ONT-993 | Up to 48 hours | 
| AUC[0-t] | PK endpoint of ONT-993 | Up to 48 hours | 
| (AUC[0-inf]) | PK endpoint of ONT-993 | Up to 48 hours | 
| %AUCextrap | PK endpoint of ONT-993 | Up to 48 hours | 
| λz | PK endpoint of ONT-993 | Up to 48 hours | 
| t½ | PK endpoint of ONT-993 | Up to 48 hours | 
| MRT | PK endpoint of ONT-993 | Up to 48 hours | 
| Incidence of adverse events (AEs) | As determined by assessment of AEs, clinical laboratory tests, physical examinations, vital signs measurements, and 12-lead ECG | Up to 9 days |