A Safety, Tolerability, and Pharmacokinetic Study of Tucatinib in Healthy Japanese and Caucasian Subjects

Study Overview
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Brief Summary
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This study is being done to compare the pharmacokinetics (PK) and safety/tolerability of tucatinib in healthy Japanese and Caucasian participants. Three cohorts of healthy Japanese and Caucasian men and women will be admitted to the Clinical Research Unit (CRU) and receive multiple oral doses of tucatinib over 14 days with and without food. Subjects will be in the study for up to 45 days, including the screening period. Due to practical considerations, each cohort will be dosed sequentially (this is not a dose escalation study).

Official Title
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A Phase 1, Open Label, Safety, Tolerability, and Pharmacokinetic Study of Tucatinib (ONT-380) in Healthy Japanese and Caucasian Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index between 18 and 32 kg/m^2 and a total body weight between 50 and 100 kg In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead electrocardiograms, vital signs measurements, or clinical laboratory evaluations Female subjects participating in the study will be of non-childbearing potential. Male subjects will be surgically sterile for at least 90 days or will agree to use contraception during the study and for 90 days after last dose of study drug. Japanese subjects: Must have been born in Japan Must have 2 biological Japanese parents and 4 biological Japanese grandparents as confirmed by interview Must have spent less than 10 years outside of Japan, and has no significant changes in lifestyle, including diet, since leaving Japan Exclusion Criteria: Significant history of metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder Current condition possibly affecting drug absorption History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance History of stomach or intestinal surgery or resection that would potentially alter absorption or excretion of orally administered drugs History of alcoholism or drug/chemical abuse within 2 years of check-in History of regular alcohol consumption exceeding 7 drinks/week for female subjects or 14 drinks/week for male subjects Positive hepatitis panel and/or positive human immunodeficiency (HIV) test Liver function tests, serum creatinine, hemoglobin, or hematocrit values outside of the normal reference range Single 12-lead ECG demonstrating QTcF>450 msec for males or >470 msec for females Participation in a clinical study involving administration of an investigational drug in the past 30 days from last dose or 5 half-lives (whichever is longer) Use of any products known to alter drug absorption, metabolism or elimination processes, including St. John's wort and known strong inhibitors or inducers of CYP3A4 or CYP2C8, within 30 days Use of or intention to use any prescription or nonprescription products, including vitamins, minerals and herbal preparations within 14 days Use of tobacco- or nicotine-containing products within 3 months Receipt of blood products within 2 months Donation of blood from 56 days before the Screening Visit, plasma from 2 weeks before the Screening Visit or platelets from 6 weeks before the Screening Visit Poor peripheral venous access Have previously completed or withdrawn from this study or any other study investigating tucatinib and have previously received the study drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>50 mg twice daily on Days 1-13 and once daily on Day 14 | Drug: Tucatinib<br>* Administered via oral tablet<br>|
| Experimental: Cohort 2<br>150 mg twice daily on Days 1-13 and once daily on Day 14 | Drug: Tucatinib<br>* Administered via oral tablet<br>|
| Experimental: Cohort 3<br>300 mg twice daily on Days 1-13 and once daily on Day 14 | Drug: Tucatinib<br>* Administered via oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) of tucatinib |  | 14 days | 
| Cmax of ONT-993 |  | 14 days | 
| Time of the maximum observed concentration (tmax) of tucatinib |  | 14 days | 
| Tmax of ONT-993 |  | 14 days | 
| AUC from time 0 to the time of last quantifiable concentration (AUClast) of tucatinib |  | 14 days | 
| AUClast of ONT-993 |  | 14 days | 
| AUC from time 0 to 12 hours postdose (AUC0-12hr) of tucatinib |  | 14 days | 
| AUC0-12hr of ONT-993 |  | 14 days | 
| AUC from time 0 extrapolated to infinity (AUC0-inf) of tucatinib |  | 1 day | 
| AUC from time 0 extrapolated to infinity (AUC0-inf) of ONT-993 |  | 1 day | 
| Percentage of AUC0-inf due to extrapolation (%AUCextrap) of tucatinib |  | 1 day | 
| %AUCextrap of ONT-993 |  | 1 day | 
| Apparent total clearance (CL/F) of tucatinib |  | 14 days | 
| Apparent volume of distribution during the terminal phase (Vz/F) of tucatinib |  | 14 days | 
| Metabolite-to-parent molar ratio based on AUC (MRAUC) of ONT-993 |  | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) |  | 17 days |