Effects of Tucatinib on Cardiac Repolarization in Healthy Participants

Study Overview
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Brief Summary
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This study is looking at how the study drug, tucatinib, affects the heart. Tucatinib is being studied as a possible treatment for breast cancer. This study will recruit healthy volunteers. There are 3 parts in the study. Each volunteer will be in all 3 parts. One part will be to take the study drug, the second part will be to take a placebo (pill with no medicine), and the third part will be to take moxifloxacin. The volunteers will only know what part of the study they are in when they take moxifloxacin. For the study drug and placebo parts, volunteers will take 2 pills by mouth for 5 days. For the moxifloxacin part, volunteers will take 1 pill by mouth for 1 day.

Detailed Description
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This study will evaluate the effects of a steady state therapeutic dose of tucatinib on QTcF (QT interval corrected for heart rate using Fridericia's method) in healthy individuals. In this design, study treatment will be dosed in 3 sequential treatment periods: Treatment A: Oral doses of 300mg tucatinib for 5 days Treatment B: Oral doses of matching placebo for tucatinib for 5 days Treatment C: A single oral dose of 400 mg of moxifloxacin Patients will be randomized based on 2-Williams-square design to 1 of 6 treatment sequences to maintain the study blind for tucatinib and placebo.

Official Title
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A Phase 1, Randomized, Partially Double-Blind, Placebo- and Positive-controlled Study to Evaluate the Effect of Tucatinib on Cardiac Repolarization in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: tucatinib
* Drug: placebo
* Drug: moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Good health, determined by medical history, physical examination, 12-lead ECG, vital signs measurements, or clinical laboratory evaluations Body mass index (BMI) between 18 and 32 kg/m^2 Body weight between 50 and 100 kg Female subjects must be of non-childbearing potential Male subjects must agree to use contraception or be surgically sterile for at least 90 days Exclusion Criteria: Significant history of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder Any condition affecting drug absorption History of hypersensitivity or allergy to any drug compound, food, or other substance Single 12-lead ECG demonstrating QTcF >450 msec for males or >470 msec for females, or history/evidence of long QT syndrome History of alcoholism or drug/chemical abuse within 2 years Use of prescription products within 30 days prior to check in Use of nonprescription products within 14 days prior to check in, including vitamins, minerals, and herbal supplements Use of tobacco- or nicotine-containing products within 3 months prior to check in

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence ABC<br>tucatinib + placebo + moxifloxacin (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|
| Experimental: Treatment Sequence CAB<br>moxifloxacin + tucatinib + placebo (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|
| Experimental: Treatment Sequence BCA<br>placebo + moxifloxacin + tucatinib (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|
| Experimental: Treatment Sequence CBA<br>moxifloxacin + placebo + tucatinib (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|
| Experimental: Treatment Sequence ACB<br>tucatinib + moxifloxacin + placebo (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|
| Experimental: Treatment Sequence BAC<br>placebo + tucatinib + moxifloxacin (administered in sequential treatment periods) | Drug: tucatinib<br>* 300mg oral dose<br>Drug: placebo<br>* Matching placebo for tucatinib<br>Drug: moxifloxacin<br>* 400mg single oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-corrected change-from-baseline in QTcF | QTcF is the QT interval corrected for heart rate using Fridericia's method. | Up to 32 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in heart rate (HR) |  | Up to 32 days | 
| Change from baseline in QTcF |  | Up to 32 days | 
| Change from baseline in PR interval |  | Up to 32 days | 
| Change from baseline in QRS interval |  | Up to 32 days | 
| Placebo-corrected change from baseline in HR |  | Up to 32 days | 
| Placebo-corrected change from baseline in PR interval |  | Up to 32 days | 
| Placebo-corrected change from baseline in QRS interval |  | Up to 32 days | 
| • Number of participants who experience increases in absolute QTcF interval values >450 msec |  | Up to 32 days | 
| • Number of participants who experience QTcF interval changes from predose baseline of >30msec |  | Up to 32 days | 
| • Number of participants who experience an increase in PR interval from predose baseline of >25% to a PR >200 msec |  | Up to 32 days | 
| • Number of participants who experience an increase in QRS interval from predose baseline >25% to a QRS >120 msec |  | Up to 32 days | 
| • Number of participants who experience a decrease in heart rate >25% from baseline to a heart rate <50 |  | Up to 32 days | 
| • Number of participants who experience an increase in heart rate >25% from baseline to a heart rate >100 |  | Up to 32 days | 
| Frequency of treatment-emergent changes of T-wave morphology and U-wave presence |  | Up to 32 days | 
| Area under the concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC[0-inf]) for tucatinib and ONT-993 |  | Up to 26 days | 
| AUC from time 0 to the time of the last quantifiable concentration for tucatinib and ONT-993 |  | Up to 26 days | 
| Percentage of AUC[0-inf] due to extrapolation for tucatinib and ONT-993 |  | Up to 26 days | 
| Maximum observed concentration for tucatinib and ONT-993 |  | Up to 26 days | 
| Time of maximum observed concentration for tucatinib and ONT-993 |  | Up to 26 days | 
| Apparent terminal elimination half-life for tucatinib and ONT-993 |  | Up to 26 days | 
| Apparent total clearance for tucatinib |  | Up to 26 days | 
| Apparent volume of distribution during the terminal phase for tucatinib |  | Up to 26 days | 
| Metabolic ratio based on AUC for ONT-993 |  | Up to 26 days | 
| Incidence of adverse events (AEs) |  | Up to 32 days |