Effects of Tucatinib on Cardiac Repolarization in Healthy Participants

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: tucatinib; Drug: placebo; Drug: moxifloxacin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Clinical Research Unit - Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Seagen Inc.
• Investigators: Study Director: Joseph Woolery, PharmD, BCOP, Seagen Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2018
• Primary Completion (Actual): March 11, 2019
• Study Completion (Actual): March 11, 2019

Study Registration Dates

• First Submitted: December 10, 2018
• First Submitted That Met QC Criteria: December 13, 2018
• First Posted (Actual): December 17, 2018

Study Record Updates

• Last Update Posted (Actual): April 12, 2019
• Last Update Submitted That Met QC Criteria: April 11, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Moxifloxacin; Tucatinib
• Other Study ID Numbers: ONT-380-011

Drug and device information, study documents

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