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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: Tucatinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Tustin, California, United States, 92780
      • Orange County Research Center
  • Florida
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • NOCCR Knoxville and Volunteer Research Group
  • Texas
    • San Antonio, Texas, United States, 78215
      • Texas Liver Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2018
• Primary Completion (Actual): May 7, 2019
• Study Completion (Actual): May 7, 2019

Study Registration Dates

• First Submitted: October 24, 2018
• First Submitted That Met QC Criteria: October 25, 2018
• First Posted (Actual): October 29, 2018

Study Record Updates

• Last Update Posted (Actual): May 20, 2019
• Last Update Submitted That Met QC Criteria: May 16, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tucatinib
• Other Study ID Numbers: ONT-380-009

Drug and device information, study documents

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