A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib

Drug-drug Interaction Clinical Trial

Official title:

A Phase 1, Open-Label, Fixed-sequence, 5-part, Drug-drug Interaction Study of Tucatinib to Evaluate the Effects of CYP3A4 and CYP2C8 Inhibition and Induction on the Pharmacokinetics of Tucatinib and to Evaluate the Effects of Tucatinib on the Pharmacokinetics of Substrates of CYP3A4, CYP2C8, CYP2C9, and P-glycoprotein in Healthy Male and Female Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03723395
• Other study ID #: ONT-380-012
• Status: Completed
• Phase: Phase 1
• Start date: September 17, 2018
• Est. completion date: December 28, 2018

Study information

• Verified date: December 2019
• Source: Seattle Genetics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is being done to look at how tucatinib could affect the way other drugs work. This study will look at healthy volunteers and how tucatinib affects their liver enzymes. Liver enzymes can change how drugs work in the body. There are 5 parts to this study. Parts A and C are looking at how the body breaks down tucatinib when there are lower levels of certain liver enzymes. Part B is looking at how the body breaks down tucatinib when there are high levels of certain liver and stomach enzymes. Parts D and E are looking at how tucatinib could change the levels of some liver and stomach enzymes in the body. This will help us know more about how tucatinib should be given to patients.

Description:

This is a fixed-sequence, drug-drug interaction study of tucatinib conducted in 5 parts in healthy subjects. Part A will evaluate the effect of the strong CYP3A4 inhibitor itraconazole on the pharmacokinetics (PK) of tucatinib. Part B will evaluate the effect of rifampin, a strong inducer of CYP3A4 and CYP2C8, on the PK of tucatinib. Part C will evaluate the effect of the strong CYP2C8 inhibitor gemfibrozil on the PK of tucatinib. Part D will evaluate the effects of tucatinib on the PK of substrate probes of the metabolizing enzymes CYP2C8 (repaglinide), CYP2C9 (tolbutamide), and CYP3A4 (midazolam). Part E will evaluate the effect of tucatinib on the PK of a substrate probe of the transporter P-gp (digoxin). Parts A, B, C, D, and E of the study are independent of one another and do not need to be conducted in a particular order.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: December 28, 2018
• Est. primary completion date: December 21, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Body mass index (BMI) between 18 and 32 kg/m^2

• In good health, determined be no clinically significant findings from medical history, physical examination, and screening evaluations

• Female subjects must be of nonchildbearing potential

• Male subjects must agree to use contraception or must be surgically sterile for at least 90 days prior to enrollment

• Able to understand and sign informed consent form

Exclusion Criteria:

• Any condition affecting drug absorption (including stomach or intestinal surgery)

• Significant history of metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder

• History of hypersensitivity, intolerance, or allergy to any drug compounds, food, or other substance (unless approved by Investigator)

• Participation in a clinical study involving an investigational drug within the past 30 days

• Use or intend to any prescription medications within 28 days prior to check in

• Use of tobacco- or nicotine-containing products within 28 days prior to check in

• History of hyperbilirubinemia

• History of alcoholism or drug abuse within 2 years

• 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 virus (HIV) test

Related Conditions & MeSH terms

• Drug-drug Interaction

Intervention

Drug:
• tucatinib
300mg dose, orally administered
• itraconazole
200mg dose
• rifampin
600mg dose
• gemfibrozil
600mg tablets
• repaglinide
1mg dose
• tolbutamide
500mg dose
• midazolam
2mg dose
• digoxin
0.5 mg dose

Locations

Country	Name	City	State
United States	Covance Clinical Research Unit	Dallas	Texas
United States	Covance Clinical Research Unit	Daytona Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Seattle Genetics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the concentration-time curve (AUC) from time 0 to infinity	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	AUC from time 0 to the time of the last quantifiable concentration	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	Percentage extrapolation in AUC	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	Maximum observed concentration	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	Time of maximum observed concentration	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	Apparent terminal elimination half-life	PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)	Up to 22 days
Primary	Apparent total clearance	PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).	Up to 22 days
Primary	Apparent volume of distribution	PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).	Up to 22 days
Primary	Metabolite-to-parent ratio based on AUC	PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)	Up to 22 days
Secondary	Incidence of adverse events (AEs)	Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Incidence of laboratory abnormalities	Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	12-lead electrocardiogram (ECG) assessment	PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Vital signs measurements	Oral temperature. Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Vital signs measurements	Respiratory rate. Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Vital signs measurements	Blood pressure (systolic and diastolic). Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Vital signs measurements	Heart rate. Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	Physical examinations	Incidence of AEs resulting from clinically significant findings in examination of general appearance, skin, thorax/lungs, cardiovascular system, and abdomen. Parts A, B, C, D, and E (all)	Up to 58 days
Secondary	AUC within a dosing interval	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	AUC from time 0 to infinity	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 8 days
Secondary	AUC from time 0 to the time of the last quantifiable concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Percentage extrapolation in AUC	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Maximum observed concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Time of maximum observed concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Apparent terminal elimination half-life	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Apparent total clearance	PK parameter of tucatinib; Parts D and E only	Up to 8 days
Secondary	Apparent total clearance at steady state	PK parameter of tucatinib; Parts D and E only	Up to 15 days
Secondary	Apparent volume of distribution	PK parameter of tucatinib; Parts D and E only	Up to 8 days
Secondary	Apparent volume of distribution at steady state	PK parameter of tucatinib; Parts D and E only	Up to 15 days
Secondary	Accumulation ratio	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Secondary	Metabolite-to-parent ratio based on AUC	PK parameter of ONT-993; Parts D and E only	Up to 15 days