Clinical trial NCT03723395: A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug-drug Interaction
Lead sponsor: Seagen Inc.
Sponsor class: INDUSTRY
First posted: 2018-10-29
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Area under the concentration-time curve (AUC) from time 0 to infinity
timeFrame: Up to 22 days
measure: AUC from time 0 to the time of the last quantifiable concentration
timeFrame: Up to 22 days
measure: Percentage extrapolation in AUC
timeFrame: Up to 22 days
measure: Maximum observed concentration
timeFrame: Up to 22 days
measure: Time of maximum observed concentration
timeFrame: Up to 22 days
measure: Apparent terminal elimination half-life
timeFrame: Up to 22 days
measure: Apparent total clearance
timeFrame: Up to 22 days
measure: Apparent volume of distribution
timeFrame: Up to 22 days
measure: Metabolite-to-parent ratio based on AUC
timeFrame: Up to 22 days
Secondary outcomes:
measure: Incidence of adverse events (AEs)
timeFrame: Up to 58 days
measure: Incidence of laboratory abnormalities
timeFrame: Up to 58 days
measure: 12-lead electrocardiogram (ECG) assessment
timeFrame: Up to 58 days
measure: Vital signs measurements
timeFrame: Up to 58 days
measure: Vital signs measurements
timeFrame: Up to 58 days
measure: Vital signs measurements
timeFrame: Up to 58 days
measure: Vital signs measurements
timeFrame: Up to 58 days
measure: Physical examinations
timeFrame: Up to 58 days
measure: AUC within a dosing interval
timeFrame: Up to 15 days
measure: AUC from time 0 to infinity
timeFrame: Up to 8 days
measure: AUC from time 0 to the time of the last quantifiable concentration
timeFrame: Up to 15 days
measure: Percentage extrapolation in AUC
timeFrame: Up to 15 days
measure: Maximum observed concentration
timeFrame: Up to 15 days
measure: Time of maximum observed concentration
timeFrame: Up to 15 days
measure: Apparent terminal elimination half-life
timeFrame: Up to 15 days
measure: Apparent total clearance
timeFrame: Up to 8 days
measure: Apparent total clearance at steady state
timeFrame: Up to 15 days
measure: Apparent volume of distribution
timeFrame: Up to 8 days
measure: Apparent volume of distribution at steady state
timeFrame: Up to 15 days
measure: Accumulation ratio
timeFrame: Up to 15 days
measure: Metabolite-to-parent ratio based on AUC
timeFrame: Up to 15 days
Other outcomes:
Locations:
city: Daytona Beach
country: United States
facility: Covance Clinical Research Unit
state: Florida
city: Dallas
country: United States
facility: Covance Clinical Research Unit
state: Texas
Study officials:
affiliation: Seagen Inc.
name: Alex Vo, PhD
role: STUDY_DIRECTOR
References:
citation: Topletz-Erickson A, Lee A, Rustia EL, Sun H, Mayor JG, Abdulrasool LI, Walker L, Endres CJ. Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers. Clin Pharmacokinet. 2022 Oct;61(10):1417-1426. doi: 10.1007/s40262-022-01144-z. Epub 2022 Aug 6.