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

Study Overview
=================
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.

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

Conditions
-----------------
Drug-drug Interaction

Intervention / Treatment
-----------------
* Drug: tucatinib
* Drug: itraconazole
* Drug: rifampin
* Drug: gemfibrozil
* Drug: repaglinide
* Drug: tolbutamide
* Drug: midazolam
* Drug: digoxin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Tucatinib plus Itraconazole | Drug: tucatinib<br>* 300mg dose, orally administered<br>Drug: itraconazole<br>* 200mg dose<br>|
| Experimental: Part B<br>Tucatinib plus Rifampin | Drug: tucatinib<br>* 300mg dose, orally administered<br>Drug: rifampin<br>* 600mg dose<br>|
| Experimental: Part C<br>Tucatinib plus Gemfibrozil | Drug: tucatinib<br>* 300mg dose, orally administered<br>Drug: gemfibrozil<br>* 600mg tablets<br>|
| Experimental: Part D<br>Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam | Drug: tucatinib<br>* 300mg dose, orally administered<br>Drug: repaglinide<br>* 1mg dose<br>Drug: tolbutamide<br>* 500mg dose<br>Drug: midazolam<br>* 2mg dose<br>|
| Experimental: Part E<br>Tucatinib plus Digoxin | Drug: tucatinib<br>* 300mg dose, orally administered<br>Drug: digoxin<br>* 0.5 mg dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Parts A, B, C, D, and E (all) | Up to 58 days | 
| Incidence of laboratory abnormalities | Parts A, B, C, D, and E (all) | Up to 58 days | 
| 12-lead electrocardiogram (ECG) assessment | PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all) | Up to 58 days | 
| Vital signs measurements | Oral temperature. Parts A, B, C, D, and E (all) | Up to 58 days | 
| Vital signs measurements | Respiratory rate. Parts A, B, C, D, and E (all) | Up to 58 days | 
| Vital signs measurements | Blood pressure (systolic and diastolic). Parts A, B, C, D, and E (all) | Up to 58 days | 
| Vital signs measurements | Heart rate. Parts A, B, C, D, and E (all) | Up to 58 days | 
| 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 | 
| AUC within a dosing interval | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| AUC from time 0 to infinity | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 8 days | 
| 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 | 
| Percentage extrapolation in AUC | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| Maximum observed concentration | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| Time of maximum observed concentration | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| Apparent terminal elimination half-life | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| Apparent total clearance | PK parameter of tucatinib; Parts D and E only | Up to 8 days | 
| Apparent total clearance at steady state | PK parameter of tucatinib; Parts D and E only | Up to 15 days | 
| Apparent volume of distribution | PK parameter of tucatinib; Parts D and E only | Up to 8 days | 
| Apparent volume of distribution at steady state | PK parameter of tucatinib; Parts D and E only | Up to 15 days | 
| Accumulation ratio | PK parameters of tucatinib and ONT-993; Parts D and E only | Up to 15 days | 
| Metabolite-to-parent ratio based on AUC | PK parameter of ONT-993; Parts D and E only | Up to 15 days |