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Completed

NCT Number: NCT03723395

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

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.

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Key information

Conditions

Drug-drug Interaction

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Covance Clinical Research Unit, Daytona Beach, Florida, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Tucatinib

Drug

300mg dose, orally administered

Itraconazole

Drug

200mg dose

Rifampin

Drug

600mg dose

Gemfibrozil

Drug

600mg tablets

repaglinide

Drug

1mg dose

tolbutamide

Drug

500mg dose

midazolam

Drug

2mg dose

Digoxin

Drug

0.5 mg dose

Primary outcomes

  1. Area under the concentration-time curve (AUC) from time 0 to infinity

    Time frame: Up to 22 days

    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)

  2. AUC from time 0 to the time of the last quantifiable concentration

    Time frame: Up to 22 days

    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)

  3. Percentage extrapolation in AUC

    Time frame: Up to 22 days

    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)

  4. Maximum observed concentration

    Time frame: Up to 22 days

    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)

  5. Time of maximum observed concentration

    Time frame: Up to 22 days

    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)

  6. Apparent terminal elimination half-life

    Time frame: Up to 22 days

    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)

  7. Apparent total clearance

    Time frame: Up to 22 days

    PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).

  8. Apparent volume of distribution

    Time frame: Up to 22 days

    PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).

  9. Metabolite-to-parent ratio based on AUC

    Time frame: Up to 22 days

    PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)

Secondary outcomes

  1. Incidence of adverse events (AEs)

    Time frame: Up to 58 days

    Parts A, B, C, D, and E (all)

  2. Incidence of laboratory abnormalities

    Time frame: Up to 58 days

    Parts A, B, C, D, and E (all)

  3. 12-lead electrocardiogram (ECG) assessment

    Time frame: Up to 58 days

    PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all)

  4. Vital signs measurements

    Time frame: Up to 58 days

    Oral temperature. Parts A, B, C, D, and E (all)

  5. Vital signs measurements

    Time frame: Up to 58 days

    Respiratory rate. Parts A, B, C, D, and E (all)

  6. Vital signs measurements

    Time frame: Up to 58 days

    Blood pressure (systolic and diastolic). Parts A, B, C, D, and E (all)

  7. Vital signs measurements

    Time frame: Up to 58 days

    Heart rate. Parts A, B, C, D, and E (all)

  8. Physical examinations

    Time frame: Up to 58 days

    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)

  9. AUC within a dosing interval

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  10. AUC from time 0 to infinity

    Time frame: Up to 8 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  11. AUC from time 0 to the time of the last quantifiable concentration

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  12. Percentage extrapolation in AUC

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  13. Maximum observed concentration

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  14. Time of maximum observed concentration

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  15. Apparent terminal elimination half-life

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  16. Apparent total clearance

    Time frame: Up to 8 days

    PK parameter of tucatinib; Parts D and E only

  17. Apparent total clearance at steady state

    Time frame: Up to 15 days

    PK parameter of tucatinib; Parts D and E only

  18. Apparent volume of distribution

    Time frame: Up to 8 days

    PK parameter of tucatinib; Parts D and E only

  19. Apparent volume of distribution at steady state

    Time frame: Up to 15 days

    PK parameter of tucatinib; Parts D and E only

  20. Accumulation ratio

    Time frame: Up to 15 days

    PK parameters of tucatinib and ONT-993; Parts D and E only

  21. Metabolite-to-parent ratio based on AUC

    Time frame: Up to 15 days

    PK parameter of ONT-993; Parts D and E only

Sponsors and collaborators

Lead sponsor

Seagen Inc.

Industry

Registry information

Official study 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

Important dates

Study start
2018
Primary completion
2018
Study completion
2018
First posted
Oct 29, 2018
Registry last updated
Dec 18, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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