Safety and Pharmacokinetics of Zanubrutinib (BGB-3111) in Healthy Subjects and Those With Impaired Liver Function

A Phase 1, Open-label, Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Zanubrutinib (BGB-3111) in Subjects With Varying Degrees of Hepatic Impairment

This study is designed to evaluate the safety and pharmacokinetics of zanubrutinib in subjects with impaired liver function in comparison with healthy subjects

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency & Healthy Subjects
• Intervention / Treatment: Drug: Zanubrutinib

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33124
      • University of Miami
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and/or female subjects in good health as determined by past medical history, physical examination, vital signs, ECG and laboratory tests at screening.
• Subjects must have a body mass index (BMI) between 18 and 40 kg/m2 to participate at screening.
• Female subject must be of non-childbearing potential, i.e. surgically sterile at least 6 months prior to screening with supportive clinical documentation OR post-menopausal must have no regular menstrual bleeding for at least 12 months prior to inclusion. Menopause will be confirmed by a plasma FSH level of >40 IU/L
• Male subjects must agree to practice 2 highly effective methods of birth control at least one method must be barrier technique.

Additional Inclusion Criteria for Healthy Subjects Only:

• In good health as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests at screening; subjects without diseases/conditions
• Matched with a hepatic impaired patient (mild, moderate or severe, as applicable) using the following criteria: sex, age ±10 years and body mass index (BMI)± 10 kilograms

Additional Inclusion Criteria for Hepatic Impaired Subjects Only:

• History of cirrhosis with supportive documentation (ultrasonography, computed tomography scan, liver biopsy, magnetic resonance imaging, clinical laboratory tests results or physical signs consistent with a clinical diagnosis of liver cirrhosis.
• Child-Pugh Clinical Assessment Score consistent with degree of hepatic impairment.
• Blood pressure of 90 to 155 mmHg (systolic) and 50 to 100 mmHg (diastolic).
• Otherwise considered healthy in general as determined by physical examination findings and laboratory assessments within normal limits.

Exclusion Criteria:

• Subjects with a clinically relevant history or presence of any clinically significant disease.
• History of drug or alcohol abuse within the 12 months prior to dosing.
• A positive human immunodeficiency virus (HIV) Type 1 or 2 test result at screening.
• History of blood donation of 500 mL or more of blood within 2 months prior to screening
• A positive tuberculosis test result.

Additional Exclusion Criteria for Hepatic Impaired Subjects Only:

• Received a liver transplant
• Acute or exacerbating hepatitis
• Active Stage 3 or 4 hepatic encephalopathy
• Previously diagnosed with hepatocellular carcinoma, or a history of cholestatic liver disease or biliary sepsis within the past 2 years.
• Additional Exclusion Criteria for Healthy Subjects Only: A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
• History of any clinically significant chronic and/or active hepatic disease.

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
Experimental: Normal Hepatic Function; Participants with normal hepatic function will be administered a single oral dose of Zanubrutinib (80 mg).	Drug: Zanubrutinib; A single oral dose of 80 mg Zanubrutinib will be administered.
Experimental: Mild Hepatic Impairment; Participants with mild hepatic impairment (Child-Pugh Class A, score of 5 to 6, inclusive) will be administered a single dose of Zanubrutinib (80 mg).	Drug: Zanubrutinib; A single oral dose of 80 mg Zanubrutinib will be administered.
Experimental: Moderate Hepatic Impairment; Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) will be administered a single dose of Zanubrutinib (80 mg).	Drug: Zanubrutinib; A single oral dose of 80 mg Zanubrutinib will be administered.
Experimental: Severe Hepatic Impairment; Participants with severe hepatic impairment (Child-Pugh Class C, score of 10 to 15, inclusive) will be administered a single dose of Zanubrutinib (80 mg).	Drug: Zanubrutinib; A single oral dose of 80 mg Zanubrutinib will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of Zanubrutinib (BGB-3111) to evaluate protocol specified PK parameters	Plasma concentration of Zanubrutinib (BGB-3111) to evaluate Area Under the Plasma Concentration-Time Curve (AUC) of Zanubrutinib	Days 1, 2 & 3
Plasma concentration of Zanubrutinib (BGB-3111) to evaluate protocol specified PK parameters	Plasma concentration of Zanubrutinib (BGB-3111) to evaluate Maximum Observed Plasma Concentration (Cmax) of Zanubrutinib	Days 1, 2 & 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events (AE)	Percentage of Participants with Treatment-Emergent Adverse Events (AE)	up to Day 17

Collaborators and Investigators

• Sponsor: BeiGene

Publications and helpful links

General Publications

• Ou YC, Preston RA, Marbury TC, Tang Z, Novotny W, Tawashi M, Li TK, Sahasranaman S. A phase 1, open-label, single-dose study of the pharmacokinetics of zanubrutinib in subjects with varying degrees of hepatic impairment. Leuk Lymphoma. 2020 Jun;61(6):1355-1363. doi: 10.1080/10428194.2020.1719097. Epub 2020 Feb 7.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2018
• Primary Completion (Actual): October 19, 2018
• Study Completion (Actual): October 19, 2018

Study Registration Dates

• First Submitted: March 7, 2018
• First Submitted That Met QC Criteria: March 13, 2018
• First Posted (Actual): March 14, 2018

Study Record Updates

• Last Update Posted (Actual): April 24, 2020
• Last Update Submitted That Met QC Criteria: April 22, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetics; healthy subjects; Zanubrutinib; hepatic impairment; BGB-3111
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: BGB-3111-107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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