Interaction Study of Zanubrutinib With Moderate and Strong CYP3A Inhibitors in Participants With B-Cell Malignancies

A Drug-Drug Interaction Study of Zanubrutinib With Moderate and Strong CYP3A Inhibitors in Patients With B-Cell Malignancies

The primary objective of this study was to assess the steady-state zanubrutinib pharmacokinetics (PK) when co-administered with moderate and strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitors.

Study Overview

• Status: Completed
• Conditions: B-cell Malignancies
• Intervention / Treatment: Drug: Zanubrutinib; Drug: Fluconazole; Drug: Diltiazem; Drug: Voriconazole; Drug: Clarithromycin

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
  • Queensland
    • Tugun, Queensland, Australia, 4224
      • John Flynn Private Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Bedford PK, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Frankston, Victoria, Australia, 3199
      • Peninsula Private Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Histologically or cytologically confirmed CLL/SLL, MCL, WM, or MZL.
2. Relapsed or refractory disease after at least 1 prior line of systemic therapy. Participants with MZL are required to have failed an anti-CD20 monoclonal antibody-containing chemotherapy regimen.
3. Baseline Eastern Cooperative Oncology Group performance status of 0 to 1.
4. Meet protocol guidelines for adequate bone marrow, kidney, liver, and cardiac function.

Key Exclusion Criteria:

1. Requirement of chronic treatment with strong and moderate CYP3A inhibitors or inducers or with drugs that are not allowed to be used in combination with diltiazem, clarithromycin, fluconazole, or voriconazole.
2. History of stroke or intracranial hemorrhage (within 6 months of treatment start).
3. Known hypersensitivity or contraindication to zanubrutinib, diltiazem, clarithromycin, fluconazole, or voriconazole.
4. Prior exposure to zanubrutinib or other Bruton tyrosine kinase inhibitor
5. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Zanubrutinib with or without Moderate CYP3A; Cycle 1 (30 days): Participants were administered zanubrutinib at a dose of 320 mg once a day from Day 1 to Day 3; From Day 4 to Day 10, fluconazole was administered once a day at a dose of 400 mg with zanubrutinib at a reduced dose of 80 mg twice a day; On Day 11 and Day 12, zanubrutinib monotherapy was administered at 80 mg twice a day, followed by 320 mg once a day from Day 13 to Day 21; From Day 22 to Day 28, diltiazem was administered once a day at a dose of 180 mg with 80 mg zanubrutinib twice a day; On Day 29 and Day 30, zanubrutinib monotherapy was administered 80 mg twice a day. Cycles 2 to 6 (28 days each cycle): Zanubrutinib 160 mg twice a day or 320 mg once a day.	Drug: Zanubrutinib; Capsules administered at a dose and frequency as specified in the treatment arm; Other Names: BGB-3111; BRUKINSA; Drug: Fluconazole; Capsules administered at a dose and frequency as specified in the treatment arm; Drug: Diltiazem; Capsules administered at a dose and frequency as specified in the treatment arm
Experimental: Arm B: Zanubrutinib with or without Strong CYP3A; Cycle 1 (30 days): Participants were administered zanubrutinib at a dose of 320 mg once a day from Day 1 to Day 3; From Day 4 to Day 10, voriconazole was administered twice a day at a dose of 200 mg (total daily dose of 400 mg) with zanubrutinib at a reduced dose of 80 mg once a day; On Day 11 and Day 12, zanubrutinib monotherapy was administered at 80 mg once a day, followed by 320 mg once a day from Day 13 to Day 21; From Day 22 to Day 28, clarithromycin was administered twice a day at a dose of 250 mg (total daily dose of 500 mg) with 80 mg zanubrutinib once a day; On Day 29 and Day 30, zanubrutinib monotherapy was administered 80 mg once a day. Cycles 2 to 6 (28 days each cycle): Zanubrutinib 160 mg twice a day or 320 mg once a day.	Drug: Zanubrutinib; Capsules administered at a dose and frequency as specified in the treatment arm; Other Names: BGB-3111; BRUKINSA; Drug: Voriconazole; Capsules administered at a dose and frequency as specified in the treatment arm; Drug: Clarithromycin; Capsules administered at a dose and frequency as specified in the treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Arm A: Area Under Plasma Concentration-time Curve up to the Last Measurable Concentration (AUC0-t)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm B: Area Under Plasma Concentration-time Curve up to the Last Measurable Concentration (AUC0-t)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm A: Area Under Plasma Concentration-time Curve From Time 0 Extrapolated to 24 Hours (AUC0-24h)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm B: Area Under Plasma Concentration-time Curve From Time 0 Extrapolated to 24 Hours (AUC0-24h)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm A: Maximum Observed Concentration (Cmax)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm B: Maximum Observed Concentration (Cmax)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm A: Time of the Maximum Observed Concentration (Tmax)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm B: Time of the Maximum Observed Concentration (Tmax)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm A: Apparent Terminal Elimination Half-life (t1/2)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)
Arm B: Apparent Terminal Elimination Half-life (t1/2)	Predose, 0.5, 1, 2, 3, 4, 6, 8 and 10 hours on Cycle 1 Day 3, Day 10, and Day 28 (30-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events (AEs)	Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinical laboratory tests	From the date of first study drug administration to 30 days after last dose (up to approximately 15 months)

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Study Director: Study Director, BeiGene

Publications and helpful links

General Publications

• Tariq B, Ou YC, Stern JC, Mundra V, Wong Doo N, Walker P, Lewis KL, Lin C, Novotny W, Sahasranaman S, Opat S. A phase 1, open-label, randomized drug-drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies. Leuk Lymphoma. 2023 Feb;64(2):329-338. doi: 10.1080/10428194.2022.2150820. Epub 2022 Dec 8.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2020
• Primary Completion (Actual): February 21, 2022
• Study Completion (Actual): February 21, 2022

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 15, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Calcium-Regulating Hormones and Agents; Tyrosine Kinase Inhibitors; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Protein Kinase Inhibitors; Membrane Transport Modulators; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Calcium Channel Blockers; Vasodilator Agents; Cytochrome P-450 CYP3A Inhibitors; Antihypertensive Agents; Cytochrome P-450 CYP2C9 Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Zanubrutinib; Clarithromycin; Diltiazem; Fluconazole; Voriconazole
• Other Study ID Numbers: BGB-3111-113

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No