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

NCT04551963 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: BGB-3111-113
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 7

Brief Summary

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.

Conditions

B-cell Malignancies

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (1)

• Number of Participants Experiencing Adverse Events (AEs)

  From the date of first study drug administration to 30 days after last dose (up to approximately 15 months)

Study Arms (2)

Arm A: Zanubrutinib with or without Moderate CYP3A

EXPERIMENTAL

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; Drug: Fluconazole; Drug: Diltiazem

Arm B: Zanubrutinib with or without Strong CYP3A

EXPERIMENTAL

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; Drug: Voriconazole; Drug: Clarithromycin

Interventions

Zanubrutinib DRUG

Capsules administered at a dose and frequency as specified in the treatment arm

Also known as: BGB-3111, BRUKINSA

Arm A: Zanubrutinib with or without Moderate CYP3A; Arm B: Zanubrutinib with or without Strong CYP3A

Fluconazole DRUG

Capsules administered at a dose and frequency as specified in the treatment arm

Arm A: Zanubrutinib with or without Moderate CYP3A

Diltiazem DRUG

Capsules administered at a dose and frequency as specified in the treatment arm

Arm A: Zanubrutinib with or without Moderate CYP3A

Voriconazole DRUG

Capsules administered at a dose and frequency as specified in the treatment arm

Arm B: Zanubrutinib with or without Strong CYP3A

Clarithromycin DRUG

Capsules administered at a dose and frequency as specified in the treatment arm

Arm B: Zanubrutinib with or without Strong CYP3A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed CLL/SLL, MCL, WM, or MZL.
• 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.
• Baseline Eastern Cooperative Oncology Group performance status of 0 to 1.
• Meet protocol guidelines for adequate bone marrow, kidney, liver, and cardiac function.

You may not qualify if:

• 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.
• History of stroke or intracranial hemorrhage (within 6 months of treatment start).
• Known hypersensitivity or contraindication to zanubrutinib, diltiazem, clarithromycin, fluconazole, or voriconazole.
• Prior exposure to zanubrutinib or other Bruton tyrosine kinase inhibitor
• 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.

Sponsors & Collaborators

• BeiGene: lead

Study Sites (7)

Concord Repatriation General Hospital

Concord, New South Wales, 2139, Australia

Location

John Flynn Private Hospital

Tugun, Queensland, 4224, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Flinders Medical Centre

Bedford PK, South Australia, 5042, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Peninsula Private Hospital

Frankston, Victoria, 3199, Australia

Location

Linear Clinical Research

Nedlands, Western Australia, 6009, Australia

Location

Related Publications (1)

• 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.

  PMID: 36480811 RESULT

MeSH Terms

Interventions

zanubrutinib; Fluconazole; Diltiazem; Voriconazole; Clarithromycin

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: BeiGene

clinicaltrials@beigene.com

+1-877-828-5568

Study Officials

• Study Director

  BeiGene

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2020
• First Posted: September 16, 2020
• Study Start: November 15, 2020
• Primary Completion: February 21, 2022
• Study Completion: February 21, 2022
• Last Updated: October 26, 2024
• Results First Posted: November 27, 2023

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

AU (7)