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

BeiGene

Status and phase: Completed; Phase 1

Conditions: B-cell Malignancies

Treatments: Drug: Zanubrutinib; Drug: Fluconazole; Drug: Diltiazem; Drug: Clarithromycin; Drug: Voriconazole

Study type: Interventional

Funder types: Industry

Identifiers

NCT04551963

BGB-3111-113

Details and patient eligibility

About

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.

Enrollment: 26 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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26 participants in 2 patient groups

Arm A: Zanubrutinib with or without Moderate CYP3A

Experimental group

Description:

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.

Treatment:

Drug: Diltiazem

Drug: Fluconazole

Drug: Zanubrutinib

Arm B: Zanubrutinib with or without Strong CYP3A

Experimental group

Description:

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.

Treatment:

Drug: Voriconazole

Drug: Clarithromycin

Drug: Zanubrutinib