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.
Sex: All, ages: 18 Years to any
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.
Participant flow
| Milestone | Arm A: Zanubrutinib With or Without Moderate CYP3A | Arm B: Zanubrutinib With or Without Strong CYP3A |
|---|
| Started | 13 | 13 |
| Completed | 11 | 12 |
| Not completed | 2 | 1 |
Outcome results
- Arm A: Area Under Plasma Concentration-time Curve up to the Last Measurable Concentration (AUC0-t) (Primary), Geometric mean, h*ng/mL: Arm A: Zanubrutinib With or Without Moderate CYP3A 1899.32 +/- 44.95
- Arm B: Area Under Plasma Concentration-time Curve up to the Last Measurable Concentration (AUC0-t) (Primary), Geometric mean, h*ng/mL: Arm B: Zanubrutinib With or Without Strong CYP3A 1550.40 +/- 49.20
- Arm A: Area Under Plasma Concentration-time Curve From Time 0 Extrapolated to 24 Hours (AUC0-24h) (Primary), Geometric mean, h*ng/mL: Arm A: Zanubrutinib With or Without Moderate CYP3A 2035.32 +/- 46.97
- Arm B: Area Under Plasma Concentration-time Curve From Time 0 Extrapolated to 24 Hours (AUC0-24h) (Primary), Geometric mean, h*ng/mL: Arm B: Zanubrutinib With or Without Strong CYP3A 1578.12 +/- 49.53
- Arm A: Maximum Observed Concentration (Cmax) (Primary), Geometric mean, ng/mL: Arm A: Zanubrutinib With or Without Moderate CYP3A 520.78 +/- 39.18
- Arm B: Maximum Observed Concentration (Cmax) (Primary), Geometric mean, ng/mL: Arm B: Zanubrutinib With or Without Strong CYP3A 428.88 +/- 43.56
- Arm A: Time of the Maximum Observed Concentration (Tmax) (Primary), Median, Hours: Arm A: Zanubrutinib With or Without Moderate CYP3A 2.03 (1.0 to 4.0)
- Arm B: Time of the Maximum Observed Concentration (Tmax) (Primary), Median, Hours: Arm B: Zanubrutinib With or Without Strong CYP3A 3.00 (1.0 to 4.0)
- Arm A: Apparent Terminal Elimination Half-life (t1/2) (Primary), Geometric mean, Hours: Arm A: Zanubrutinib With or Without Moderate CYP3A 2.15 (1.4 to 4.5)
- Arm B: Apparent Terminal Elimination Half-life (t1/2) (Primary), Geometric mean, Hours: Arm B: Zanubrutinib With or Without Strong CYP3A 1.79 (1.2 to 2.5)
- Number of Participants Experiencing Adverse Events (AEs) (Secondary), Count of participants, Participants: Arm A: Zanubrutinib With or Without Moderate CYP3A 12; Arm B: Zanubrutinib With or Without Strong CYP3A 12
Adverse events
Time frame: From the date of first study drug administration to 30 days after last dose (up to approximately 15 months)
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Arm A: Zanubrutinib With or Without Moderate CYP3A | 1/13 (7.7%) | 3/13 (23.1%) | 12/13 (92.3%) |
| Arm B: Zanubrutinib With or Without Strong CYP3A | 0/13 (0.0%) | 1/13 (7.7%) | 12/13 (92.3%) |
Serious adverse events by term
| Term | Organ system | Arm A: Zanubrutinib With or Without Moderate CYP3A | Arm B: Zanubrutinib With or Without Strong CYP3A |
|---|
| Fall | Injury, poisoning and procedural complications | 1/13 | 0/13 |
| Traumatic haemorrhage | Injury, poisoning and procedural complications | 0/13 | 1/13 |
| Neck pain | Musculoskeletal and connective tissue disorders | 1/13 | 0/13 |
| Mantle cell lymphoma refractory | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/13 | 0/13 |
| Radiculopathy | Nervous system disorders | 1/13 | 0/13 |
| Pneumonia cryptococcal | Infections and infestations | 1/13 | 0/13 |
Other adverse events by term
| Term | Organ system | Arm A: Zanubrutinib With or Without Moderate CYP3A | Arm B: Zanubrutinib With or Without Strong CYP3A |
|---|
| Rash | Skin and subcutaneous tissue disorders | 1/13 | 2/13 |
| Petechiae | Skin and subcutaneous tissue disorders | 1/13 | 1/13 |
| Constipation | Gastrointestinal disorders | 1/13 | 3/13 |
| Diarrhoea | Gastrointestinal disorders | 0/13 | 3/13 |
| Abdominal pain upper | Gastrointestinal disorders | 0/13 | 2/13 |
| Contusion | Injury, poisoning and procedural complications | 3/13 | 4/13 |
| Fall | Injury, poisoning and procedural complications | 1/13 | 2/13 |
| Back pain | Musculoskeletal and connective tissue disorders | 2/13 | 3/13 |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | 0/13 | 2/13 |
| Neck pain | Musculoskeletal and connective tissue disorders | 2/13 | 0/13 |
| Upper respiratory tract infection | Infections and infestations | 1/13 | 1/13 |
| Neutropenia | Blood and lymphatic system disorders | 2/13 | 2/13 |
| Fatigue | General disorders | 0/13 | 2/13 |
| Oedema peripheral | General disorders | 1/13 | 1/13 |
| Blood creatinine increased | Investigations | 0/13 | 2/13 |