Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies

A Phase I/II, Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to Investigate the Safety and Pharmacokinetics of the BTK Inhibitor BGB-3111 in Subjects With B-Cell Lymphoid Malignancies

This study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies.

Inclusion Criteria:

1. Aged ≥ 18 years, voluntarily consented to the study.
2. WHO classification defined B-lymphoid malignancy, with the exception of Burkitt lymphoma/leukemia, plasma cell myeloma, acute lymphoblastic leukemia, lymphoblastic lymphoma, and plasmablastic lymphoma.
3. Requirement for treatment in the opinion of the investigator.
4. Disease which has relapsed, or is refractory, following at least one line of therapy, with no therapy of higher priority available.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Adequate hematologic function, as defined by neutrophils ≥ 1.0 x 10^9/L and platelets ≥ 50 x 10^9/L; participants with neutrophils < 1.0 x 10^9/L due to marrow infiltration are allowed to receive growth factors to bring pre-treatment neutrophils to ≥ 1.0 x 10^9/L.
7. Adequate renal function, as defined by creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24 hour urine collection).
8. Adequate liver function, as defined by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), and bilirubin ≤ 1.5 x ULN (unless documented Gilbert's syndrome).
9. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN.
10. Female participants of childbearing potential and non-sterile males must practice at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: total abstinence from sexual intercourse, double-barrier contraception, IUD or hormonal contraceptive initiated at least 3 months prior to first dose of study drug.
11. Male participants must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.

Exclusion Criteria:

1. Current central nervous system (CNS) involvement by disease
2. Current histologically transformed disease.
3. Prior Bruton's tyrosine kinase (BTK) inhibitor treatment.
4. Allogeneic stem cell transplantation within 6 months, or has active graft-versus-host disease (GVHD) requiring ongoing immunosuppression.
5. Receipt of the following treatment prior to first dose of zanubrutinib: corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 2 weeks, monoclonal antibody within 4 weeks.
6. Not recovered from toxicity of any prior chemotherapy to grade ≤ 1.
7. History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other modality) with curative intent.
8. Uncontrolled systemic infection requiring parenteral anti-microbial therapy.
9. Major surgery in the past 4 weeks.
10. Known HIV, or active hepatitis B or hepatitis C infection (detected positive by PCR).
11. Cardiovascular disease resulting in New York Heart Association function status of ≥ 3.
12. Significant active renal, neurologic, psychiatric, hepatic or endocrinologic disease that in the investigator's opinion would adversely impact on his/her participating in the study.
13. Inability to comply with study procedures.
14. On medications which are cytochrome P450 (CYP) 3A inhibitors.