Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate Safety and Efficacy of BGB-3111, a Bruton's Tyrosine Kinase (BTK) Inhibitor in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

This was a single-arm, open-label, multi-center Phase 2 study in participants with histologically documented CLL/SLL who have relapsed after or refractory to ≥ 1 prior treatment regimen(s). The study is composed of an initial screening phase, a single-arm treatment phase, and a follow-up phase.

Key Inclusion Criteria:

1. Confirmed diagnosis with at least one criterion for treatment according to International workshop on chronic lymphocytic leukemia (IWCLL)
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. Measurable disease by contrast enhanced computerized tomography / magnetic resonance imaging (CT/MRI).
4. Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥2 treatment cycles).
5. Documented failure to achieve at least partial response (PR) or documented disease progression after response to the most recent treatment regimen. Refractory disease is defined as treatment failure (stable disease, non-response, progressive disease [PD]) or disease progression within 6 months after the most recent prior therapy (Hallek et al, 2008).
6. Neutrophils ≥ 0.75 x 109/L independent of growth factor support within 7 days of study entry
7. Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days of study entry
8. Creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD])
9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN
10. Bilirubin ≤2 x ULN (unless documented Gilbert's syndrome)
11. International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 x ULN.
12. Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 6 months after transplant.
13. Life expectancy of >4 months
14. Echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥50%; (AHA, 2016)

Key Exclusion Criteria:

1. Current or history of central nervous system (CNS) lymphoma
2. Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor
3. Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days.
4. Major surgery within 4 weeks of screening
5. Not recovered from toxicity of any prior anti-cancer therapy to <Grade 1 (except for alopecia, absolute neutrophil count (ANC) and platelets.
6. 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
7. Currently active clinically significant cardiovascular disease
8. QTcF >480 msecs based on Fridericia's formula or other significant electrocardiogram abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV block
9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
10. Active infection including infections requiring oral or intravenous anti-microbials
11. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction [PCR]).
12. Has received allogenic hematopoietic stem cell transplantation prior to enrollment
13. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the participants's safety, or put the study at risk
14. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer
15. Known or clinically suspected Richter's transformation at the time of study entry
16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

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