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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Relapsed or Refractory Chronic Lymphocytic Leukemia, Relapsed or Refractory Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Confirmed diagnosis with at least one criterion for treatment according to International workshop on chronic lymphocytic leukemia (IWCLL) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Measurable disease by contrast enhanced computerized tomography / magnetic resonance imaging (CT/MRI). Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥2 treatment cycles). 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). Neutrophils ≥ 0.75 x 109/L independent of growth factor support within 7 days of study entry Platelets ≥ 50 x 109/L, independent of growth factor support or transfusion within 7 days of study entry 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]) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN Bilirubin ≤2 x ULN (unless documented Gilbert's syndrome) International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 x ULN. Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 6 months after transplant. Life expectancy of >4 months Echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥50%; (AHA, 2016) Key Exclusion Criteria: Current or history of central nervous system (CNS) lymphoma Prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days. Major surgery within 4 weeks of screening Not recovered from toxicity of any prior anti-cancer therapy to <Grade 1 (except for alopecia, absolute neutrophil count (ANC) and platelets. 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 Currently active clinically significant cardiovascular disease 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 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 Active infection including infections requiring oral or intravenous anti-microbials Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction [PCR]). Has received allogenic hematopoietic stem cell transplantation prior to enrollment 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 Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer Known or clinically suspected Richter's transformation at the time of study entry History of stroke or intracranial hemorrhage within 6 months prior to enrollment NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanubrutinib<br> | Drug: Zanubrutinib<br>* Zanubrutinib 160 mg (two - 80 mg white opaque capsules) taken by mouth (PO) twice a day (BID)<br>* Other names: BGB-3111;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by Independent Review Committee (IRC) | ORR is defined as the number of participants who achieve a best response of CR or, CRi, Nodular Partial Response, PR, and PR with Lymphocytosis as assessed by IRC per the modified IWCLL Guidelines in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL. | Up to 1 year and 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS): Percentage of Participants Progression/Death Event Free | PFS is defined as the time from treatment initiation to first documentation of progression by International workshop on chronic lymphocytic leukemia (IWCLL) criteria/revised criteria for response for malignant lymphoma or death, whichever is earlier. | 6, 12, 24, and 36 months | 
| Duration of Response (DOR): Event Free Rate - Percentage of Participants Who Remained Event Free | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever occurs first | 6, 12, 24, and 36 months | 
| Time to Response (TTR) | TTR is defined as the time from treatment initiation to first signs of response | Up to 3.5 years | 
| Overall Response Rate as Determined by the Investigator | Overall response was defined as achieving a best overall response of CR, CRi, nodular partial response (nPR), PR, or partial response with lymphocytosis (PR-L). | up to 3.5 years | 
| Number of Participants Experiencing Adverse Events (AEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All AEs were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010). A treatment emergent adverse event (TEAE) is defined as an adverse event that has an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation or initiation of new anticancer therapy, whichever occurs first. | Up to 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton's tyrosine kinase, Chronic lymphocytic leukemia, Relapsed/refractory, Zanubrutinib