Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Condition: Relapsed or Refractory Chronic Lymphocytic Leukemia; Relapsed or Refractory Small Lymphocytic Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Zanubrutinib
Intervention description: Zanubrutinib 160 mg (two - 80 mg white opaque capsules) taken by mouth (PO) twice a day (BID)
Intervention MeSH terms: Zanubrutinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 91.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bruton's tyrosine kinase; Chronic lymphocytic leukemia; Relapsed/refractory; Zanubrutinib

Summary:

      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.
    

Eligibility criteria:

        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.