A Phase Two Study of Venetoclax Plus Zanubrutinib in Newly Diagnosed CLL and After Front-Line Time-Limited Venetoclax-Based Therapy
This phase II trial tests the effect of venetoclax in combination with standard of care (SOC) zanubrutinib in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Zanubrutinib blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. It is a type of tyrosine kinase inhibitor. Giving venetoclax in combination with SOC zanubrutinib may be safe and tolerable and may reduce the number of cancer cells that remain in the body in patients with CLL or SLL that have not previously received treatment or at least two years have passed since completing initial treatment.
• Diagnosis of CLL/SLL meeting criteria established in International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria
• Age ≥ 18 years
• Indications for treatment as defined by the iwCLL 2018 Guidelines
• Received prior treatment or not depending on cohort
‣ Frontline cohort:
• CLL/SLL who are treatment-naïve and have met criteria 1 through 3 above
⁃ Second line cohort:
• Must have received time-limited venetoclax based therapy in the front line. This is defined as treatment with venetoclax and an-anti-CD20 antibody, venetoclax and a BTKi, or treatment with venetoclax and a BTKi, and an anti-CD20 monoclonal antibody that was given for a fixed-duration. Patients who discontinue ibrutinib, due to intolerance, in a BTKi and venetoclax +/- obinutuzumab combination are eligible provided they completed other drugs in the regimen and in the opinion of the treating investigator the intolerance will not limit treatment with zanubrutinib and venetoclax. Patients who discontinued BTKi other than ibrutinib or who discontinued venetoclax due to intolerance will be excluded
∙ At least 2 years since completion of initial CLL treatment
∙ Only 1 prior line of therapy. Treatment with rituximab or other anti-CD20 monoclonal antibody for idiopathic thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) is not considered a prior line of CLL/SLL therapy
• Eastern Cooperative Oncology Group (ECOG) performance 0-2
• Absolute neutrophil count (ANC) \> 1000/mm\^3 (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Platelets \> 30,000/mm\^3 at screening (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Hemoglobin \> 7 g/dL (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement
• Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease
• Creatinine clearance (CrCl) ≥ 50 according to modified Cockcroft-Gault equation
• Willing and able to complete study activities and treatment
• Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
• Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 1 week following the last dose of zanubrutinib or 30 days following the last dose of venetoclax, whichever is longer