Venetoclax Plus Zanubrutinib for the Treatment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
brief summary
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.
detailed description
PRIMARY OBJECTIVE:
I. To determine undetectable minimal residual disease (uMRD) rates in CLL patients receiving fixed-duration combined treatment with venetoclax plus zanubrutinib.
SECONDARY OBJECTIVES:
I. Overall response rate. (Frontline Cohort) II. Rate of complete remission. (Frontline Cohort) III. Duration of response. (Frontline Cohort) IV. Duration of uMRD if achieved. (Frontline Cohort) V. Time to next treatment. (Frontline Cohort) VI. Rate of adverse events with zanubrutinib and venetoclax treatment. (Frontline Cohort) VII. Overall response rate. (Second Line Cohort) VIII. Rate of complete remission. (Second Line Cohort) IX. Rate of uMRD at cycle 15 of treatment. (Second Line Cohort) X. Duration of response. (Second Line Cohort) XI. Duration of uMRD if achieved. (Second Line Cohort) XII. Time to next treatment. (Second Line Cohort) XIII. Rate of adverse events with zanubrutinib and venetoclax treatment. (Second Line Cohort)
EXPLORATORY OBJECTIVES:
I. Estimated 36-months progression-free survival. II. Progression-free survival for both cohorts. III. Overall survival for both cohorts. IV. Patient and disease characteristics associated with achieving uMRD status. V. Development of resistance mutations associated with BTK inhibitor (BTKi) and venetoclax.
VI. BH3 profiling at baseline and after cycle (C)3 of treatment with zanubrutinib.
VII. Impact of treatment on measures of immune function. VIII. Incidence of laboratory and clinical tumor lysis syndrome (TLS) during venetoclax ramp-up, change in TLS risk category after zanubrutinib lead-in (C1-3), and interventions for electrolyte changes.
OUTLINE: Patients who have not previously been treated are assigned to Cohort I and patients who completed initial treatment are assigned to Cohort II.
COHORT I (FRONTLINE COHORT): Patients receive SOC zanubrutinib orally (PO) once daily (QD) or twice daily (BID) per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity.
COHORT II (SECOND LINE COHORT): Patients receive SOC zanubrutinib PO QD or BID per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity.
official title
A Phase Two Study of Venetoclax Plus Zanubrutinib in Newly Diagnosed CLL and After Front-Line Time-Limited Venetoclax-Based Therapy