The purpose of this study is to determine the proportion of participants who achieve undetectable measurable residual disease (uMRD) in previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational \[drug/device/intervention\] to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has approved sonrotoclax for the treatment of patients with mantle cell lymphoma. However, the U.S. FDA has not approved sonrotoclax for the treatment of patients with CLL/SLL. The U.S. FDA has approved zanubrutinib and obinutuzumab as a treatment option for CLL/SLL. The U.S. FDA has not approved tacabrutideg (BGB-16673). The combinations of zanubrutinib, obinutuzumab, and sonrotoclax (BOSon regimen) or tacabrutideg (BGB-16673), obinutuzumab, and sonrotoclax (DOSon) are not an approved regimen for CLL or SLL and are investigational in this study. Zanubrutinib blocks a protein in B-cells (immune cells) called Bruton tyrosine kinase (BTK). BTK helps CLL/SLL cells live and grow. By blocking BTK, zanubrutinib may slow down or stop the activity of CLL/SLL cells, which can lead to improvement in the symptoms associated with CLL/SLL. Tacabrutideg (BGB-16673) degrades a protein in B-cells (immune cells) called Bruton tyrosine kinase (BTK). BTK helps CLL/SLL cells live and grow. By degrading BTK, tacabrutideg may slow down or stop the activity of CLL/SLL cells, which can lead to improvement in the symptoms associated with CLL/SLL. Obinutuzumab is a drug that targets a protein called CD20, which is found on the surface of B cells, the white blood cells that are affected by CLL/SLL. When obinutuzumab attaches to CD20, it directly both destroys the B cells and makes them more "visible" to the immune system. The immune system then attacks and destroys the cancerous B cells. Sonrotoclax blocks a protein called B-cell lymphoma-2 (Bcl-2). Bcl-2 helps certain blood cancer cells live and replicate. By blocking Bcl-2, sonrotoclax can slow or stop blood cancer cells replicating and allow natural cell death to occur, thereby causing blood cancer cell death. This research study uses the clonoSEQ test to detect measurable residual disease (MRD). The U.S. Food and Drug Administration (FDA) has approved the clonoSEQ MRD test for patients with CLL/SLL. However, using this test to guide the duration of therapy is investigational in this study. Although we hope that this test can be used to provide a more personalized treatment plan for participants with CLL/SLL, there is also a risk that this results in some participants receiving more or less treatment than they otherwise would receive. In this research study, we are hoping to learn how safe and effective the combinations of BOSon (zanubrutinib, obinutuzumab and sonrotoclax) or DOSon (tacabrutideg, obinutuzumab and sonrotoclax) are for people who require therapy for CLL/SLL. It is expected that about 80 people will take part in this research study, including 40 people treated with BOSon and 40 people treated with DOSon.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Bruton's Tyrosine Kinase (BTK) inhibitor
B-cell lymphoma 2 (BCL2) protein inhibitor
Anti-CD20 monoclonal antibody
Massachusetts General Hospital
Boston, Massachusetts, United States
RECRUITINGMemorial Sloan Kettering Cancer Center
New York, New York, United States
RECRUITINGRate of Undetectable MRD (uMRD) at Best Response
The proportion of patients achieving undetectable MRD in peripheral blood using the ClonoSEQ assay (cutoff, \<10-5). The number of responses will be reported with a proportion with 95% exact binomial confidence interval.
Time frame: Day 1 to 2 years after final patient enrolled
Proportion of Participants with Tumor Lysis Syndrome (TLS) Laboratory Abnormalities Requiring Intervention
The proportion of participants who have 1 or more TLS laboratory abnormalities requiring intervention on a ramp-up date with normal pre-dose TLS parameters and ALC \<25,000/µl during the sonrotoclax ramp-up. The number of responses will be reported with a proportion with 95% exact binomial confidence interval.
Time frame: Day 1 to completion date of sonrotoclax ramp-up
Frequency of uMRD at Best Response
The proportion of patients achieving uMRD in both peripheral blood (PB) and bone marrow (BM) by ClonoSEQ (cutoff, \<10-5).
Time frame: Day 1 to 2 years after final patient enrolled
Rate of uMRD at interim (C10D28 for BOSon and C12D28 for DOSon) and after 24 cycles
The proportion of patients achieving uMRD in both PB and BM by ClonoSEQ (cutoff, \<10-5) at interim (C10D28 for BOSon and C12D28 for DOSon) and after 24 cycles
Time frame: Day 1 to interim (C10D28 for BOSon and C12D28 for DOSon) and to after 24 cycles
Rate of Complete Response (CR) or CR with Incomplete Marrow Recovery (CRi), or Partial Response (PR)
Patients will have their response classified per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.
Time frame: Day 1 to 2 years after final patient enrolled
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Bruton's Tyrosine Kinase (BTK) degrader
Progression-free survival (PFS), Overall Survival (OS), MRD4-Free Survival, and MRD5-free survival
PFS is the time from treatment start to the earlier of progression or death due to any cause. OS is the time from treatment start to death due to any cause. MRD4-Free Survival is the time from treatment start to the earlier of detectable MRD ≥10-4 by immunosequencing (Adaptive ClonoSEQ assay), progression, or death due to any cause. MRD5-Free Survival the time from treatment start to the earlier of detectable MRD ≥10-5 by immunosequencing (Adaptive ClonoSEQ assay), progression, or death due to any cause. Time-to-event endpoints will be evaluated using the Kaplan-Meier method. Survival distributions may be described as medians or 1- and 2-year probabilities with 95% confidence intervals. Uni- and multi-variable Cox regressions may also be performed and will be summarized with hazard ratios, 95% confidence intervals, and Wald p-values.
Time frame: Day 1 to first documented disease progression or date of death from any cause, assessed for 2 year after final patient enrolled
Proportion of Participants Without TLS-related Laboratories Requiring Clinical Intervention
TLS is defined according to Howard criteria. The nature, frequency, severity, and timing of TLS will be tabulated and summarized descriptively.
Time frame: Day 1 to end of Cycle 3 (each cycle is 28 days)
Distribution of TLS Risk
TLS is defined according to Howard criteria. The nature, frequency, severity, and timing of TLS will be tabulated and summarized descriptively.
Time frame: Day 1 to end of Cycle 2 (each cycle is 28 days)
Incidence and Severity of Treatment-Emergent Adverse Events
Patients will have their toxicities graded and reported at every visit according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The nature, frequency, severity, and timing of adverse events will be tabulated and summarized descriptively. The safety analyses will include all participants who received at least one dose of study treatment.
Time frame: Day 1 to 2 years after final patient enrolled