Zanubrutinib and Sonrotoclax for the Treatment of Relapsed Chronic Lymphocytic Leukemia /Small Lymphocytic Leukemia, ZeuS-2 Trial

NCT07812246 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: 251076NCI-2026-06340P30CA033572
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 3

Brief Summary

This phase II trial tests how well giving zanubrutinib and sonrotoclax works for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) that has come back after a period of improvement (relapsed). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sonrotoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) and BCL-XL inhibitors. It may stop the growth of tumor cells and may kill them by blocking Bcl-2 and Bcl-XL, proteins needed for cell survival. Giving zanubrutinib and sonrotoclax may work well for the treatment of relapsed CLL/SLL.

Conditions

Recurrent Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• Overall response rate

  Overall response defined as achieving best response of complete response (CR) or partial response (PR) after the start of protocol therapy and prior to disease progression and/or start of other anti-lymphoma therapy. Overall response rate will be calculated as the proportion of response-evaluable participants achieving an overall response. Will be estimated as a binary proportion; the 95% Clopper-Pearson confidence interval will be calculated when needed.

  Up to 5 years

Secondary Outcomes (6)

• Complete response rate

  Up to 5 years

• Minimal residual disease (MRD) negativity

  Up to 5 years

• Progression free survival

  From start of protocol treatment to time of disease relapse/progression or death due to any cause, up to 5 years

• Duration of response

  From first achievement of CR or PR to time of disease relapse/progression or death due to any cause, up to 5 years

• Overall survival

  From start of protocol treatment to time of death, up to 5 years

Study Arms (1)

Treatment (zanubrutinib and sonrotoclax)

EXPERIMENTAL

CYCLE 1-4: Patients receive zanubrutinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. CYCLE 5+: Patients receive zanubrutinib PO QD and sonrotoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration, CT scan/MRI and blood sample collection throughout the study. Patients may undergo lymph node biopsy during screening and optionally at time of progression.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Lymph Node Biopsy; Procedure: Magnetic Resonance Imaging; Drug: Sonrotoclax; Drug: Zanubrutinib

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Treatment (zanubrutinib and sonrotoclax)

Lymph Node Biopsy PROCEDURE

Undergo lymph node biopsy

Also known as: Biopsy of Lymph Node

Treatment (zanubrutinib and sonrotoclax)

Sonrotoclax DRUG

Given PO

Also known as: B-cell Lymphoma-2 Inhibitor BGB-11417, Bcl-2 Inhibitor BGB-11417, Beqalzi, BGB 11417, BGB-11417, BGB11417

Treatment (zanubrutinib and sonrotoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Treatment (zanubrutinib and sonrotoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (zanubrutinib and sonrotoclax)

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (zanubrutinib and sonrotoclax)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (zanubrutinib and sonrotoclax)

Zanubrutinib DRUG

Given PO

Also known as: BGB 3111, BGB-3111, BGB3111, Brukinsa, BTK-InhB

Treatment (zanubrutinib and sonrotoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented informed consent of the participant and/or legally authorized representative.
• Assent, when appropriate, will be obtained per institutional guidelines
• Age: ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Histological or flow cytometry confirmed diagnosis of B-CLL/SLL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO)
• CLL has progressed at least 6 months after completion of first-line fixed-duration novel drug (non-chemotherapy) regimen, including but not limited to venetoclax (V) + CD20 monoclonal antibody (monoclonal antibody \[mAb\], e.g., obinutuzumab (O); BTK inhibitor (zanubrutinib or acalabrutinib or ibrutinib) + V ± CD20 mAb
• Active disease meeting criteria for requiring treatment per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines (one of the following):
• A minimum of any one of the following constitutional symptoms:
• Unintentional weight loss \> 10% within the previous 6 months prior to screening.
• Extreme fatigue (unable to work or perform usual activities).
• Fevers of greater than 100.5°F for ≥ 2 weeks without evidence of infection.
• Night sweats without evidence of infection.
• Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia.
• Massive (i.e., \> 6 cm below the left costal margin), progressive or symptomatic splenomegaly.
• Massive nodes or clusters (i.e., \> 10 cm in longest diameter) or progressive lymphadenopathy.

You may not qualify if:

• Chronic use of corticosteroids in excess of 20 mg/day prednisone
• Major surgery (under general anesthesia) ≤4 weeks of the first dose of study drug
• Prior chemotherapy
• Refractory to prior BTK or BCL2 inhibitor (defined as relapsed within/\< 6 months after completion of initial fixed duration regimen)
• Vaccination with a live vaccine within 35 days prior to the first dose of study drug or at any time during planned study treatment
• Requires ongoing treatment with a strong CYP3A inducer
• Requires ongoing treatment with inhibitors of P-gp and BCRP
• Requires ongoing treatment with warfarin or warfarin derivatives
• Concurrent participation in another therapeutic clinical trial
• Use of the following substances prior to the first dose of study drug:
• ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug: strong and moderate inhibitors or inducers of CYP3A
• ≤ 7 days before the first dose of study drug: corticosteroid (\> 20 mg prednisone or equivalent) given with antineoplastic intent
• Known current central nervous system involvement by lymphoma/leukemia
• Known Richter's transformation
• Any uncontrolled or clinically significant cardiovascular disease including the following:

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (3)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

City of Hope at Irvine Lennar

Irvine, California, 92618, United States

Location

City of Hope Atlanta Cancer Center

Newnan, Georgia, 30265, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Specimen Handling; Biopsy; Sentinel Lymph Node Biopsy; Magnetic Resonance Spectroscopy; zanubrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Lymph Node Excision; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Tanya Siddiqi

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2026
• First Posted: September 10, 2026
• Study Start (Estimated): August 4, 2027
• Primary Completion (Estimated): August 13, 2028
• Study Completion (Estimated): August 13, 2028
• Last Updated: September 10, 2026

Record last verified: 2026-09

Locations

US (3)