Zanubrutinib, Obinutuzumab, and Sonrotoclax in Previously Untreated Patients With CLL or SLL

NCT06849713 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 25-007
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma (SLL)

Keywords

CLL; SLL; untreated

Outcome Measures

Primary Outcomes (2)

• Rate 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.

  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.

  Day 1 to completion date of sonrotoclax ramp-up

Secondary Outcomes (7)

• Frequency of uMRD at Best Response

  Day 1 to 2 years after final patient enrolled

• Rate of uMRD after 10 and 24 cycles

  Day 1 to end of 10 cycles and end of 24 cycles

• Rate of Complete Response (CR) or CR with Incomplete Marrow Recovery (CRi), or Partial Response (PR)

  Day 1 to 2 years after final patient enrolled

• Progression-free survival (PFS), Overall Survival (OS), MRD4-Free Survival, and MRD5-free survival

  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

  Day 1 to end of Cycle 3 (each cycle is 28 days)

Study Arms (1)

Zanubrutinib, obinutuzumab, and sonrotoclax

EXPERIMENTAL

Zanubrutinib will be taken orally twice daily on days 1-28 of each cycle. Sonrotoclax will be taken orally once daily on days 1-28 starting cycle 3 day 1. Obinutuzumab will be given into the vein (by intravenous infusion) at the following timepoints: Days 1, 8, and 15 of cycle 1, Day 2 of cycle 1, and Day 1 of cycles 2 through 6. The total regimen treatment duration depends on early MRD response kinetics (ΔMRD400). The total regimen treatment duration will be 10 cycles for patients who achieve ΔMRD400 and 24 cycles for patients who do not achieve ΔMRD400 (including the 2-month zanubrutinib/obinutuzumab lead-in). Drug diaries will be provided to participants to document information about zanubrutinib and sonrotoclax.

Drug: Zanubrutinib; Drug: Sonrotoclax; Drug: Obinutuzumab

Interventions

Zanubrutinib DRUG

Bruton's Tyrosine Kinase (BTK) inhibitor

Also known as: BGB-3111

Zanubrutinib, obinutuzumab, and sonrotoclax

Sonrotoclax DRUG

B-cell lymphoma 2 (BCL2) protein inhibitor

Also known as: BGB-11417

Zanubrutinib, obinutuzumab, and sonrotoclax

Obinutuzumab DRUG

Anti-CD20 monoclonal antibody

Zanubrutinib, obinutuzumab, and sonrotoclax

Eligibility Criteria

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

You may qualify if:

• Participant must have CLL or SLL (WHO criteria).
• Participant must require treatment according to iwCLL guidelines.
• Participants must have no prior systemic therapy for CLL or SLL, except:
• Prior local radiation for symptomatic disease is permitted.
• Short course systemic corticosteroids is permissible for disease control, improvement of performance status, or non-cancer indication. However, duration of steroid course must be ≤14 days with maximum daily dose of ≤100 mg prednisone, ≤20 mg dexamethasone, or equivalent, and must be discontinued prior to study treatment (last dose may be administered up until the morning of / prior to study treatment). Inhaled steroids, topical steroids, and replacement / stress corticosteroids are permitted independent of above rules. In cases of autoimmune complications of CLL (e.g., ITP or AIHA), steroid usage is permitted.
• Age ≥18 years.
• ECOG performance status of 0, 1 or 2.
• Participants must meet the following organ and marrow function as defined below:
• absolute neutrophil count ≥1,000/µL without growth factor support (filgrastim within 5 days or PEGfilgrastim within 10 days of test), unless clearly due to disease under study (per investigator)
• platelets ≥75,000/µL, or ≥20,000/µL if clearly due to disease under study (per investigator)
• total bilirubin ≤2 x institutional upper limit of normal (ULN), or ≤3 x institutional ULN if due to Gilbert's syndrome, or with PI approval if clearly due to disease under study
• AST(SGOT)/ALT(SGPT) ≤2.5 x × institutional ULN
• CrCl or GFR ≥30 mL/min as estimated by the Cockcroft-Gault equation, the CKD-EPI equation, or as measured by 24-hour urine collection
• For females of childbearing potential, a serum pregnancy test must be negative within screening period.
• For female patients of childbearing potential: agreement to use highly effective form(s) of contraception (i.e., one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) or remain abstinent (refrain from heterosexual intercourse) during the treatment period and to continue its use for ≥ 30 days after the last dose of zanubrutinib or ≥ 90 days after the last dose of sonrotoclax, and for ≥18 months fter the last dose of obinutuzumab (whicher is later).

You may not qualify if:

• Known histologic transformation from CLL or SLL to an aggressive lymphoma (i.e., Richter's transformation).
• Known central nervous system involvement with CLL or SLL.
• Other diagnosis of active malignancy or systemic therapy within 2 years of study treatment. Note: An active malignancy or systemic therapy within 2 years for another malignancy, whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Also, local/regional therapy with curative intent such as surgical resection or localized radiation at any timepoint is permitted.
• Any uncontrolled illness that in the opinion of the investigator would preclude administration of study therapy (e.g., significant active infections, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction).
• Congestive heart failure, New York Heart Association III/IV. Unstable angina within 3 months before screening, myocardial infarction within 6 months before screening. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes). Heart rate-corrected QT interval \> 480 milliseconds based on Fridericia's formula corrected for bundle branch block as appropriate. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
• Receipt of a live-virus vaccine within 28 days prior to initiation of study treatment or need for live-virus vaccine at any time during study treatment.
• Active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds).
• Known bleeding diathesis. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
• Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study.
• Known CNS hemorrhage or stroke within 6 months of the study.
• History of progressive multifocal leukoencephalopathy.
• History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection.
• Patients with a history of HIV infection that is well controlled on antiretroviral therapy are eligible if all of the following criteria are met: (1) undetectable HIV viral load by standard clinical assay AND (2) CD4+ T cell count of \>/=200 cells/microliter). NOTE: Many HIV regimens are excluded based on drug interactions, and concomitant antiretroviral therapy must be acceptable per protocol.
• Participants with occult or prior HBV infection (defined as positive total hepatitis B core antibody \[HBcAb\] and negative HBsAg) may be included if HBV DNA is undetectable, and if the participant is willing to take appropriate anti-viral prophylaxis as indicated and HBV DNA monitoring on study.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• BeOne Medicines: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; obinutuzumab

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

Study Officials

• Jacob Soumerai, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jacob Soumerai, MD

CONTACT

617-724-4000; jsoumerai@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 12, 2025
• First Posted: February 27, 2025
• Study Start: May 16, 2025
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2030
• Last Updated: September 25, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (2)