Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)

NCT03824483 | Recruiting Phase 2 FDA Drug

• 1 other identifier: 18-427
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 8

Brief Summary

The purpose of this study is to determine the rate of minimum residual disease (MRD) negative response (i.e. the rate of no evidence of disease) of the study drugs, zanubrutinib, obinutuzumab, and venetoclax, given in combination as a treatment for CLL and/or SLL.

Conditions

Small Lymphocytic Leukemia (SLL); Chronic Lymphocytic Leukemia (CLL)

Keywords

Zanubrutinib; Obinutuzumab; Venetoclax; 18-427

Outcome Measures

Primary Outcomes (1)

• establish the rate of minimum residual disease (MRD) undetectable response

  Patients will have their minimum residual disease (MRD) response classified by bone marrow peripheral blood flow cytometry with a sensitivity of 10-4.

  1 year

Study Arms (1)

BOVEN regimen

EXPERIMENTAL

Patients will be given zanubrutinib (160mg by mouth BID) and obinutuzumab (1000mg IVPB on Days 1\*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). \* On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC \>25,000 cells/ul or baseline lymph nodes \>5 cm diameter). Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.

Drug: Zanubrutinib; Drug: Obinutuzumab; Drug: Venetoclax

Interventions

Obinutuzumab DRUG

obinutuzumab (1000mg IVPB on Days 1\*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). \* On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC \>25,000 cells/ul or baseline lymph nodes \>5 cm diameter).

Also known as: GA101

BOVEN regimen

Venetoclax DRUG

Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.

Also known as: ABT-199

BOVEN regimen

Zanubrutinib DRUG

zanubrutinib (160mg by mouth BID)

BOVEN regimen

Eligibility Criteria

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

You may qualify if:

• \- Signed, informed consent
• Ability and willingness to comply with the requirements of the study protocol
• Age ≥18 years
• Diagnosis of the following histories according to the WHO criteria
• CLL or SLL
• MCL
• For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting for at least 1% of circulating WBC.
• No prior systemic therapy for disease under study 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 (must be ≤ 14 days and \< 100 mg/day prednisone or ≤ 20 mg/day dexamethasone). Steroids must be discontinued prior to study treatment. Inhaled steroids for asthma, topical steroids, and replacement/Stress corticosteroids are permitted. Low-dose steroids for ITP are also permitted up to the equivalent prednisone 20mg/daily at time of eligibility review.
• ECOG performance status of 0 to 2
• Adequate hematologic parameters unless due to disease under study:
• Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion)
• Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion)
• Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement due to disease under study (per investigator discretion)

You may not qualify if:

• Other malignancies:
• Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter"s transformation)
• Active malignancy or systemic therapy for another malignancy within 3 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 3 years of treatment is permitted
• Other diagnosis of active cancer
• Co-morbidities:
• \- 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)
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1
• Known bleeding diathesis
• 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 (PML)
• History of HIV 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 need to cleared by the clinical pharmacist and approved by the site PI)
• Active hepatitis B (chronic or acute) or hepatitis C infection a. Patients 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. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing.

Sponsors & Collaborators

• BeOne Medicines: collaborator
• Memorial Sloan Kettering Cancer Center: lead
• Roche-Genentech: collaborator
• Massachusetts General Hospital: collaborator

Study Sites (8)

Northwestern University

Evanston, Illinois, 60208, United States

RECRUITING

Massachusetts General Hospital (Data Collection and Specimen Analysis)

Boston, Massachusetts, 02114, United States

RECRUITING

Memorial Sloan Kettering at Basking Ridge

Basking Ridge, New Jersey, 07920, United States

RECRUITING

Memorial Sloan Kettering Monmouth

Middletown, New Jersey, 07748, United States

RECRUITING

Memorial Sloan Kettering Commack

Commack, New York, 11725, United States

RECRUITING

Memorial Sloan Kettering Westchester

Harrison, New York, 10604, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

RECRUITING

Memorial Sloan Kettering Nassau

Uniondale, New York, 11553, United States

RECRUITING

Related Publications (2)

• Kumar A, Soumerai J, Abramson JS, Barnes JA, Caron P, Chhabra S, Chabowska M, Dogan A, Falchi L, Grieve C, Haydu JE, Johnson PC, Joseph A, Kelly HE, Labarre A, Lue JK, Martignetti R, Mi J, Moskowitz A, Owens C, Plummer S, Puccio M, Salles G, Seshan V, Simkins E, Slupe N, Zhang H, Zelenetz AD. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. 2025 Jan 30;145(5):497-507. doi: 10.1182/blood.2024025563.

  PMID: 39437708 DERIVED

• Soumerai JD, Mato AR, Dogan A, Seshan VE, Joffe E, Flaherty K, Carter J, Hochberg E, Barnes JA, Hamilton AM, Abramson JS, Batlevi CL, Matasar MJ, Noy A, Owens CN, Palomba ML, Kumar A, Takvorian T, Ni A, Choma M, Friedman C, Chadha P, Simkins E, Ruiters J, Sechio S, Portman D, Ramos L, Nolet N, Mahajan N, Martignetti R, Mi J, Scorsune K, Lynch J, McGree B, Hughes S, Grieve C, Roeker LE, Thompson M, Johnson PC, Roshal M, Huang J, Biondo J, Wu Q, Jacob A, Abdel-Wahab O, Zelenetz AD. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021 Dec;8(12):e879-e890. doi: 10.1016/S2352-3026(21)00307-0.

  PMID: 34826411 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib; obinutuzumab; venetoclax

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

• Andrew Zelenetz, MD, PhD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrew Zelenetz, MD, PhD

CONTACT

212-639-2656; zeleneta@mskcc.org

Anthony Mato, MD

CONTACT

212-639-8596

Study Design

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

Model Details: Patients will be enrolled in a single-stage phase 2 design.

Study Record Dates

• First Submitted: January 29, 2019
• First Posted: January 31, 2019
• Study Start: February 22, 2019
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: May 7, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ICF

Locations

US (8)