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Chronic Lymphocytic Leukemia (CLL)Phase 2NCT03824483

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

A Phase 2 study testing Zanubrutinib, Obinutuzumab and Venetoclax in people with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL), run by Memorial Sloan Kettering Cancer Center at 8 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Zanubrutinib, Obinutuzumab and Venetoclax
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
230 participants
Where
8 sitesUnited States
Study dates
22 Feb 2019to Feb 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 40Show fewer
  • 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)
  • Adequate renal and hepatic function, per laboratory reference range at Screening as follows:
  • AST/SGOT, ALT/SGPT ≤2.0 x ULN b. Total bilirubin ≤ 2.0 x ULN unless:
  • Considered secondary to Gilbert"s syndrome, in which case ≤3 x ULN ii. Considered due to disease under study (Per PI or Co-PI discretion)
  • Creatinine clearance of eGFR>30 mL/min according to the Cockcroft-Gault Equation
  • For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment
  • 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 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later)
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>/= 12 continuous months of amenorrhea with no identified cause other than menopause), and it not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  • Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • For men with a female partner of childbearing potential or a pregnant female partnet: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib AND, 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later)
  • The reliability of sexual abstinence should be evaluated in relation duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception - Willingness to not donate or bank sperm or oocytes during the entire study treatment period and after treatment discontinuation for 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later)
  • Additional Eligibility Criteria for CLL Cohort:
  • 1. Diagnosis of untreated CLL or SLL according to WHO criteria 2. For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting for at least 1% of circulating WBC 3. No prior systemic therapy for CLL: prior single site of local radiation for symptomatic disease is permitted 4. Subject requires treatment according to IWCLL guidelines (See Appendix A)
  • Additional Eligibility Criteria for TP53 Mutant MCL cohorts:
  • 1. Diagnosis of untreated stage II-IV mantle cell lymphoma
  • Prior radiotherapy for localized disease is permitted 2. Presence of TP53 mutation irrespective of variant allele frequency (TP53 cohort)
  • OR
  • Presence of p53 overexpression by immunohistochemistry defined as strong nuclear staining of >30% positive nuclei.
  • Additional Eligibility Criteria for Transplant Ineligible MCL cohort:
  • Diagnosis of untreated stage II-IV mantle cell lymphoma
  • Prior radiotherapy for localized disease is permitted
  • Patients must meet one of the following criteria (a or b):
  • Age ≥65 years If age <65 years of age, then patients must be ineligible for HDT/ASCT on the basis of comorbidity or organ dysfunction.
  • Specifically, patients must meet at least one of the following criteria below:
  • i.. Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidney dysfunction, precluding high dose therapy secondary to expected increased morbidity and mortality. ii. ECOG 2 iii. Ejection fraction ≥35% and <45% iv. Impaired pulmonary function test with DLCO <50% expected v. Medical conditions which in the opinion of the treating physician in consultation with the study PI or Co-PI and DMT preclude HDT/ASCT.

Who cannot join

  • 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)
Show all 39Show fewer
  • 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.
  • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • Congestive heart failure, New York Heart Association classification III/IV
  • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
  • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
  • Known condition or other clinical situation that would affect oral absorption
  • Psychiatric illness/social situations that would interfere with study compliance
  • Inability to swallow a large number of tablets
  • Concomitant medications and drug interactions:
  • Administration within 7 days prior to the first dose of study drug or concurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19. The same applied for moderate inhibitors or inducers of CY_3A
  • Live-virus vaccines given within 28 days prior to the initiation of study treatment
  • Immunotherapy
  • Hormone therapy (other than contraceptives, hormone replacement therapy, or megestrol acetate)
  • Any therapies intended for the treatment of lymphoma/leukemia whether FDA approved or experimental (outside of this study)
  • Radiation therapy intended to treat MCL or CLL/SLL
  • Warfarin or warfarin derivatives
  • Consumption of one or more of the following within 3 days prior to the first dose of study drug:
  • Grapefruit or grapefruit products Seville oranges, including marmalade containing Seville oranges Star Fruit (carambola)
  • Prior therapy:
  • Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
  • Obinutuzumab is contraindicated in patients with a known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its excipients
  • Prior systemic therapy for CLL; prior single site of local radiation for symptomatic disease is permitted
  • Other:
  • Females who are currently pregnant or breastfeeding
  • Participation in a separate investigational therapeutic study unless authorized by the investigator

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Memorial Sloan Kettering at Basking Ridge

    Basking Ridge, New Jersey, 07920

  • Massachusetts General Hospital (Data Collection and Specimen Analysis)

    Boston, Massachusetts, 02114

  • Memorial Sloan Kettering Commack

    Commack, New York, 11725

  • Memorial Sloan Kettering Westchester

    East White Plains, New York, 10604

  • Northwestern University

    Evanston, Illinois, 60208

  • Memorial Sloan Kettering Monmouth

    Middletown, New Jersey, 07748

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • Memorial Sloan Kettering Nassau

    Uniondale, New York, 11553

Other trials in United States

About this study

Official title: Phase 2 Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) and Mantle Cell Lymphoma (MCL)

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.

Being tested
Zanubrutinib, Obinutuzumab, Venetoclax
Keywords
Zanubrutinib, Obinutuzumab, Venetoclax, 18-427
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ZanubrutinibDrug

    zanubrutinib (160mg by mouth BID)

  • ObinutuzumabDrug

    Also called GA101

    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).

  • VenetoclaxDrug

    Also called ABT-199

    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.

Study groups in NCT03824483
Study groupRoleWhat they receive
BOVEN regimenExperimentalPatients 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.
Receives: Drug: Zanubrutinib; Drug: Obinutuzumab; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jan 2019
  2. Study start22 Feb 2019
  3. Primary completionFeb 2027 (estimated)
  4. Study completionFeb 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Patients will be enrolled in a single-stage phase 2 design.
Masking
None (open label)
Enrolment
230 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03824483
Sponsor's protocol ID
18-427
Status last verified
Sep 2026
First submitted
29 Jan 2019
Last updated
3 Sep 2026
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Publications

  • Soumerai JD, Thompson MC, Dogan A, Seshan V, Flaherty KL, Slupe N, Carter J, Hochberg E, Barnes JA, Abramson JS, Noy A, Owens C, Palomba ML, Kumar A, Roeker L, Takvorian RW, Epstein-Peterson ZD, Geyer MB, Salles G, Stuver R, Caron P, Islam P, Haque T, Ghione P, Steiner RE, Torka P, David KA, Lue JK, Hamlin PA, Moskowitz A, Falchi L, Haydu JE, Johnson PC, Mi J, Mahajan N, Pendleton J, Labarre A, Chabowska M, Choma M, Grieve C, Joseph A, Dorsey C, Brutus J, Martignetti R, Nazzaro R, Coyle J, Maas O, Meemanage V, Simkins E, Kakolu A, Gordon C, Baez E, Beatty B, Apazidis A, Gulotta M, Ratcliff S, Hirata J, Shahkarami M, Jacob AP, Abdel-Wahab O, Zelenetz AD. Zanubrutinib, obinutuzumab, and venetoclax in CLL: long-term follow up, MRD kinetics, retreatment, T-cell profiling, and PKs. Blood Adv. 2026 Nov 10;10(21):7393-7405. doi: 10.1182/bloodadvances.2026020221.

    PubMed 42379251

  • 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.

    PubMed 39437708

  • 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.

    PubMed 34826411

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Zanubrutinib, Obinutuzumab and Venetoclax in people with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL), run by Memorial Sloan Kettering Cancer Center at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 40 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 3 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

establish the rate of minimum residual disease (MRD) undetectable response (time frame: 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03824483, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2026.

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