TriangleNCT03336333 · CITED IN SOURCE DOCUMENTS
A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- ACTIVE NOT RECRUITING
- Registry last update
- 2026-03-09
To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)
Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR
Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups
Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR
Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR
Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups
Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire
Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire.
Cohort 2: Overall Response Rate (ORR)
Cohort 2: Progression-free Survival (PFS)
Cohort 2: Duration of Response (DOR)
Cohort 3: Overall Response Rate (ORR)
Cohort 3: Progression-free Survival (PFS)
Cohort 3: Duration of Response (DOR)
Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4)
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F
Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12)
Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib
Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- Key Inclusion Criteria: * Unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) * Confirmed diagnosis of CD20-positive CLL or SLL, requiring treatment * Measurable disease by imaging * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * Life expectancy ≥ 6 months * Adequate bone marrow function * Adequate renal and hepatic function Key Exclusion Criteria: * Previous systemic treatment for CLL/SLL * Requires ongoing need for corticosteroid treatment * Known prolymphocytic leukemia or history of or suspected Richter's transformation. * Clinically significant cardiovascular disease * Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix of breast, or localized Gleason score 6 prostate cancer * History of severe bleeding disorder * History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug * Severe or debilitating pulmonary disease * Inability to swallow capsules or disease affecting gastrointestinal function * Active infection requiring systemic treatment * Known central nervous system involvement by leukemia or lymphoma * Underlying medical condition that will render the administration of study drug hazardous or obscure interpretation of toxicity or AEs * Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C infection * Major surgery ≤ 4 weeks prior to start of study treatment * Pregnant or nursing females * Vaccination with live vaccine within 35 days prior to the first dose of study drug. * Ongoing alcohol or drug addiction * Known hypersensitivity to zanubrutinib, bendamustine, rituximab, or venetoclax (as applicable) or any other ingredients of the study drugs * Requires ongoing treatment with strong cytochrome P450 (CYP3A) inhibitor or inducer * Concurrent participation in another therapeutic clinical study NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)
- intervention Names
- Drug: Bendamustine
- Drug: Rituximab
- label
- Cohort 1: Bendamustine + Rituximab
- type
- EXPERIMENTAL
- description
- Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)
- intervention Names
- Drug: Zanubrutinib
- label
- Cohort 1: Zanubrutinib
- type
- EXPERIMENTAL
- description
- Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)
- intervention Names
- Drug: Bendamustine
- Drug: Rituximab
- label
- Cohort 1a (China only): Bendamustine + Rituximab
- type
- EXPERIMENTAL
- description
- Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)
- intervention Names
- Drug: Zanubrutinib
- label
- Cohort 1a (China only): Zanubrutinib
- type
- EXPERIMENTAL
- description
- Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)
- intervention Names
- Drug: Zanubrutinib
- label
- Cohort 2: Zanubrutinib
- type
- EXPERIMENTAL
- description
- Approximately 110 participants, 50 without del17p and 60 with del\[17p\] or TP53 mutation will receive zanubrutinib plus venetoclax; Participants will also receive zanubrutinib starting on Cycle 1 Day 1 then daily for a minimum of 27 cycles, or until unacceptable toxicity or disease progression, whichever occurs first. Participants will receive venetoclax starting Cycle 4 Day 1 according to a 5-week dose-up schedule then daily until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Each cycle is 28 days. (Arm D)
- intervention Names
- Drug: Zanubrutinib
- Drug: Venetoclax
- label
- Cohort 3: Venetoclax + Zanubrutinib
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Cohort 1: Zanubrutinib
- Cohort 1a (China only): Zanubrutinib
- Cohort 2: Zanubrutinib
- Cohort 3: Venetoclax + Zanubrutinib
- description
- Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
- name
- Zanubrutinib
- other Names
- BGB-3111
- BRUKINSA
- type
- DRUG
- arm Group Labels
- Cohort 1: Bendamustine + Rituximab
- Cohort 1a (China only): Bendamustine + Rituximab
- description
- Administered intravenously (IV) at a dose of 90 mg/m\^2/day on the first 2 days of each cycle for 6 cycles.
- name
- Bendamustine
- other Names
- Treanda, Ribomustin, and Levact
- type
- DRUG
- arm Group Labels
- Cohort 1: Bendamustine + Rituximab
- Cohort 1a (China only): Bendamustine + Rituximab
- description
- Administered intravenously (IV) at a dose of 375 mg/m\^2 on day 0 of cycle 1, and at a dose of 500 mg/m\^2 on day 1 of cycles 2 to 6
- name
- Rituximab
- other Names
- Rituxan, MabThera
- type
- DRUG
- arm Group Labels
- Cohort 3: Venetoclax + Zanubrutinib
- description
- 400 mg tablets administered orally once daily.
- name
- Venetoclax
- other Names
- Venclexta, Venclyxto
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 590
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the ICR per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with small lymphocytic lymphoma (SLL).
- measure
- Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)
- time Frame
- Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021)
- secondary Outcomes
- description
- ORR in Cohort 1 is defined as the percentage of participants who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by the ICR.
- measure
- Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR
- time Frame
- Up to 5 years
- measure
- Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups
- time Frame
- Up to 5 years
- description
- OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.
- measure
- Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR
- time Frame
- Up to 5 years
- description
- Duration of response in Cohort 1 determined using the iwCLL criteria with modification for treatment related lymphocytosis (in participants with CLL) and the Lugano Classification for non-Hodgkin lymphoma (NHL; in participants with SLL), is defined as the time from the date that criteria for response (ie, partial response with lymphocytosis \[PR-L\] or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first.
- measure
- Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR
- time Frame
- Up to 5 years
- measure
- Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups
- time Frame
- Up to 5 years
- description
- PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the investigator per iwCLL guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL.
- measure
- Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
- time Frame
- Up to 5 years
- measure
- Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
- time Frame
- Up to 5 years
- measure
- Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire
- time Frame
- Up to 5 years
- measure
- Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire.
- time Frame
- Up to 5 years
- measure
- Cohort 2: Overall Response Rate (ORR)
- time Frame
- Up to 5 years
- measure
- Cohort 2: Progression-free Survival (PFS)
- time Frame
- Up to 5 years
- measure
- Cohort 2: Duration of Response (DOR)
- time Frame
- Up to 5 years
Full study description
- brief Summary
- To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.
- detailed Description
- This is a global phase 3, open label, randomized study of zanubrutinib versus bendamustine plus rituximab (B+R) in participants with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including participants without del(17p) \[Cohort 1\] and participants with del(17p) \[Cohort 2 and Cohort 3\]. Participants in Cohort 1 are randomized 1:1 to zanubrutinib (Arm A) or bendamustine plus rituximab (Arm B). Randomization will be stratified by age, Binet stage, immunoglobulin variable region heavy chain (IGHV) mutational status, and geographic region. Participants in Cohort 2 will receive treatment with zanubrutinib. Participants in Cohort 3 will receive treatment with zanubrutinib and venetoclax.
Source references
- references
- citation
- Mu S, Tang Z, Novotny W, Tawashi M, Li TK, Ou Y, Sahasranaman S. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol. 2020 Feb;85(2):391-399. doi: 10.1007/s00280-019-04015-w. Epub 2019 Dec 26.
- pmid
- 31875923
- type
- RESULT
- citation
- Tam CS, Robak T, Ghia P, Kahl BS, Walker P, Janowski W, Simpson D, Shadman M, Ganly PS, Laurenti L, Opat S, Tani M, Ciepluch H, Verner E, Simkovic M, Osterborg A, Trneny M, Tedeschi A, Paik JC, Kuwahara SB, Feng S, Ramakrishnan V, Cohen A, Huang J, Hillmen P, Brown JR. Zanubrutinib monotherapy for patients with treatment naive chronic lymphocytic leukemia and 17p deletion. Haematologica. 2021 Sep 1;106(9):2354-2363. doi: 10.3324/haematol.2020.259432.
- pmid
- 33054121
- type
- RESULT
- citation
- Munir T, Martinez-Calle N, Xu S, Yang K, Ge X, Ali AK, Mohseninejad L, Dobi B, Rakonczai P, Ma H, Williams R, Aldairy W, Lamanna N. Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Oncol Ther. 2025 Dec;13(4):1055-1070. doi: 10.1007/s40487-025-00380-0. Epub 2025 Sep 13.
- pmid
- 40944848
- type
- DERIVED
- citation
- Shadman M, Munir T, Ma S, Lasica M, Tani M, Robak T, Flinn IW, Brown JR, Ghia P, Ferrant E, Tam CS, Janowski W, Jurczak W, Xu L, Tian T, Lefebure M, Agresti S, Hirata J, Tedeschi A. Zanubrutinib and Venetoclax for Patients With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With and Without Del(17p)/TP53 Mutation: SEQUOIA Arm D Results. J Clin Oncol. 2025 Jul 20;43(21):2409-2417. doi: 10.1200/JCO-25-00758. Epub 2025 May 31.
- pmid
- 40448577
- type
- DERIVED
- citation
- Shadman M, Munir T, Robak T, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Simkovic M, Osterborg A, Laurenti L, Walker PA, Opat SS, Ciepluch H, Greil R, Hanna M, Tani M, Trneny M, Brander D, Flinn IW, Grosicki S, Verner E, Tedeschi A, de Guibert S, Tumyan G, Laribi K, Garcia-Marco JA, Li JY, Tian T, Liu Y, Korolkiewicz R, Szeto A, Tam CS, Jurczak W. Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA. J Clin Oncol. 2025 Mar;43(7):780-787. doi: 10.1200/JCO-24-02265. Epub 2024 Dec 8.
- pmid
- 39647999
- type
- DERIVED
- citation
- Kittai AS, Allan JN, James D, Bridge H, Miranda M, Yong ASM, Fam F, Roos J, Shetty V, Skarbnik A, Davids MS. An indirect comparison of acalabrutinib with and without obinutuzumab vs zanubrutinib in treatment-naive CLL. Blood Adv. 2024 Jun 11;8(11):2861-2869. doi: 10.1182/bloodadvances.2023012142.
- pmid
- 38598745
- type
- DERIVED
- citation
- Moslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024 May 28;8(10):2478-2490. doi: 10.1182/bloodadvances.2023011641.
- pmid
- 38502198
- type
- DERIVED
- citation
- Ghia P, Barnes G, Yang K, Tam CS, Robak T, Brown JR, Kahl BS, Tian T, Szeto A, Paik JC, Shadman M. Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Curr Med Res Opin. 2023 Nov;39(11):1505-1511. doi: 10.1080/03007995.2023.2262381. Epub 2023 Oct 12.
- pmid
- 37752878
- type
- DERIVED
- citation
- Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Simkovic M, Shadman M, Osterborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trneny M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5. Epub 2022 Jul 7.
- pmid
- 35810754
- type
- DERIVED
Source notices and limitations
Discovery and provenance
- release id
- ctgov-registry-7ad944f6deaf1f5cd6122126
- edge id
- nct-edge-dabf49847ab71cebde4a
- requested nct id
- NCT03336333
- primary nct id
- NCT03336333
- source kind
- fda_spl_label
- source record id
- 29341b77-7deb-445a-ae2c-a8e01c932daf
- source file sha256
- fc39a8c5cf96bf95ca20b85578140167b66b2741f7d9217f500d9ba0847ac058
- payload sha256
- fd2712032578951d9a69a43d700d6c3d3cc4c0f9b1074b169fcf5d9d827a4950
- payload
- application numbers
- NDA213217
- NDA218785
- clinical indication matching status
- not_inferred
- end exclusive
- true
- id
- nct-edge-dabf49847ab71cebde4a
- link basis
- explicit_NCT_identifier_in_acquired_source
- nct id
- NCT03336333
- occurrences
- context exact
- ed controlled trials. SEQUOIA The efficacy of BRUKINSA in patients with previously untreated CLL/SLL was evaluated in a multicenter, open-label trial (SEQUOIA; NCT03336333). The trial required patients to be unsuitable for FCR therapy defined as either age ≥65 years or age 18 to <65 with a total Cumulative Illness Rating Scale (C
- end
- 8282
- exact text
- NCT03336333
- start
- 8271
- offset unit
- unicode_code_points
- source file
- /tmp/cancer-full-research/indications/raw/labels-00100.json
- source file sha256
- fc39a8c5cf96bf95ca20b85578140167b66b2741f7d9217f500d9ba0847ac058
- source json pointer
- /results/49/clinical_studies/0
- source kind
- fda_spl_label
- source record id
- 29341b77-7deb-445a-ae2c-a8e01c932daf
- source string basis
- parsed_JSON_string_unmodified
- source string sha256
- 568216a9881d887242989d7a2614d2fe2f7e4dd08e6f60e050342cb67cd8e676
- spl effective time
- 20260721
- spl set id
- 3e08fe23-d70e-424c-bc51-1222e320f902
Preserved source evidence · Not medical advice