A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL (SEQUOIA)

• ClinicalTrials.gov Identifier: NCT03336333
• Recruitment Status: Active, not recruiting
• First Posted: November 8, 2017
• Results First Posted: November 7, 2023
• Last Update Posted: November 9, 2023
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Tracking Information

• First Submitted Date: November 1, 2017
• First Posted Date: November 8, 2017
• Results First Submitted Date: October 16, 2023
• Results First Posted Date: November 7, 2023
• Last Update Posted Date: November 9, 2023
• Actual Study Start Date: October 31, 2017
• Actual Primary Completion Date: May 7, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 16, 2023)

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) ]

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).

• Original Primary Outcome Measures (submitted: November 7, 2017): Progression-free survival between treatment groups in Cohort 1 (BGB-3111 vs. bendamustine plus rituximab) as determined by independent central review [ Time Frame: From randomization to the date of first documentation of disease progression or death, whichever occurs first, assessed up to 5 years. ]

Current Secondary Outcome Measures (submitted: October 16, 2023)

• Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR [ Time Frame: Up to 5 years ]
  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.
• Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups [ Time Frame: Up to 5 years ]
• Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR [ Time Frame: Up to 5 years ]
  OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.
• Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR [ Time Frame: Up to 5 years ]
  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.
• Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups [ Time Frame: Up to 5 years ]
• Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) [ Time Frame: Up to 5 years ]
  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.
• Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) [ Time Frame: Up to 5 years ]
• 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 ]
• 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 ]
• Cohort 2: Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]
• Cohort 2: Progression-free Survival (PFS) [ Time Frame: Up to 5 years ]
• Cohort 2: Duration of Response (DOR) [ Time Frame: Up to 5 years ]
• Cohort 3: Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]
• Cohort 3: Progression-free Survival (PFS) [ Time Frame: Up to 5 years ]
• Cohort 3: Duration of Response (DOR) [ Time Frame: Up to 5 years ]
• Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4) [ Time Frame: Up to 5 years ]
• Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 5 years ]
• Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F [ Time Frame: Predose up to 12 hours postdose ]
• Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) [ Time Frame: Predose up to 12 hours postdose ]
• Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib [ Time Frame: Predose up to 12 hours postdose ]

Original Secondary Outcome Measures (submitted: November 7, 2017)

• Overall response rate between treatment groups in Cohort 1 as determined by independent central review and by investigator assessment. [ Time Frame: From time of best response recorded from randomization until data cut or start of new anticancer treatment, assessed up to 5 years. ]
• Overall survival between treatment groups in Cohort 1 [ Time Frame: From time of randomization until date of death due to any reason, assessed up to 5 years. ]
• Duration of response between treatment groups in Cohort 1 determined by independent central review and by investigator assessment [ Time Frame: From date that response criteria are first met to the date of first documentation of disease progression or death, whichever occurs first, assessed up to 5 years. ]
• Progression-free survival between treatment groups in Cohort 1 determined by investigator assessment [ Time Frame: From randomization to the date of first documentation of disease progression or death, whichever occurs first, assessed up to 5 years. ]
• Overall response rate in Cohort 2 as determined in independent central review [ Time Frame: From time of best response recorded from randomization until data cut or start of new anticancer treatment, assessed up to 5 years. ]
• Overall survival in Cohort 2 [ Time Frame: From time of first BGB-3111 dose administration until date of death due to any reason, assessed up to 5 years. ]
• Progression-free survival in Cohort 2 determined by independent central review [ Time Frame: From the date of first BGB-3111 dose administration to the date of first documentation of disease progression or death, whichever occurs first, assessed up to 5 years. ]
• Duration of response in Cohort 2 determined by independent central review [ Time Frame: From date that response criteria are first met to the date of first documentation of disease progression or death whichever occurs first, assessed up to 5 years. ]
• Incidence, nature and severity of adverse events between treatment groups in Cohort 1 [ Time Frame: From date of first study drug dose to approximately 30 days after end of treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL
• Official Title: An International, Phase 3, Open-Label, Randomized Study of BGB-3111 Compared With Bendamustine Plus Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Intervention

• Drug: Zanubrutinib
  Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
  Other Names:

  • BGB-3111
  • BRUKINSA
• Drug: Bendamustine
  Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.
  Other Name: Treanda, Ribomustin, and Levact
• Drug: Rituximab
  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
  Other Name: Rituxan, MabThera
• Drug: Venetoclax
  400 mg tablets administered orally once daily.
  Other Name: Venclexta, Venclyxto

Study Arms

• Experimental: Cohort 1: Bendamustine + Rituximab
  Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)
  Interventions:

  • Drug: Bendamustine
  • Drug: Rituximab
• Experimental: Cohort 1: Zanubrutinib
  Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)
  Intervention: Drug: Zanubrutinib
• Experimental: Cohort 1a (China only): Bendamustine + Rituximab
  Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)
  Interventions:

  • Drug: Bendamustine
  • Drug: Rituximab
• Experimental: Cohort 1a (China only): Zanubrutinib
  Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)
  Intervention: Drug: Zanubrutinib
• Experimental: Cohort 2: Zanubrutinib
  Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)
  Intervention: Drug: Zanubrutinib
• Experimental: Cohort 3: Venetoclax + Zanubrutinib
  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)
  Interventions:

  • Drug: Zanubrutinib
  • Drug: Venetoclax

Publications *

• 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.
• 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.
• 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. Erratum In: Lancet Oncol. 2023 Mar;24(3):e106.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 16, 2023): 590
• Original Estimated Enrollment (submitted: November 7, 2017): 467
• Estimated Study Completion Date: September 2026
• Actual Primary Completion Date: May 7, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, China, Czechia, France, Italy, New Zealand, Poland, Russian Federation, Spain, Sweden, Taiwan, United Kingdom, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT03336333
• Other Study ID Numbers: BGB-3111-304; 2017-001551-31 ( EudraCT Number ); CTR20190416 ( Registry Identifier: Center for drug evaluation, NMPA )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: BeiGene
• Original Responsible Party: Same as current
• Current Study Sponsor: BeiGene
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; BeiGene

• PRS Account: BeiGene
• Verification Date: November 2023