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

BeiGene

Status and phase: Active, not recruiting; Phase 3

Conditions: Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia

Treatments: Drug: Rituximab; Drug: Venetoclax; Drug: Bendamustine; Drug: Zanubrutinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT03336333

CTR20190416 (Registry Identifier)

BGB-3111-304

2017-001551-31 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 590 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

590 participants in 6 patient groups

Cohort 1: Bendamustine + Rituximab

Experimental group

Description:

Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)

Treatment:

Drug: Rituximab

Drug: Bendamustine

Cohort 1: Zanubrutinib

Experimental group

Description:

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)

Treatment:

Drug: Zanubrutinib

Cohort 1a (China only): Bendamustine + Rituximab

Experimental group

Description:

Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)

Treatment:

Drug: Rituximab

Drug: Bendamustine

Cohort 1a (China only): Zanubrutinib

Experimental group

Description:

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)

Treatment:

Drug: Zanubrutinib

Cohort 2: Zanubrutinib

Experimental group

Description:

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)

Treatment:

Drug: Zanubrutinib

Cohort 3: Venetoclax + Zanubrutinib

Experimental group

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)

Treatment:

Drug: Zanubrutinib

Drug: Venetoclax