BTK Inhibitor BGB-3111 in Chinese Participants With Diffuse Large B-Cell Lymphoma (Non-GCB) and Indolent Lymphoma (FL and MZL)

• Sponsor: BeiGene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03520920
• Collaborator: (none)
• Enrollment: 41
• Locations: 4
• Arms: 2
• Actual Duration (Months): 31.8
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This was a multicenter, open-label, phase 2 study to evaluate efficacy, safety, and tolerability of BGB-3111 (zanubrutinib) 160 milligrams (mg) twice daily (BID) in combination with rituximab in Chinese participants with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (non-GCB [non-germinal center B-cell-like] subtype) and R/R indolent lymphoma (follicular lymphoma [FL] and marginal zone lymphoma [MZL]).

Condition or Disease	Intervention/Treatment	Phase
Marginal Zone Lymphoma; Follicular Lymphoma; Diffuse Large B-Cell Lymphoma	Drug: Zanubrutinib; Drug: Rituximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study to Assess the Safety, Tolerability, and Activity of BGB-3111 in Combination With Rituximab in Chinese Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (Non-GCB Subtype) and Relapsed/Refractory Indolent Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)
• Actual Study Start Date: Jan 4, 2018
• Actual Primary Completion Date: Aug 28, 2020
• Actual Study Completion Date: Aug 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: R/R Non-GCB DLBCL Participants with non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Drug: Zanubrutinib; Administered zanubrutinib 160 mg orally (PO) BID continuously; Other Names: BGB-3111 ; Drug: Rituximab; Administered rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Experimental: R/R FL or MZL Participants with R/R FL or MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Drug: Zanubrutinib; Administered zanubrutinib 160 mg orally (PO) BID continuously; Other Names: BGB-3111 ; Drug: Rituximab; Administered rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) As Measured By The Investigator [Up to approximately 2.5 years]

   The percentage of participants whose best overall response met partial response (PR) or complete response (CR) criteria among all participants. The 95% confidence interval (CI) was calculated with the Clopper-Pearson method.

Secondary Outcome Measures

1. Duration Of Response (DOR) As Determined By Investigator [Up to approximately 2.5 years]

   The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.

2. DOR: Event-free Rate [Up to approximately 2.5 years]

   The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.

3. Progression-free Survival (PFS) As Determined By Investigator [Up to approximately 2.5 years]

   The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.

4. PFS: Event-free Rate [Up to approximately 2.5 years]

   The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.

5. Overall Survival (OS) [Up to approximately 2.5 years]

   The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.

6. OS: Survival Rate [Up to approximately 2.5 years]

   The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Survival rates were estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.

7. Time To Response (TTR) As Determined By The Investigator [Up to approximately 2.5 years]

   The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better).

8. Median TTR [Up to approximately 2.5 years]

   The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better).

9. Complete Response Rate As Determined By The Investigator [Up to approximately 2.5 years]

   The percentage of participants whose best overall response met complete response or complete metabolic response criteria among all participants are reported. The 95% CI was calculated with Clopper-Pearson method.

10. Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) And Serious TEAEs [Up to approximately 2.5 years]

    A treatment-emergent adverse event was defined as an adverse event with an onset or worsening (if present pretreatment) starting on or after the first dose of study drug up to 30 days after discontinuation of zanubrutinib or 90 days after discontinuation of rituximab, whichever occurred later; or initiation of new anticancer therapy if it occurred prior to the other 2 dates. Worsening of a treatment-emergent adverse event to Grade 5 beyond Day 30 after the last dose of zanubrutinib or Day 90 after the last dose rituximab was also considered a treatment-emergent adverse event if the event occurred prior to initiation of new anticancer therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. ≥ Age 18 years at time of signing of informed consent.

2. Measurable disease by computed tomography (CT) or positron emission tomography/CT or magnetic resonance imaging, defined as ≥1 nodal lesion that was >1.5 centimeters (cm) in the longest diameter, or ≥1 extra-nodal lesion (for example, hepatic nodules) that was >1 cm in the longest diameter.

3. Availability of archival or fresh tumor tissue sample from an evaluable core or excisional biopsy.

4. Participants meet the following criteria:

5. Cohort 1: R/R non-GCB DLBCL i. Histologically confirmed non-GCB DLBCL per Hans criteria with non-transformed disease; additional methodologies for confirming non-GCB DLBCL may have been considered in consultation with the medical monitor.

1. Relapsed disease (disease progression after most recent therapy for DLBCL occurring more than 6 months after the completion of last therapy) or refractory disease (failure to achieve complete response [CR] or partial response [PR] to therapy for non-GCB DLBCL or disease progression within 6 months after completion of the most recent therapy for non-GCB DLBCL). iii. Must have received at least one standard anthracycline ± rituximab-based treatment (for example, rituximab plus cyclophosphamide, doxorubicin [or epirubicin, hydroxydaunorubicin, or similar], vincristine, and prednisone) or cyclophosphamide, vincristine, and prednisone +/- rituximab for DLBCL.

1. Cohort 2: R/R FL or R/R MZL i. Histologically confirmed CD20+ FL (Grade 1, 2, or 3a) or MZL. ii. Relapsed disease (disease progression after most recent therapy for FL or MZL occurring more than 6 months after the completion of last therapy) or refractory disease (failure to achieve complete response (CR) or partial response (PR) to most recent therapy for FL or MZL, or disease progression within 6 months after completion of the most recent therapy for FL or MZL).

2. Laboratory parameters as specified below:

3. Hematologic: Platelet count ≥75 x 10^{9/liter (L) independent of growth factor or transfusion within 7 days of study entry; absolute neutrophil count (ANC) ≥1 x 10}9/L independent of growth factor within 7 days of study entry, hemoglobin >8 grams/deciliter within 7 days of study entry.

4. Hepatic: Total bilirubin ≤ 2x upper limit of normal (ULN) unless documented Gilbert's syndrome; aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine transaminase/serum glutamic-pyruvic transaminase ≤3x ULN.

5. Renal: Creatinine clearance ≥30 milliliters/minute (as estimated by the Cockcroft-Gault equation based on ideal body weight or as measured by nuclear medicine scan or 24-hour urine collection).

6. International normalized ratio and activated partial thromboplastin time ≤1.5x ULN. Participants with anti-phospholipid syndrome, acquired von Willebrand disease, factor inhibitors or on vitamin K antagonist may have been enrolled after discussion with the Medical Monitor.

7. Left ventricular ejection fraction ≥50%.

8. Life expectancy ≥6 months.

9. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

10. Female participants of childbearing potential must have practiced highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥90 days after the last dose of zanubrutinib, or 12 months after the last dose of rituximab, whichever is longer.

11. Male participants were eligible if vasectomized or if they agreed to the use of barrier contraception in combination with other methods above during the study treatment period and for ≥90 days after the last dose of zanubrutinib.

12. Able to provide written informed consent and could understand and comply with the requirements of the study.

Key Exclusion Criteria:

1. Known central nervous system lymphoma or leukemia.

2. Histological confirmed gastric mucosa-associated lymphoid tissue type MZL.

3. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

4. Clinically significant cardiovascular disease.

5. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.

6. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.

7. Severe or debilitating pulmonary disease.

8. Hypersensitivity reaction to zanubrutinib or rituximab or any of the other ingredients of the study drugs.

9. Prior Bruton tyrosine kinase inhibitor treatment.

10. Required ongoing treatment with a strong cytochrome P450 protein inhibitor or inducer.

11. Vaccination with a live vaccine within 28 days of the first dose of study drug.

12. Hematopoietic stem cell transplantation within 6 months of first dose of study drug.

13. Receipt of the following treatment prior to first dose of study drug:

14. Corticosteroids at doses >20 mg/day prednisone equivalent or steroids given with anti-neoplastic intent within 7 days prior to first dose of study drug.

15. Chemotherapy or radiotherapy within 4 weeks.

16. Monoclonal antibody within 4 weeks.

17. Investigational therapy within 4 weeks.

18. Chinese patent medicine with anti-neoplastic intent within 4 weeks.

19. Not recovered from toxicity of any prior anti-cancer therapy to ≤Grade 1, except for alopecia, ANC, hemoglobin (Hgb), and platelets. For ANC, Hgb and platelets, see inclusion criterion #5.

20. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.

21. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, history of bariatric surgery, or partial or complete bowel obstruction.

22. Major surgery within 4 weeks prior to first dose of study treatment.

23. Active fungal, bacterial and/or viral infection requiring systemic therapy.

24. Known infection with human immunodeficiency virus, or serologic status reflecting active hepatitis B or C infection as follows:

25. Presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibody (anti-HBc). Participants with presence of anti-HBc, but absence of HBsAg, were eligible if hepatitis B virus (HBV) DNA was <500 international units (IU)/mL, anti-viral therapy started before the first dose of study treatment, and if they were willing to undergo monthly monitoring for HBV reactivation.

26. Presence of hepatitis C virus (HCV) antibody. Participants with presence of HCV antibody were eligible if HCV RNA was undetectable (<15 IU/mL).

27. Pregnant or lactating women.

28. Underlying medical conditions that, in the investigator's opinion, would have rendered the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.

29. Concurrent participation in another therapeutic clinical trial.

Note: Other protocol defined Inclusion/Exclusion criteria may have applied.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China
2	Tongji Hospital, Tongji Medical College of HUST	Wuhan	Hubei	China
3	The Affiliated Hospital of Xuzhou Medical University	Xuzhou	Jiangsu	China
4	Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai	China

Sponsors and Collaborators

• BeiGene

Investigators

• Principal Investigator: Study Director, BeiGene

Study Documents (Full-Text)

• Study Protocol - Mar 28, 2019
• Statistical Analysis Plan - Sep 11, 2020

More Information

Publications

None provided.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03520920
• Other Study ID Numbers: BGB-3111-213; CTR20170965
• First Posted: May 11, 2018
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Rituximab; Zanubrutinib

Study Results

Participant Flow

Recruitment Details	This study was conducted at 4 study centers in China, all of which enrolled participants. The first enrolled participants received their first dose on 04 January 2018, and the last participant enrolled received their first dose on 20 December 2018. A total of 41 participants with non-Hodgkin lymphoma (NHL) were enrolled into the study, and all received ≥1 dose of study treatment.

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with relapsed/refractory (R/R) non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL) received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 milligrams (mg) orally (PO) twice daily (BID) continuously and rituximab 375 mg/meter squared (m^2) intravenously (IV) on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R follicular lymphoma (FL) received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R marginal zone lymphoma (MZL) received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Period Title: Overall Study
STARTED	20	16	5
Received at Least 1 Dose of Study Drug	20	16	5
COMPLETED	0	0	0
NOT COMPLETED	20	16	5

Baseline Characteristics

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma	Total
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Total of all reporting groups
Overall Participants	20	16	5	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (15.00)	47.6 (12.36)	61.2 (8.87)	53.0 (13.94)
Age, Customized (Count of Participants)
<65 years	14 70%	15 93.8%	3 60%	32 78%
≥65 years	6 30%	1 6.3%	2 40%	9 22%
Sex: Female, Male (Count of Participants)
Female	7 35%	8 50%	3 60%	18 43.9%
Male	13 65%	8 50%	2 40%	23 56.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	20 100%	16 100%	5 100%	41 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Body Mass Index (kilogram/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram/m^2]	23.43 (2.652)	25.04 (5.079)	24.33 (4.813)	24.17 (3.989)
Body Surface Area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.72 (0.113)	1.77 (0.295)	1.69 (0.240)	1.74 (0.213)
Eastern Cooperative Oncology Group Performance (ECOG)Status (Count of Participants)
Grade 0	13 65%	11 68.8%	3 60%	27 65.9%
Grade 1	5 25%	4 25%	2 40%	11 26.8%
Grade 2	2 10%	1 6.3%	0 0%	3 7.3%
Hepatitis B Core Antibody (Count of Participants)
Positive	6 30%	3 18.8%	2 40%	11 26.8%
Negative	14 70%	13 81.3%	2 40%	29 70.7%
Missing	0 0%	0 0%	1 20%	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) As Measured By The Investigator
Description	The percentage of participants whose best overall response met partial response (PR) or complete response (CR) criteria among all participants. The 95% confidence interval (CI) was calculated with the Clopper-Pearson method.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab) on the study.

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
Number (95% Confidence Interval) [Percentage of Participants]	35 175%	56.3 351.9%	60.0 1200%

2. Secondary Outcome

Title	Duration Of Response (DOR) As Determined By Investigator
Description	The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab) on the study. Duration of response was summarized for responders (participants with a best response of partial response or higher) only.

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	7	9	3
Median (95% Confidence Interval) [Months]	8.79	NA	22.18

3. Secondary Outcome

Title	DOR: Event-free Rate
Description	The DOR was defined as the time from the date that the response criteria were first met to the date that progressive disease (PD) was objectively documented or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
6 months	50.0 250%	88.9 555.6%	100.0 2000%
9 months	50.0 250%	77.8 486.3%	66.7 1334%
12 months	50.0 250%	64.8 405%	66.7 1334%
15 months	33.3 166.5%	51.9 324.4%	66.7 1334%
18 months	33.3 166.5%	51.9 324.4%	66.7 1334%
24 months	NA NaN	NA NaN	33.3 666%

4. Secondary Outcome

Title	Progression-free Survival (PFS) As Determined By Investigator
Description	The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
Median (95% Confidence Interval) [Months]	3.38	11.10	24.87

5. Secondary Outcome

Title	PFS: Event-free Rate
Description	The PFS was defined as time from first dose of study treatment until first documentation of progression, assessed per the Lugano Classification, or death, whichever occurred first. The event-free rate was estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
6 months	17.4 87%	73.3 458.1%	100.0 2000%
9 months	17.4 87%	66.7 416.9%	100.0 2000%
12 months	17.4 87%	46.7 291.9%	80.0 1600%
15 months	17.4 87%	46.7 291.9%	60.0 1200%
18 months	11.6 58%	40.0 250%	60.0 1200%
24 months	11.6 58%	40.0 250%	60.0 1200%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Medians were estimated by the Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
Median (95% Confidence Interval) [Months]	11.20	NA	NA

7. Secondary Outcome

Title	OS: Survival Rate
Description	The OS was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Survival rates were estimated by the Kaplan-Meier method with 95% CIs estimated using Greenwood's formula.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance. Administered zanubrutinib 160 mg PO BID continuously and rituximab 375 mg/m^2 IV on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. Each cycle was 28 days long.
Measure Participants	20	16	5
6 months	72.7 363.5%	93.3 583.1%	100.0 2000%
9 months	55.9 279.5%	93.3 583.1%	100.0 2000%
12 months	44.7 223.5%	93.3 583.1%	100.0 2000%
15 months	33.6 168%	93.3 583.1%	100.0 2000%
18 months	33.6 168%	93.3 583.1%	100.0 2000%
24 months	33.6 168%	93.3 583.1%	100.0 2000%

8. Secondary Outcome

Title	Time To Response (TTR) As Determined By The Investigator
Description	The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better).
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
Measure Participants	20	16	5
Mean (Standard Deviation) [Months]	3.56 (2.054)	6.15 (3.867)	3.67 (1.631)

9. Secondary Outcome

Title	Median TTR
Description	The TTR was defined as the time from the date of the first dose of study treatment to the date of the first qualifying response (partial response or better).
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
Measure Participants	20	16	5
Median (Full Range) [Months]	2.79	5.49	2.73

10. Secondary Outcome

Title	Complete Response Rate As Determined By The Investigator
Description	The percentage of participants whose best overall response met complete response or complete metabolic response criteria among all participants are reported. The 95% CI was calculated with Clopper-Pearson method.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
Measure Participants	20	16	5
Number (95% Confidence Interval) [Percentage of Participants]	10.0 50%	18.8 117.5%	0.0 0%

11. Secondary Outcome

Title	Number Of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) And Serious TEAEs
Description	A treatment-emergent adverse event was defined as an adverse event with an onset or worsening (if present pretreatment) starting on or after the first dose of study drug up to 30 days after discontinuation of zanubrutinib or 90 days after discontinuation of rituximab, whichever occurred later; or initiation of new anticancer therapy if it occurred prior to the other 2 dates. Worsening of a treatment-emergent adverse event to Grade 5 beyond Day 30 after the last dose of zanubrutinib or Day 90 after the last dose rituximab was also considered a treatment-emergent adverse event if the event occurred prior to initiation of new anticancer therapy.
Time Frame	Up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of study drug (zanubrutinib or rituximab).

Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma	Relapsed/Refractory Follicular Lymphoma	Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.	Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
Measure Participants	20	16	5
Participants With at Least 1 TEAE	20 100%	16 100%	5 100%
Serious TEAEs	7 35%	4 25%	0 0%

Adverse Events

Time Frame	Day 1 through approximately 2.5 years
Adverse Event Reporting Description	Participants were assessed for adverse events throughput the study and Follow-up Visit (30 days after last dose of zanubrutinib, 90 days after the last dose of rituximab, whichever occurred later). After this period, only new adverse events that were believed to be related to study treatment were reported.
Arm/Group Title	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma		Relapsed/Refractory Follicular Lymphoma		Relapsed/Refractory Marginal Zone Lymphoma
Arm/Group Description	Participants with R/R non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance.		Participants with R/R FL received zanubrutinib plus rituximab for up to progressive disease or intolerance.		Participants with R/R MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
All Cause Mortality
	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma		Relapsed/Refractory Follicular Lymphoma		Relapsed/Refractory Marginal Zone Lymphoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/20 (65%)		1/16 (6.3%)		0/5 (0%)
Serious Adverse Events
	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma		Relapsed/Refractory Follicular Lymphoma		Relapsed/Refractory Marginal Zone Lymphoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/20 (35%)		4/16 (25%)		0/5 (0%)
Blood and lymphatic system disorders
Anaemia	1/20 (5%)		0/16 (0%)		0/5 (0%)
Lymphadenopathy	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Gastrointestinal disorders
Abdominal pain	2/20 (10%)		0/16 (0%)		0/5 (0%)
General disorders
Death	1/20 (5%)		0/16 (0%)		0/5 (0%)
General physical health deterioration	1/20 (5%)		0/16 (0%)		0/5 (0%)
Pyrexia	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Infections and infestations
Lymph gland infection	1/20 (5%)		0/16 (0%)		0/5 (0%)
Lymphangitis	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Pneumonia	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Pulmonary mycosis	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Metabolism and nutrition disorders
Hypoproteinaemia	0/20 (0%)		1/16 (6.3%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)		0/16 (0%)		0/5 (0%)
Psychiatric disorders
Completed suicide	1/20 (5%)		0/16 (0%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/20 (10%)		0/16 (0%)		0/5 (0%)
Pleural effusion	1/20 (5%)		1/16 (6.3%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Relapsed/Refractory Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma		Relapsed/Refractory Follicular Lymphoma		Relapsed/Refractory Marginal Zone Lymphoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/20 (95%)		16/16 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Anaemia	4/20 (20%)		3/16 (18.8%)		2/5 (40%)
Thrombocytopenia	1/20 (5%)		3/16 (18.8%)		0/5 (0%)
Neutropenia	1/20 (5%)		1/16 (6.3%)		0/5 (0%)
Gastrointestinal disorders
Abdominal pain upper	5/20 (25%)		1/16 (6.3%)		1/5 (20%)
Diarrhoea	1/20 (5%)		2/16 (12.5%)		0/5 (0%)
Vomiting	2/20 (10%)		1/16 (6.3%)		0/5 (0%)
General disorders
Pyrexia	1/20 (5%)		3/16 (18.8%)		2/5 (40%)
Asthenia	0/20 (0%)		1/16 (6.3%)		2/5 (40%)
Oedema peripheral	1/20 (5%)		2/16 (12.5%)		0/5 (0%)
Hepatobiliary disorders
Hepatic failure	0/20 (0%)		2/16 (12.5%)		0/5 (0%)
Infections and infestations
Upper respiratory tract infection	1/20 (5%)		3/16 (18.8%)		4/5 (80%)
Pneumonia	2/20 (10%)		2/16 (12.5%)		1/5 (20%)
Urinary tract infection	0/20 (0%)		2/16 (12.5%)		2/5 (40%)
Investigations
White blood cell count decreased	5/20 (25%)		5/16 (31.3%)		3/5 (60%)
Neutrophil count decreased	4/20 (20%)		4/16 (25%)		3/5 (60%)
Alanine aminotransferase increased	3/20 (15%)		2/16 (12.5%)		1/5 (20%)
Aspartate aminotransferase increased	2/20 (10%)		2/16 (12.5%)		1/5 (20%)
Platelet count decreased	3/20 (15%)		1/16 (6.3%)		1/5 (20%)
Blood bilirubin increased	2/20 (10%)		0/16 (0%)		1/5 (20%)
Weight decreased	1/20 (5%)		1/16 (6.3%)		1/5 (20%)
Blood urine present	0/20 (0%)		2/16 (12.5%)		0/5 (0%)
Lymphocyte count decreased	0/20 (0%)		1/16 (6.3%)		1/5 (20%)
Metabolism and nutrition disorders
Hypokalaemia	2/20 (10%)		1/16 (6.3%)		0/5 (0%)
Decreased appetite	0/20 (0%)		1/16 (6.3%)		1/5 (20%)
Hyperlipidaemia	0/20 (0%)		2/16 (12.5%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/20 (5%)		1/16 (6.3%)		0/5 (0%)
Back pain	2/20 (10%)		0/16 (0%)		0/5 (0%)
Muscular weakness	0/20 (0%)		1/16 (6.3%)		1/5 (20%)
Nervous system disorders
Dizziness	1/20 (5%)		1/16 (6.3%)		0/5 (0%)
Renal and urinary disorders
Haematuria	0/20 (0%)		4/16 (25%)		2/5 (40%)
Haemoglobinuria	0/20 (0%)		1/16 (6.3%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)		4/16 (25%)		0/5 (0%)
Skin and subcutaneous tissue disorders
Purpura	1/20 (5%)		3/16 (18.8%)		1/5 (20%)
Drug eruption	0/20 (0%)		2/16 (12.5%)		0/5 (0%)
Rash maculo-papular	1/20 (5%)		0/16 (0%)		1/5 (20%)
Vascular disorders
Hypertension	0/20 (0%)		1/16 (6.3%)		1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

BeiGene has 18 months from the end of the study at all sites to publish overall study results. After the 1st multi-site publication or the expiration of publication period, Investigators are free to publish/present the results of the study. Investigators must submit all draft publications/presentations to us for review 60 days prior to the planned publication/presentation date. BeiGene may request deletion of its confidential information & may request a further delay to protect its IP rights.