Clinical trial NCT03520920
Conditions: Marginal Zone Lymphoma Follicular Lymphoma Diffuse Large B-Cell Lymphoma
Sponsor: BeiGene
Start date: 2018-01-04; Completion date: 2020-08-28
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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 \[MZL\]).

Detailed description:

Arms: arm 1: Participants with non-GCB DLBCL received zanubrutinib plus rituximab for up to progressive disease or intolerance. arm 2: Participants with R/R FL or MZL received zanubrutinib plus rituximab for up to progressive disease or intolerance.
Interventions: intervention 1: Zanubrutinib intervention 2: Rituximab
Intervention descriptions: intervention 1: Administered zanubrutinib 160 mg orally (PO) BID continuously intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
BeiGene (Beijing) Co., Ltd 
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Clinical Study Protocol 
 
 
Protocol 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) 
 
Protocol Number: 
BGB-3111-213 
 
Study Phase:  
 
 
2 
 
Investigational Product(s):              Zanubrutinib (BGB-3111) 
 
Indication: 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma (non-
GCB Subtype) and Relapsed/Refractory Indolent Lymphoma 
(Follicular Lymphoma and Marginal Zone Lymphoma) 
 
Sponsor: 
BeiGene (Beijing) Co., Ltd 
No. 30 Science Park Road,  
Zhong-Guan-Cun Life Science Park 
Changping district, Beijing 102206  
 
Sponsor Medical Monitor: 
 
Version 1.0  
(Original Protocol):  
 
22 June 2017 
Version 2.0  
(Protocol Amendment 1.0):  
28 March 2019            
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the Sponsor. 
 


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PROTOCOL APPROVAL SHEET 
 
PROTOCOL 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) 
 
PROTOCOL NO: 
 
BGB-3111-213 
 
 
 
DATE OF PROTOCOL: 
28 March 2019 
 
 
 
 
 
 
 
 
 
____________________________________ 
 
 
___________________ 
 
 
 
 
 
 
 Date 
Sponsor Medical Monitor 
 
 
 
 
 
 
 


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PROTOCOL AMENDMENT, VERSION 1.0, RATIONALE 
The main purpose of this protocol amendment is as follows: 
 
To add the result of a drug-drug interaction study with the strong CYP3A inhibitor or inducer 
(BGB-3111-104) in text and tables with correlating content revised in number-updated 
Appendix 5; 
 
To add the result of a thorough QT study (BGB-3111-106) and remove QT/QTc interval 
prolonging medications and correlating contents in tables/appendixes;  
 
To add the result of a cocktail drug-drug interaction study (BGB-3111-108) and correlating 
concomitant medications content with Appendix 7 removed;  
 
To clarify and add urinalysis and optional urea test as a replacement of BUN in comprehensive 
serum chemistry panel for safety and tolerability assessment; 
 
To add supplementary pathology information and baseline information collected retrospectively 
(eg, EBV infected history and IPI score) for exploratory analysis; 
 
To use 5-point causality assessment scale for AE causality instead of 2-point causality 
assessment; 
 
To revise the text for clarity and consistency of the definition of safety follow-up and AE/SAE 
assessment period; 
 
To use the International Nonproprietary Name ‘zanubrutinib’ for BGB-3111; 
 
To revise the abbreviation in the list, text and under tables according to the Style Guide in 
BeiGene. 
 
Throughout are administrative updates, editorial changes, and/or style and formatting revisions 
made with the purpose of improving clarity and consistency. Additionally, changes were made to 
the synopsis to match changes made in the protocol body. 
 
Key changes made from the Version 1.0 (dated 22 June 2017) to Version 2.0 (19 March 2019), are 
summarized in the protocol sections below: 


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 
In section 1.1.1, Summary of Relevant Non-clinical Data with zanubrutinib: revised the text of 
CYP according to the latest non-clinical data; 
 
Added section 1.1.5, Clinical Pharmacology: updated the information of QT interval 
prolongation and drug-drug interaction potential of zanubrutinib; 
 
In section 1.3, Study Rationale: corrected the referred study BGB-3111-1004 as BGB-3111-
1002; 
 
In section 3.2, Secondary Endpoints: deleted ‘nature’ of AEs to clarify the safety and 
tolerability evaluation of zanubrutinib; 
 
In section 4, Study Design:  
- 
added ‘disease progression or’ to clarify the continuation period of Rituximab in 
consistence with the text in the protocol; 
- 
replaced Internal Monitoring Committee (IMC) with Safety Monitoring Committee (SMC) 
in performing the safety evaluation of the study and deleted the text of additional IMC 
meetings; 
 
In section 4.1, Duration of Study: revised the text to clarify the duration of study; 
 
In section 5.1, section 7.1.1, section 7.2.3 and the number-updated footnote 19 in Appendix 2: 
added ‘to meet requirement of biomarker analysis’ to specify the archival tumor tissue and/or a 
fresh tumor biopsy collected for screening; 
 
In section 5.1, Inclusion Criteria: 
- 
item 4: added ‘occurring more than 6 months after the completion of last therapy’ to 
specify the definition of relapsed disease; 
- 
Item 5 a: corrected the order of magnitude of numberings for previous formatting error; 
 
In section 5.2, Exclusion Criteria item 19 a: revised the wording to clarify the period of 
performing anti-viral therapy and monthly monitoring on eligible patients (also in Table 4); 
 
In section 6.2.1 and 6.2.2: deleted correlating text that may lead issues later; 
 
In section 6.2.1 and 6.2.3: modified the wording to clarify study treatment preparation and 
dispensation; 
 
In section 6.4.1, Zanubrutinib: revised the text to clarify the role of investigator in study drug 
administration; 


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 
In section 6.5.2, BGB-3111 Dose Reductions for Non-hematologic Toxicity: modified the text 
of zanubrutinib dose reduction in accordance with corresponding grade of AEs; 
 
In section 6.5.3, Dose Modification for Rituximab: revised the acceptable rituximab dose delay 
start time as cycle 4; 
 
In section 6.6.1, Prior Therapy: revised ‘The exclusion criteria specify that patients will not 
have received prior systemic therapy’ to ‘The inclusion criteria specify that patients will have 
received prior systemic therapy’; 
 
In section 6.6.2, Concomitant Therapy: revised the wording for clarification; 
 
In section 6.6.2.1, Permitted Medications: To add language about the potential for opportunistic 
infections, including Pneumocystis jirovecii pneumonia (PJP), in patients with hematologic 
malignancies, particularly those having received prior lymphodepleting chemotherapy or 
having prolonged corticosteroid exposure, and guidance to consider prophylaxis treatment per 
institutional standards. 
 
In section 6.6.3, Potential Interactions Between the Study Drugs and Concomitant Medications 
and number-updated Appendix 5, CYP3A Inhibitors and Inducers: 
- 
updated the information of CYP3A inhibitors/inducers as concomitant medications with 
‘Table 2: Dose Modification Table for Zanubrutinib when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers’ added (with the following-numbered 
tables renumbered), based on BGB-3111-104 study;  
- 
removed the content of concomitant medications that are primarily metabolized by 
isoenzymes of CYP2C8, CYP2C9 and CYP2C19, based on BGB-3111-108 study (also 
removed Appendix 7); 
- 
removed QT/QTc interval prolonging medication and Appendix 5, Medications Which are 
Known to Prolong the QT Interval and/or Induce Torsades de Pointes (with the following-
numbered appendix renumbered), based on BGB-3111-106 study; 
- 
 added the concomitant medications of narrow therapeutic index drugs metabolized by 
CYP3A4 and CYP2C19. 
 
In section 6.7, End of Treatment:  
- 
added ‘If a patient underwent study drug interruption > 7 days, before decision of EOT, 
EOT visit can be done within the interval of 30 ± 3 days after the last dose of study drug, 


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combining assessments at both EOT and safety Follow-up visits.’ for clarification of EOT 
visit (also in section 7.1.4 and the footnote 4 in Appendix 2); 
- 
replaced ‘central review’ with ‘investigator and medical monitor’ in the confirmation of 
disease progression development; 
- 
added ‘Need for long-term’ for clarification of prohibited concomitant therapy 
administration; 
 
In section 6.8.1, Safety Follow-up: revised the wording as ‘30 days (±3 days) after the last dose 
of study drug (zanubrutinib or rituximab, whichever occurs later), or prior to the start of new 
anticancer therapy, whichever occurs first.’ for clarification of safety follow-up period and 
consistency with other BeiGene protocols; 
 
In section 6.8.2, Efficacy Follow-up: added ‘since Cycle 1 Day 1’ and deleted ‘new anti-cancer 
therapy’ to specify and correct the period of performing tumor imaging; 
 
In section 6.8.3, Survival Follow-up: revised the text for clarification of survival follow-up 
process; 
 
In section 6.9, End of Study: 
- 
deleted ‘The study will be considered complete once all patients have had disease 
progression, discontinued treatment due to intolerance, died, withdrew from study, or 
completed study treatment for a total of 2 years, whichever occurs first’ for simplification 
and clarification; 
- 
added ‘at the time of study closure’ to clarify the time point; 
 
In section 7.1.1, Screening:  
- 
added ‘and disease history’ and deleted ‘and surgery’ to clarify and correct the medical 
history considered at screening; 
- 
added IPI score and previous EBER result (if available) in the disease medical history item 
for exploratory analysis (updated the correlating content also in Appendix 2); 
- 
added ‘for patients with non-GCB DLBCL in cohort 1 while only patients with FL in 
cohort 2’ for clarification of PET scan; (also in section 7.1.4, End of Treatment) 
- 
deleted ‘and pulse oximetry’ in vital signs item; (also in section 7.1.2, section 7.1.3, 
section 7.1.4, and section 7.1.5) 


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- 
deleted ‘must be performed within 3 days of the first dose of zanubrutinib’ in item serum 
pregnancy test as its unnecessary specification (also in section 7.3.6.6 and the number-
updated footnote 18 in Appendix 2); 
 
In section 7.1.2, section 7.1.3, section 7.1.4 and section 7.1.5: added item Urinalysis, with 
correlating supplementary information where needs specification; 
 
In section 7.1.3: added zanubrutinib pre-dose item for supplement in pharmacokinetics blood 
draw; 
 
In section 7.1.4, End of Treatment: added ‘for confirmation of progressive disease, if 
progressive disease is the reason for discontinuation of treatment’ to specify the CT 
assessment; 
 
In section 7.1.5, Safety Follow-up: revised the wording for clarification of the safety follow-up 
period; 
 
In section 7.2.1.2, PET:  
- 
added ‘for patients with non-GCB DLBCL and FL until progressive disease, withdrawal of 
consent, death, lost to follow-up, or end of study, whichever occurs first.’ to specify the 
appropriate patients on whom perform PET scanning for tumor assessment; 
- 
added ‘Response assessment for ORR will be by PET scan and categorized as per the 
Lugano Classification (Appendix 3) for clarification (also revised the schedule of 
assessment in Appendix 2); 
 
In section 7.3.1, Adverse Events: revised the wording for correction and clarification of 
AE/SAE collection period; 
 
In section 7.3.2: deleted ‘Significant new findings that begin or worsen after informed consent 
must be recorded on the Adverse Event page of the patient’s eCRF’ for clarification and 
consistency with the context; 
 
In section 7.3.5, Electrocardiogram: deleted ‘The Screening ECG should be performed in 
triplicate’ as in Appendix 2, footnote 10 for duplication in the section; 
 
In section 7.3.6.2, Clinical Chemistry and Immunoglobulins: added urine test as the 
replaceable one for BUN test; 
 
Added section 7.3.6.4, Urinalysis and the corresponding item in Appendix 2 with footnote 15 
for clarification of the urine test (with the following-numbered sections and footnotes in 
Appendix 2 renumbered); 


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 
In section 7.3.6.6, Pregnancy Test: deleted ‘(within 3 days before the first dose of study drug)’ 
to correct the time performing pregnancy test at screening; 
 
In section 7.4.1, Biomarker Analysis: added the text of other pathology information for 
exploratory analysis; 
 
In section 9.1.1.2, Assessment of Causality: replaced 2-point causality assessment scale for AE 
causality with 5-point causality assessment based on the actual case; 
 
In section 9.1.1.3, section 9.6, section 9.7, renumbered section 9.9 and section 9.10: added 
‘designee’ as replaceable role for Sponsor in performing the correlating function; 
 
In section 9.4.1, Adverse Event Reporting Period: revised the text for clarification and 
consistency with other BeiGene protocols;  
 
Removed section 9.9, Adverse Events of Special Interest, and correlating content in section 
9.7.1, section 10.3.1 and Table 5 (with the following-numbered section renumbered); 
 
In section 9.7.2, Completion and Transmission of the Serious Adverse Event Report: deleted 
telephone notification in the case that both EDC system and facsimile transmission are 
nonoperational; 
 
In renumbered section 9.9, Pregnancy Reporting: revised the wording for clarification and 
correction; 
 
Removed section 9.10.1, Time Period for Collection Pregnancy Information, with the revised 
content narrated in section 9.9; 
 
In section 10, Statistical Methods and Sample Size Determination: deleted the text that is 
included in the SAP; 
 
Revised the title of section 10.1.1, Analysis Population as ‘Analysis Sets’:  
- 
revised ‘Population’ as ‘Analysis Set’ for correction; 
- 
changed ‘any dose’ to ‘at least 1 dose’ for clarification; 
- 
deleted ‘Patients will be assigned to the treatment arms as treated.’ for it’s a single-arm 
study; 
- 
revised ‘major protocol deviations’ as ‘important protocol deviations’; 
- 
revised the wording for clarification of analysis sets for exploratory parameters; 
 
In section 10.2, Efficacy Data Analysis: added ‘TTR’ for supplement; 
 
In section 10.3.1, Adverse Event:  


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- 
revised the text for clarification of TEAE definition; 
- 
revised the definition of treatment-related AEs; 
- 
deleted ‘Adverse events representing clear evidence of disease progression will not be 
considered relevant to the assessment of toxicity.’ for not relevant to this section; 
 
In section 10.3.2 and section 10.3.4: deleted ‘treatment group’ for correction; 
 
In section 10.3.3, Electrocardiogram: deleted the summarization of ECG change from baseline; 
for the ECG will only be collected at screening, C1D1 and safety follow-up visit, it doesn’t 
make any sense to summarize change from baseline.; 
 
In section 10.3.5, Extent of Exposure: revised the wording for correction and clarification; 
 
In Appendix 2: revised Footnote 2, 4, 7, 8, 10, 18, 19, 21,22, 25 for correction and clarification. 


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SYNOPSIS 
Name of 
Sponsor/Company: 
BeiGene (Beijing) Co., Ltd 
Protocol No: 
BGB-3111-213 
Protocol 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) 
Study Drug: 
 
Zanubrutinib (also known as BGB-3111) 
 
Rituximab  
Phase: 
Phase 2 
Comparator: 
None 
Background and 
Rationale: 
Signaling via an aberrantly activated B-cell receptor is known to play a critical 
role in the pathogenesis of B-cell malignancies by promoting survival and 
clonal expansion of malignant B-cells. Rituximab, an anti-CD20 monoclonal 
antibody, is widely used in the treatment of CD20+ B-cell malignancies, both 
as a component of combination regimens and as single agent, with anti-tumor 
activity of rituximab dependent in part on antibody-dependent cellular 
cytotoxicity (ADCC). Phase 2 experiences with ibrutinib in combination with 
rituximab have demonstrated that the combinations are active, lack 
overlapping toxicity, and can be combined at full monotherapy doses of the 
respective agents (Burger et al 2014, Fowler et al 2015, Wang et al 2016). 
Zanubrutinib is a more potent, more specific second-generation Bruton 
tyrosine kinase (BTK) inhibitor that has demonstrated a well-tolerated and 
acceptable safety profile in the ongoing global and China Phase 1 studies 
(BGB-3111-AU-003 and BGB-3111-1002). Zanubrutinib is more selective 
against off-target kinases including interleukin-2-inducible T cell kinase 
(ITK), and is associated with less interference of the ADCC effect induced by 
anti-CD20 antibodies in pre-clinical studies. In preclinical xenograft models, 
zanubrutinib has also demonstrated good combination activity with rituximab. 
In light of the preliminary efficacy and safety data of the ongoing global and 
China Phase 1 studies of zanubrutinib (BGB-3111-AU-003 and BGB-3111-
1002) in B-cell malignancies, the encouraging data of combination 
zanubrutinib and obinutuzumab, and demonstration of combination activity for 
zanubrutinib and rituximab in preclinical models, the safety, tolerability,  
pharmacokinetics (PK) and preliminary efficacy of zanubrutinib in 
combination with rituximab for non-germinal center B-cell-like (GCB) 
diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma in Chinese 
patients will be explored in this study. 


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Study Design: 
This is a Phase 2, multicenter, single-arm, open-label study evaluating the 
safety and efficacy of zanubrutinib 160 mg twice daily in combination with 
rituximab in the following patients: 
Cohort 1 (n=20): relapsed/refractory (R/R) non-GCB DLBCL 
Cohort 2 (n=20): R/R follicular (FL) or marginal zone lymphoma (MZL) 
Rituximab will be administered at 375 mg/m2 intravenously on Cycle 1 Days 
1, 8, 15, 22, and on Day 1 of Cycles 4, 6, 8, 10. 
Zanubrutinib will be administered at 160 mg orally twice daily. Zanubrutinib 
will be administered at least 30 minutes prior to the initiation of the rituximab 
infusion. 
Treatment with zanubrutinib may be continued until disease progression or an 
unacceptable drug-related toxicity occurs. Rituximab is continued for a total of 
8 doses or until disease progression or an unacceptable drug-related toxicity. 
Patients may withdraw from study treatment due to an adverse event, disease 
progression, withdrawal of consent. For patients still on study drug at the time 
of study closure and continuing to benefit from study drug, the Sponsor will 
make study drug available for continued treatment in a long-term extension 
study. 
The continuous safety evaluation of this study will be performed by an internal 
Safety Monitoring Committee (SMC) as outlined in the SMC charter.  
Safety evaluation by the SMC will start after 6 patients have completed at least 
1 cycle (28 days) of study treatment, and approximately every 6 months to 
review ongoing safety thereafter according to the progress of study and 
necessity. Enrollment will be held during the SMC evaluation period (after 6 
patients have enrolled) until the SMC has approved re-opening of the trial. 
Pharmacokinetic blood sampling for zanubrutinib will be performed at (1) pre-
dose on Cycle 1 Day 1; (2) 2 hours after zanubrutinib dosing on Cycle 1 Day 1 
(± 30 minutes); (3) pre-dose on Cycle 4 Day 1; and (4) 2 hours after 
zanubrutinib dosing on Cycle 4 Day 1(± 30 minutes). Pharmacokinetics blood 
sampling for rituximab will be performed at (1) pre-dose on Cycle 1 Day 1; 
(2) within 30 minutes after end of infusion on Cycle 1 Day 1; (3) pre-dose on 
Cycle 4 Day 1; (4) within 30 minutes after end of infusion on Cycle 4 Day 1. 
Study Duration: 
Approximately 2 years from the time of last enrollment until the end of study 
Objectives: 
All primary and secondary objectives will evaluate zanubrutinib plus 
rituximab in patients with R/R non-GCB DLBCL, R/R FL, and R/R MZL 
Primary: 
 
To evaluate efficacy, as measured by overall response rate by 
investigator 


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Secondary: 
 
To evaluate efficacy, as measured by the following: 
o Duration of response as determined by investigator 
o Progression-free survival as determined by investigator 
o Overall survival 
o Rate of complete response (CR) or complete metabolic 
response (CMR) as determined by investigator 
o Time to response as determined by investigator 
 
Safety and tolerability of zanubrutinib in combination with rituximab 
Exploratory: 
• 
To characterize the PK of zanubrutinib in combination with rituximab 
in patients with R/R non-GCB DLBCL, R/R FL, and R/R MZL 
• 
To evaluate the correlation between clinical/genomic risk factors and 
clinical outcomes in R/R non-GCB DLBCL, R/R FL, and R/R MZL 
• 
To explore mechanisms of disease resistance in samples from patients 
who fail to achieve partial response (PR) or better after at least 6 
months of study treatment, and from those who manifest disease 
relapse in R/R non-GCB DLBCL, R/R FL, and R/R MZL 
Planned Number of 
Patients: 
Approximately 40 
Study Population: 
Inclusion Criteria:  
1. Age ≥ 18 years at time of signing of informed consent. 
2. Measurable disease by computed tomography (CT) or positron 
emission tomography (PET)/CT or magnetic resonance imaging 
(MRI), defined as ≥ 1 nodal lesion that is > 1.5 cm in the longest 
diameter, or ≥ 1 extra-nodal lesion (eg, hepatic nodules) that is > 1 cm 
in the longest diameter. 
3. Availability of archival or a fresh tumor tissue sample from an 
evaluable core or excisional biopsy (paraffin embedded block or 10-15 
unstained formalin-fixed paraffin-embedded [FFPE] slides) to meet 
the requirement of biomarker analysis. 
4. Patients meet the following criteria: 
a. Cohort 1: R/R non-GCB DLBCL 
i. Histologically confirmed non-GCB DLBCL per Hans 
criteria (Hans et al 2004) with non-transformed 


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disease; additional methodologies for confirming non-
GCB DLBCL may be considered in consultation with 
the medical monitor 
ii. 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 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 (eg, 
R-CHOP) or CVP ± R for DLBCL  
b. 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 CR or 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) 
5. Laboratory parameters as specified below: 
a. Hematologic: Platelet count ≥ 75 x 109/L independent of 
growth factor or transfusion within 7 days of study entry; 
absolute neutrophil count (ANC) ≥ 1 x 109/L independent of 
growth factor within 7 days of study entry, hemoglobin (Hgb) 
> 8 g/dL within 7 days of study entry 
b. Hepatic: Total bilirubin ≤ 2x upper limit of normal (ULN) 
unless documented Gilbert’s syndrome; aspartate 
aminotransferase (AST)/serum glutamic-oxaloacetic 
transaminase (SGOT) and alanine transaminase (ALT)/serum 
glutamic-pyruvic transaminase (SGPT) ≤ 3 x ULN 
c. Renal: Creatinine clearance ≥ 30 mL/min (as estimated by the 
Cockcroft-Gault equation based on ideal body weight or as 
measured by nuclear medicine scan or 24-hour urine 
collection) 


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d. International normalized ratio (INR) and activated partial 
thromboplastin time (aPTT) ≤ 1.5 x ULN. Patients with anti-
phospholipid syndrome, acquired von Willebrand disease, 
factor inhibitors or on vitamin K antagonist may be enrolled 
after discussion with the medical monitor 
6. Left ventricular ejection fraction (LVEF) ≥ 50%. 
7. Life expectancy ≥ 6 months. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 
0, 1, or 2. 
9. Female patients of childbearing potential must practice 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. These methods include the following: 
a. Combined (estrogen and progestogen containing) hormonal 
contraception associated with the inhibition of ovulation 
i. Oral, intravaginal or transdermal 
b. Progestogen-only hormonal contraception associated with the 
inhibition of ovulation 
i. Oral, injectable, implantable 
c. An intrauterine device  
d. Intrauterine hormone-releasing system  
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence (defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the 
study treatment, starting the day 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). Total sexual abstinence should only be used as a 
contraceptive method if it is in line with the patients’ usual 
and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to 
investigational medicinal product, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female 
condoms with or without spermicide) is not considered a 
highly effective method of contraception and if used, this 


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method must be used in combination with another acceptable 
method listed above. 
10. Male patients are eligible if vasectomized or if they agree 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. 
11. Able to provide written informed consent and can understand and 
comply with the requirements of the study. 
Exclusion Criteria:  
1. Known central nervous system lymphoma or leukemia. 
2. Histological confirmed gastric mucosa-associated lymphoid tissue 
(MALT) type MZL. 
3. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura. 
4. Clinically significant cardiovascular disease including the following: 
a. Myocardial infarction within 6 months before screening 
b. Unstable angina within 3 months before screening 
c. New York Heart Association Class III or IV congestive heart 
failure  
d. History of clinically significant arrhythmias (eg, sustained 
ventricular tachycardia, ventricular fibrillation, torsades de 
pointes) 
e. QT interval corrected using Fridericia’s formula (QTcF) 
> 480 msecs based on Fredericia’s formula 
f. History of Mobitz II second-degree or third-degree heart 
block without a permanent pacemaker in place 
g. Uncontrolled hypertension as indicated by a minimum of 2 
consecutive blood pressure measurements showing systolic 
blood pressure > 170 mm Hg and diastolic blood pressure 
> 105 mm Hg at screening 
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. 


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8. Hypersensitivity reaction to zanubrutinib or rituximab or any of the 
other ingredients of the study drugs. 
9. Prior BTK inhibitor treatment. 
10. Requires ongoing treatment with a strong Cytochrome P450 3A 
(CYP3A) inhibitor or inducer (see Appendix 5). 
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:  
a. 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. 
b. Chemotherapy or radiotherapy within 4 weeks. 
c. Monoclonal antibody within 4 weeks. 
d. Investigational therapy within 4 weeks. 
e. Chinese patent medicine with anti-neoplastic intent within 4 
weeks. 
14. Not recovered from toxicity of any prior anti-cancer therapy to 
≤ Grade 1, except for alopecia, ANC, Hgb and platelets. For ANC, 
Hgb and platelets, see Inclusion criterion #5.  
15. 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. 
16. 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. 
17. Major surgery within 4 weeks prior to first dose of study treatment. 
18. Active fungal, bacterial and/or viral infection requiring systemic 
therapy. 
19. Known infection with human immunodeficiency virus (HIV), or 


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serologic status reflecting active hepatitis B or C infection as follows: 
a. Presence of hepatitis B surface antigen (HBsAg) or anti-
hepatitis B core antibody (anti-HBc). Patients with presence 
of anti-HBc, but absence of HBsAg, are eligible if hepatitis B 
virus (HBV) DNA is < 500 IU/mL; anti-viral therapy will be 
started before the first dose of study drug, and maintained 
throughout the study treatment with monthly monitoring for 
HBV reactivation. 
b. Presence of hepatitis C virus (HCV) antibody. Patients with 
presence of HCV antibody are eligible if HCV RNA is 
undetectable (<15 IU/mL).  
See Section 7.3.6.5 and Table 4 for more information. 
20. Pregnant or lactating women. 
21. Underlying medical conditions that, in the investigator’s opinion, will 
render the administration of study drug hazardous or obscure the 
interpretation of toxicity or AEs. 
22. Concurrent participation in another therapeutic clinical trial. 
Test Product, Dose, 
and Mode of 
Administration: 
 
Zanubrutinib will be administered as two 80-mg capsules by mouth 
twice a day (160 mg twice a day) with or without food at approximately 
the same time starting from Cycle 1 Day 1. The capsules should be taken 
approximately 12 hours apart, ± 2 hour time window. On days where 
both study drugs are administered, zanubrutinib will be given first and 
30 minutes later, the infusion of rituximab will be initiated. 
 
Rituximab will be administered intravenously at a dose of 375 mg/m2 in 
accordance with the Prescribing Information dose for NHL. There is a 
front loading four-weekly infusion of rituximab in Cycle 1 during time 
of initial highest disease burden, followed by infusions on Day 1 of 
Cycles 4, 6, 8, and 10. 
Study Assessments: 
Response will be assessed by computed tomography (CT) scan and 
categorized as per the Lugano Classification (Cheson et al 2014). Tumor 
assessment by CT with contrast of neck, chest, abdomen, and pelvis will be 
performed at protocol specified time points. CT scan with contrast will occur 
at Screening, Week 12, and every 12 weeks thereafter until progressive 
disease, withdrawal of consent, death, lost to follow-up, or end of study, 
whichever occurs first. Total body MRI is allowed if CT with contrast is 
contraindicated. Positron emission tomography (PET)/CT may be used in lieu 
of a CT with contrast only if the CT of the PET/CT has been performed with 
diagnostic quality and contrast is administered. 


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Tumor assessment by PET scan will be performed at Screening, Week 24, 
Week 48, progressive disease suspected clinically or by CT (MRI if CT 
contraindicated), and CR suspected clinically or by CT (MRI if CT 
contraindicated), for sites with PET scanning capability, until progressive 
disease, withdrawal of consent, death, lost to follow-up, or end of study, 
whichever occurs first.  
Safety assessments should be performed at all visits by the investigator 
throughout the study. Safety assessments will consist of monitoring all adverse 
events (AEs) and serious AEs (SAEs), regular monitoring of blood tests, urine 
tests, vital signs, weight, ECOG performance status, and physical 
examinations. Patients will be evaluated for AEs (all grades per the National 
Cancer Institute-Common Terminology Criteria for Adverse Events, Version 
4.03 [NCI-CTCAE Version 4.03]), SAEs and any AEs requiring study drug 
interruption or discontinuation, starting from Screening until 30 days after last 
dose of zanubrutinib or 90 days after the last dose of rituximab, whichever is 
longer. 
For schedule of study visits, refer to Appendix 2, Schedule of Assessments. 
Concomitant 
medications: 
 
Patients with high tumor burden should be monitored closely and 
prophylactic measures, including allopurinol or rasburicase, may be 
instituted per institutional standards. Tumor lysis syndrome has not 
been currently reported with zanubrutinib treatment, but has been 
reported in some cases with rituximab. 
 
Bisphosphonate use is permitted if the patient has already been on it 
for 3 or more months and on a stable dose.  
 
Corticosteroid courses of limited duration (2 weeks or less) and dose 
(<20 mg prednisone per day, or equivalent) are permitted, if used to 
treat a concomitant (non-cancer) medical condition, with the exception 
of glucocorticoids used for management of rituximab-related infusion 
reaction.  
 
Patients with hematologic malignancies, particularly those having 
received prior lymphodepleting chemotherapy or having prolonged 
corticosteroid exposure, are pre-disposed to opportunistic infections as 
a result of disease and treatment-related factors. In patients with a high 
risk for opportunistic infections, including Pneumocystis jirovecii 
pneumonia (PJP), prophylaxis should be considered as per 
institutional standards. 
 
Patients should not receive other anticancer therapy (cytotoxic, 
biologic, or hormone other than for replacement) while on treatment in 
this study. 


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 
Other anticancer therapy should not be administered until disease 
progression (as per clinical practice standards at the study center), 
unmanageable toxicity, or no further clinical benefit occurs which 
requires permanent discontinuation of the study drug. 
 
Chinese patent medicine for treatment of cancer are not allowed on 
study. Chinese herbal medications in the use of anti-cancer treatment 
is prohibited 
 
Live vaccines are prohibited during Screening and while on study 
treatment. 
 
Administration of zanubrutinib with strong/moderate CYP3A 
inhibitors or CYP3A inducers (refer to Appendix 5 for a list of these 
medications) and grapefruit juice and Seville oranges should be used 
with caution as they may affect the metabolism of zanubrutinib. If at 
all possible, patients are encouraged not to use strong/moderate 
CYP3A inhibitors and inducers and should consider using alternative 
agents. If these agents will be used, follow the dose modification 
instruction in Table 2. The medical monitor should be consulted in 
these situations. Please refer to the FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers 2019 for a 
more complete list.  
 
Clinical drug-drug interaction study indicated that zanubrutinib is a 
mild inducer of CYP3A4 and CYP2C19. Narrow therapeutic index 
drugs that are metabolized by CYP3A4 (alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should 
be used with caution, as zanubrutinib may decrease the plasma 
exposures of these drugs. Since blood levels and effectiveness of 
drugs that are substrates for CYP3A (eg, steroidal contraceptives) may 
be reduced by CYP3A inducers, if patients are using hormonal 
contraceptives such as birth control pills or devices, a second barrier 
method of contraception (eg, condoms) is recommended to be used. 
The coadministration of oral P-gp substrates with a narrow therapeutic 
index (eg, digoxin) should be used with caution as zanubrutinib may 
increase their concentrations. 
Study Endpoints: 
 
Primary Endpoint: 
 
Overall response rate (ORR) as measured by investigator 
Secondary Endpoints: 
 
Duration of response as determined by investigator 


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 
Progression-free survival as determined by investigator 
 
Overall survival 
 
Rate of complete response or complete metabolic response as determined 
by investigator 
 
Time to response as determined by investigator 
 
Safety and tolerability of zanubrutinib in combination with rituximab as 
evaluated by the incidence and severity of AEs, clinical laboratory 
abnormalities, deaths and cause of death 
Exploratory Endpoints: 
Statistical Methods: 
 
The analyses for both efficacy and safety endpoints will be performed in the 
Safety Analysis Set defined as all patients who received at least 1 dose of 
zanubrutinib or rituximab on the study. The primary endpoint of ORR will be 
determined by the crude proportion as crude proportion (number of patients 
who achieve PR or higher) as best response. The estimate of ORR with 95% 
exact confidence interval will be presented in each cohort. CR and CMR will 
be analyzed using the same methods applied for ORR analysis. Listings for 
time to event secondary efficacy endpoints (progression-free survival [PFS], 
duration of response [DOR], overall survival [OS], and time to response) will 
be generated. The distribution of time to event secondary efficacy endpoints 
will be estimated where applicable.  
All patients for whom valid zanubrutinib PK can be estimated and no 
important protocol deviations affecting PK will be included in the PK Analysis 
Set on an as treated basis. Similarly, patients for whom valid rituximab PK can 
be estimated and no important protocol deviations affecting PK will be 
included in the PK Analysis Set on an as treated basis. For exploratory 
parameters, all patients for whom can be estimated on with evaluable data will 
be included in the summaries. 
All safety and tolerability data recorded during the study will be listed and 
summarized as appropriate. Continuous variables will be summarized using 
descriptive statistics and by time points where applicable. Categorical 
variables will be summarized in frequency tables. 


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The sample size is 20 for each cohort, totaling 40 for the study. No formal 
statistical hypothesis testing will be performed for study endpoints and the 
sample size was not determined by statistical power consideration. 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL SHEET ...........................................................................................2 
PROTOCOL AMENDMENT, VERSION 1.0, RATIONALE ............................................3 
SYNOPSIS ...............................................................................................................................10 
TABLE OF CONTENTS .........................................................................................................22 
LIST OF TABLES ...................................................................................................................25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................26 
1 
INTRODUCTION .......................................................................................................28 
1.1 
Zanubrutinib .....................................................................................................29 
1.1.1 
Summary of Relevant Non-clinical Data with zanubrutinib .............29 
1.1.2 
Dose Selection for zanubrutinib ........................................................31 
1.1.3 
Preliminary Efficacy Data with zanubrutinib ....................................32 
1.1.4 
Preliminary Safety Data with zanubrutinib .......................................33 
1.1.5 
Clinical Pharmacology ......................................................................34 
1.2 
Rituximab .........................................................................................................35 
1.3 
Study Rationale ................................................................................................36 
2 
OBJECTIVES ..............................................................................................................37 
2.1 
Primary Objective ............................................................................................37 
2.2 
Secondary Objectives.......................................................................................37 
2.3 
Exploratory Objectives ....................................................................................37 
3 
STUDY ENDPOINTS .................................................................................................38 
3.1 
Primary Endpoint .............................................................................................38 
3.2 
Secondary Endpoints .......................................................................................38 
3.3 
Exploratory Endpoints .....................................................................................38 
4 
STUDY DESIGN.........................................................................................................38 
4.1 
Duration of Study .............................................................................................39 
5 
STUDY POPULATION ..............................................................................................40 
5.1 
Inclusion Criteria .............................................................................................40 
5.2 
Exclusion Criteria ............................................................................................43 
6 
STUDY TREATMENTS .............................................................................................45 
6.1 
Study Treatment ...............................................................................................45 
6.2 
Study Treatment Preparation and Dispensation ...............................................45 
6.2.1 
Packaging and Labeling ....................................................................45 
6.2.2 
Handling and Storage ........................................................................46 
6.2.3 
Compliance and Accountability ........................................................46 
6.2.4 
Disposal and Destruction ...................................................................46 
6.3 
Patient Numbering and Treatment Assignment ...............................................46 
6.3.1 
Patient Numbering .............................................................................46 
6.3.2 
Treatment Blinding ............................................................................47 
6.4 
Dosage and Administration..............................................................................47 


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6.4.1 
Zanubrutinib ......................................................................................47 
6.4.2 
Rituximab ..........................................................................................47 
6.5 
Dose Interruption and Modification.................................................................48 
6.5.1 
Zanubrutinib Dose Reductions for Hematologic Toxicity ................48 
6.5.2 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity ..........49 
6.5.3 
Dose Modifications for Rituximab ....................................................49 
6.6 
Concomitant Medications and Non-Drug Therapies .......................................50 
6.6.1 
Prior Therapy .....................................................................................50 
6.6.2 
Concomitant Therapy ........................................................................50 
6.6.3 
Potential Interactions Between the Study Drugs and 
Concomitant Medications ..................................................................51 
6.6.4 
Surgery and Procedures .....................................................................52 
6.7 
End of Treatment .............................................................................................52 
6.8 
Follow-up Phase...............................................................................................53 
6.8.1 
Safety Follow-up ...............................................................................53 
6.8.2 
Efficacy Follow-up ............................................................................54 
6.8.3 
Survival Follow-up ............................................................................54 
6.9 
End of Study ....................................................................................................54 
6.10 
Loss to Follow-up ............................................................................................54 
7 
STUDY ASSESSMENTS ...........................................................................................55 
7.1 
Study Procedures .............................................................................................55 
7.1.1 
Screening ...........................................................................................55 
7.1.2 
Cycle 1 Day 1 (minus 3-day window) ...............................................57 
7.1.3 
Day 1 of Cycle 2 and All Subsequent Cycles (± 3-day window) ......57 
7.1.4 
End of Treatment ...............................................................................58 
7.1.5 
Safety Follow-up ...............................................................................59 
7.1.6 
Survival Follow-up ............................................................................59 
7.2 
Efficacy Assessments.......................................................................................60 
7.2.1 
Imaging Studies .................................................................................60 
7.2.2 
Bone Marrow Aspirate and Biopsy ...................................................60 
7.2.3 
Archival or Fresh Tumor Collection .................................................60 
7.3 
Safety and Tolerability Assessments ...............................................................61 
7.3.1 
Adverse Events ..................................................................................61 
7.3.2 
Physical Examination, Vital Signs, Height, and Weight ...................61 
7.3.3 
Medical and Cancer History ..............................................................62 
7.3.4 
ECOG Performance Status ................................................................62 
7.3.5 
Electrocardiogram .............................................................................63 
7.3.6 
Laboratory Evaluations .....................................................................63 
7.4 
Other Assessments ...........................................................................................66 
7.4.1 
Biomarker Analysis ...........................................................................66 
8 
DATA HANDLING AND QUALITY ASSURANCE ...............................................66 
8.1 
Data Collection ................................................................................................67 
8.2 
Data Management/Coding ...............................................................................67 
8.3 
Quality Assurance ............................................................................................68 


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9 
SAFETY MONITORING AND REPORTING...........................................................68 
9.1 
Adverse Events ................................................................................................68 
9.1.1 
Definitions and Reporting .................................................................68 
9.1.2 
Laboratory Test Abnormalities ..........................................................72 
9.1.3 
Lack of Efficacy ................................................................................72 
9.2 
Serious Adverse Events ...................................................................................72 
9.3 
Suspected Unexpected Serious Adverse Reaction ...........................................73 
9.4 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events ...................................................................................74 
9.4.1 
Adverse Event Reporting Period .......................................................74 
9.4.2 
Eliciting Adverse Events ...................................................................74 
9.5 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events ...............................................................................................................74 
9.5.1 
Diagnosis versus Signs and Symptoms .............................................74 
9.5.2 
Adverse Events Occurring Secondary to Other Events .....................75 
9.5.3 
Persistent or Recurring Adverse Events ............................................75 
9.5.4 
Disease Progression ...........................................................................75 
9.5.5 
Death ..................................................................................................76 
9.6 
Recording of Adverse Events and Serious Adverse Events ............................76 
9.7 
Prompt Reporting of Serious Adverse Events .................................................76 
9.7.1 
Time Frame for Submission of Serious Adverse Events ...................76 
9.7.2 
Completion and Transmission of the Serious Adverse Event 
Report ................................................................................................77 
9.7.3 
Regulatory Reporting Requirements for Serious Adverse Events ....78 
9.8 
Serious Adverse Events Related to Study Participation ..................................78 
9.9 
Pregnancy Reporting ........................................................................................78 
9.9.1 
Action to be Taken and Reporting if a Pregnancy Occurs ................79 
9.10 
Post-Study Adverse Events and Serious Adverse Events ................................80 
9.11 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards and Ethics Committees ...........................................................80 
10 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ..................81 
10.1 
Sample Size ......................................................................................................81 
10.1.1 
Analysis Sets .....................................................................................81 
10.1.2 
Interim Analysis ................................................................................81 
10.1.3 
Withdrawal ........................................................................................81 
10.1.4 
Pharmacokinetics ...............................................................................81 
10.2 
Efficacy Data Analysis ....................................................................................82 
10.2.1 
Primary Efficacy Endpoint ................................................................82 
10.2.2 
Secondary Efficacy Endpoints ..........................................................82 
10.3 
Safety Data Analysis ........................................................................................82 
10.3.1 
Adverse Event ...................................................................................82 
10.3.2 
Laboratory Assessments ....................................................................83 
10.3.3 
Electrocardiogram .............................................................................83 
10.3.4 
Vital Signs .........................................................................................83 
10.3.5 
Extent of Exposure ............................................................................84 
10.3.6 
Physical Examination ........................................................................84 


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10.3.7 
Other Safety Endpoints ......................................................................84 
10.4 
Explorative Endpoint Analyses ........................................................................84 
11 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .........84 
11.1 
Regulatory Authority Approval .......................................................................84 
11.2 
Investigator Responsibilities ............................................................................85 
11.2.1 
Good Clinical Practice .......................................................................85 
11.2.2 
Ethical Conduct of the Study and Ethics Approval ...........................85 
11.2.3 
Informed Consent ..............................................................................86 
11.2.4 
Investigator Reporting Requirements ................................................86 
11.2.5 
Confidentiality ...................................................................................86 
11.2.6 
Case Report Forms ............................................................................87 
11.2.7 
Drug Accountability ..........................................................................87 
11.2.8 
Inspections .........................................................................................88 
11.2.9 
Protocol Adherence ...........................................................................88 
11.3 
Sponsor Responsibilities ..................................................................................88 
11.3.1 
Protocol Modifications ......................................................................88 
11.3.2 
Study Report and Publications ..........................................................89 
11.4 
Study and Study Center Closure ......................................................................89 
11.5 
Records Retention and Study Files ..................................................................90 
11.6 
Provision of Study Results and Information to Investigators ..........................92 
11.7 
Information Disclosure and Inventions ............................................................92 
11.8 
Joint Investigator/Sponsor Responsibilities .....................................................93 
11.8.1 
Access to Information for Monitoring ...............................................93 
11.8.2 
Access to Information for Auditing or Inspections ...........................93 
12 
REFERENCES ............................................................................................................95 
13 
APPENDICES .............................................................................................................97 
Appendix 1. 
Signature of Investigator ...................................................................97 
Appendix 2. 
Schedule of Assessments ...................................................................98 
Appendix 3. 
The Lugano Classification for Response Assessment .....................103 
Appendix 4. 
Non-Hodgkin Lymphoma Staging ..................................................107 
Appendix 5. 
CYP3A Inhibitors and Inducers ......................................................108 
 
LIST OF TABLES 
 
Table 1. 
BGB-3111 Dose Reduction Levels ............................................................................ 48 
Table 2. 
Dose Modification Table for Zanubrutinib when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers ....................................................... 48 
Table 3. 
ECOG Performance Status ........................................................................................ 63 
Table 4. 
Active hepatitis B (HBV) or hepatitis C (HCV) infection (detected positive by 
polymerase chain reaction [PCR]) ............................................................................. 65 
Table 5. 
Timeframe for Reporting Serious Adverse Events and Adverse Events of Special 
Interest to the Sponsor or Designee ........................................................................... 77 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event  
ANC 
absolute neutrophil count 
aPTT  
activated partial thromboplastin time 
BTK 
Bruton tyrosine kinase 
CBC 
complete blood count 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed concentration 
CMR 
complete metabolic response 
CR 
complete response 
CRF  
case report form 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 protein 
DLBCL 
diffuse large B-cell lymphoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FL 
follicular lymphoma 
GCB 
germinal center B-cell-like 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 


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Ig 
immunoglobin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible T cell kinase 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MUGA 
Multigated acquisition scan 
MZL 
Marginal zone lymphoma 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Toxicity Criteria for 
Adverse Events 
NHL 
non-Hodgkin lymphoma 
ORR 
overall response rate 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
R/R 
relapsed/refractory 
SAE 
serious adverse event 
SLL 
small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
WM 
Waldenström macroglobulinemia 
zanubrutinib 
BGB-3111 
 


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1 
INTRODUCTION 
Bruton tyrosine kinase (BTK), a member of the non-receptor tyrosine kinases that include 
BTK/AKT, tyrosine kinase expressed in hepatocellular carcinoma (TEC), interleukin-2-inducible T 
cell kinase (ITK)/EMT/TSK, and Bone marrow tyrosine kinase gene in Chromosome X protein 
(BMX)/epithelial and endothelial tyrosine kinase (ETK), is a critical component of the B-cell 
receptor signaling cascade. The defining features of these kinases is the presence of a pleckstrin 
homology domain at their N-terminus. Bruton tyrosine kinase has a restricted expression in a subset 
of B-cells and in myeloid cells, and is involved in signaling by B-cell antigen receptor, mast cell 
FcR, interleukin (IL)-5; IL-6 receptor. Naturally occurring mutations of BTK were initially 
identified in the human immunodeficiency disease X-linked agammaglobulinemia (XLA) and 
murine X-linked immunodeficiency. The XLA phenotype includes the lack of mature circulating B-
cells and immunoglobulins (Qiu and Kung 2000). 
Antigen binding to B-cell receptor immunoglobulin heavy chains and light chains triggers activation 
of immunoreceptor tyrosine-based activation motifs in CD79A and CD79B with subsequent 
phosphorylation of spleen tyrosine kinase. Spleen tyrosine kinase recruits B-cell linker protein 
which, in turn, phosphorylates BTK and phospholipase C-gamma-2 (PLC2). In addition, SRC-
family kinases activated through IgH and IgL binding also phosphorylate CD19 which recruits PI3K 
to the B-cell receptor. These signals ultimately translate into nuclear factor-B and AKT activation, 
promoting proliferation and survival of normal and malignant B-cells (Blum 2015). Inhibition of 
BTK has emerged as a promising strategy for B-cell malignancies (Blum 2015, Young and Staudt 
2013).  
Ibrutinib, a first generation small-molecule BTK inhibitor, has demonstrated activity in several B-
cell malignancies including mantle cell lymphoma (MCL) (Tucker and Rule 2016, Wang et al 
2016), chronic lymphocytic leukemia (CLL) (Burger et al 2014, Byrd et al 2013), Waldenström 
macroglobulinemia (WM) (Castillo et al 2016, Dimopoulos et al 2017), follicular lymphoma (FL) 
(Fowler et al 2015, Ujjani et al 2016), multiple myeloma (Naymagon and Abdul-Hay 2016), and 
activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) (Wilson et al 
2015). Ibrutinib acts by forming a stable covalent bond to the amino acid cysteine at position 481 in 
the BTK active site, consequently blocking adenosine triphosphate from binding and thus 
preventing activation of BTK (Gayko et al 2015). Adverse reactions with ibrutinib treatment, 


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believed to be related to ibrutinib’s off-target activities against epidermal growth factor receptor 
(EGFR)/Janus kinase (JAK)3/TEC, include skin rash, nausea, vomiting, thrombocytopenia, 
bleeding, and atrial fibrillation. It is currently approved by the United States (US) Food and Drug 
Administration (FDA) for treatment of patients with MCL who had received at least one prior 
therapy, CLL/small lymphocytic lymphoma (SLL) with or without 17p deletion, WM, and marginal 
zone lymphoma (MZL) who had received at least one prior anti-CD20-based therapy (Imbruvica 
USPI). 
1.1 
Zanubrutinib 
Zanubrutinib (BGB-3111) is a potent, specific, and irreversible BTK inhibitor with a favorable 
pharmacologic/toxicologic profile. Preclinical data suggests that zanubrutinib is differentiated from 
ibrutinib in the following aspects:  
(1) Zanubrutinib is more selective than ibrutinib in the inhibition of BTK versus EGFR, Gardner-
Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR), Fyn-related kinase (FRK), 
human epidermal growth factor receptor (HER)2, HER4, ITK, JAK3, lymphocyte-specific 
protein tyrosine kinase (LCK), and tyrosine kinase expressed in TEC. The predicted efficacious 
dose of zanubrutinib in patients is much lower than ibrutinib. Accordingly, off-target kinase 
inhibition potentially associated with common, and occasionally severe, adverse effects 
associated with ibrutinib therapy, such as thrombocytopenia, bleeding, atrial fibrillation, rash, 
and gastrointestinal toxicities, may be reduced relative to ibrutinib;  
(2) Zanubrutinib has better oral bioavailability than ibrutinib;  
(3) Due to its weaker ITK inhibitory activity, zanubrutinib displays a significantly less inhibitory 
effect on rituximab-induced antibody dependent cell-mediated cytotoxicity (ADCC) compared 
to ibrutinib in preclinical studies (Da Roit et al 2015, Hans et al 2004), and is therefore unlikely 
to adversely impact the anti-tumor effects of rituximab. 
1.1.1 
Summary of Relevant Non-clinical Data with zanubrutinib 
Summaries of nonclinical studies are provided below. For more detailed information please refer to 
the BGB-3111 Investigator’s Brochure (IB). 


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Zanubrutinib is a potent, specific and irreversible BTK kinase inhibitor with a 50% maximum 
inhibitory concentration (IC50) of 0.3 nanomole per litre (nM). Cellular assays confirm that 
zanubrutinib inhibits B-cell receptor aggregation-triggered BTK autophosphorylation, and blocks 
downstream PLCγ2 signaling in mantle cell lymphoma cell lines. Zanubrutinib had an IC50 of 
1.8 nM in a homogeneous time resolved fluorescence-based BTKpY223 assay. It potently and 
selectively inhibited cellular growth of several mantle cell lymphoma cell lines (REC-1, Mino and 
JeKo-1) and the activated B-cell type diffuse large B-cell lymphoma cell line transmembrane 
domain 8 (TMD-8), with IC50 values from 0.36 nM to 20 nM, while it was inactive in many other 
hematologic cancer cell lines.  
In vivo studies have demonstrated that zanubrutinib induces dose-dependent antitumor effects 
against REC-1 mantle cell lymphoma xenografts engrafted either subcutaneously or systemically in 
mice, which are significantly more effective than ibrutinib. Zanubrutinib also demonstrated better 
antitumor activity than ibrutinib in TMD-8 diffuse large B cell lymphoma subcutaneous xenograft 
model. In a pharmacokinetic (PK)/pharmacodynamic study, oral administration of zanubrutinib 
resulted in time-dependent occupancy of BTK in blood and in spleen in mice, and was 
approximately 3-fold more potent than ibrutinib in mouse pharmacodynamic assays.  
In a panel of 342 human kinases, 1 µM zanubrutinib inhibited only 12 other kinases by > 70%. 
Zanubrutinib was more selective than ibrutinib for inhibition of kinase activity of BTK versus 
EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC. Cellular assays also confirmed that 
zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR (> 6-
fold). Inhibition of ITK has been reported to reduce rituximab-induced antibody-dependent cell-
mediated cytotoxicity. Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib in 
inhibiting rituximab-induced antibody-dependent cell-mediated cytotoxicity, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity than 
ibrutinib in both biochemical and cellular assays. 
Cytochrome P450 (CYP) phenotyping in human liver microsomes suggests that CYP3A was the 
major CYP isoform responsible for zanubrutinib metabolism. Zanubrutinib is a weak, reversible 
inhibitor of CYP2C8 and intestinal (but not hepatic) CYP3A4, and does not display clinically 
relevant time-dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
or CYP3A. Zanubrutinib is a weak inducer of CYP2B6 and CYP3A4, but does not induce CYP1A2. 


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Although zanubrutinib is a sensitive CYP3A4 substrate, it does not have a clinically relevant effect 
on its own exposure. Zanubrutinib may inhibit breast cancer resistance protein (BCRP) and P-
glycoprotein (P-gp) transport at clinical doses. When co-administrated with zanubrutinib, the 
exposure of narrow therapeutic window P-gp or BCRP substrated (eg, digoxin, methotrexate) may 
increase. Zanubrutinib does not inhibit the hepatic uptake transporters, OATP1B1 and OATP1B3, 
or the renal uptake transporters, organic anion transporter (OAT) 1, OAT2, and organic cation 
transporter (OCT) 2.  
The toxicity profiles of zanubrutinib have been well characterized in rats and dogs. No specific 
safety concerns were identified in vital organs/systems including cardiovascular system, respiratory 
system, and central nervous systems. No corrected QT interval (QTc) changes were noted in the 
conscious telemetry implanted dogs over 24 hours after dosing up to 100 mg/kg, or in the repeat 
dose toxicity studies in dogs over 91 days at doses up to 100 mg/kg/day. No mortality or severe 
toxicity was noted in 91-day repeat-dose toxicity studies in both rats and dogs at doses up to 300 
mg/kg and 100 mg/kg, respectively. Test article-related reversible histopathology changes were 
mainly noted in rats, including pancreas, spleen, prostate gland, cecum, colon, rectum, skin (lip 
and/or nose), and uterus. None of the above findings were considered to be adverse in the 91-day 
repeated dosing studies. No genotoxicity was noted in the genotoxicity core battery studies. 
1.1.2 
Dose Selection for zanubrutinib 
In the first-in-human (FIH), phase 1 study, BGB-3111-AU-003, the PK of BGB-3111 was linear 
between 40 mg and 320 mg daily administered orally (BGB-3111 Investigator’s Brochure). The 
absorption of zanubrutinib is rapid with median time to maximum plasma concentration of 2 hours. 
The terminal elimination half-life is approximately 4 hours at 320 mg daily. Results from a food 
effect study showed that zanubrutinib exposure was not altered by a high-fat breakfast, and mean 
area under the concentration-time curve (AUC) and maximum observed concentration (Cmax) were 
increased by 12% and 51%, respectively with standard breakfast when compared to fasting. The 
magnitude of increase in exposure with food was well within doubling of exposure associated with 
320 mg administered daily in the ongoing phase 1, and was not associated with any new safety 
findings. Therefore, zanubrutinib can be administered with or without food. The terminal 
elimination half-life is approximately 4 hours at 320 mg daily.  
Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all patients in the 


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BGB-3111-AU-003 study, while occupancy in lymph node tissue was assessed only at 160 mg 
twice daily and 320 mg daily (Tam et al 2015). At the 160 mg twice a day dose, full BTK 
occupancy was observed at trough, suggesting that sustained target occupancy could be achieved in 
disease-originating tissues, thus more efficiently inhibiting BTK on a continuous basis, further 
preventing breakthrough signaling despite cycles of new BTK synthesis. Activity has been observed 
across various B-cell malignancies (including CLL, MCL, WM and FL) at all tested dose levels; 
thus, a minimum effective dose cannot be established at this time. Conversely, there is now 
extensive research at the 160 mg twice daily and 320 mg daily dose; both schedules show a high 
level of activity without compromise of the tolerability profile as compared to lower doses of 
zanubrutinib. Therefore, the dose of 160 mg administered orally twice a day has been selected as the 
recommended phase 2 and phase 3 dose based on sustained target occupancy, high rates of objective 
response in multiple types of B-cell malignancies, and a favorable safety and tolerability profile. 
Rituximab is administered intravenously at 375 mg/m2 in accordance with the US Prescribing 
Information dose for NHL. There is a front loading, four-weekly infusion of rituximab in Cycle 1 
during time of initial highest disease burden, followed by infusions on Day 1 of Cycles 4, 6, 8, and 
10.  
1.1.3 
Preliminary Efficacy Data with zanubrutinib 
In the FIH study of zanubrutinib (BGB-3111-AU-003), the first patient, first visit occurred on 
25 August 2014. Of the 54 CLL/SLL patients evaluable for response (>12 weeks follow-up or 
discontinuation before 12 weeks) as of 15 December 2016, the objective response rate was 96% 
(52/54), with partial response (PR) in 67% (36/54), PR with lymphocytosis in 30% (16/54), stable 
disease in 1 relapsed/refractory (R/R) patient, and no assessment for 1 R/R patient because of 
adverse event (AE). No instances of disease progression or Richter transformation were reported.  
As of 31 December 2016, 41 patients with WM were evaluable for efficacy (5 non-evaluable 
patients had either baseline IgM <500 mg/dL [n=3] recent plasmapheresis [n=1] or <12 weeks’ 
follow-up [n=1]). The objective response rate was 93% (38/41), with a major response rate of 78% 
(32/41): very good partial response (VGPR) in 39% (16/41) and PR in 39% (16/41). Median time to 
response was 28 days. The sole patient with disease progression remains on zanubrutinib with 
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BGB-3111-1002 is the Phase I study in China and the first patient, first visit occurred on 05 July 
2016. The efficacy data for this study are not yet available for analysis. 
BGB-3111-GA101_Study_001 is the combination study of zanubrutinib and obinutuzumab. The 
first patient visit occurred on 22 December 2015. As of 15 December 2016, 40 patients with 
CLL/SLL (17 patients with treatment-naive [TN]; 23 patients with R/R), and 13 patients with FL 
were enrolled. Patients were evaluable for response if they had completed baseline and ≥1 on-
treatment response assessment. Objective response rates (complete response [CR] + PR+ PR with 
lymphocytosis) were 88.9%, 86.7%, and 81.8% in TN CLL/SLL, R/R CLL/SLL, and R/R FL, 
respectively, with 3 CRs in R/R CLL/SLL and 5 CRs in FL. Two patients (1 R/R CLL;1 FL) 
experienced disease progression; no instances of disease transformation occurred. 
1.1.4 
Preliminary Safety Data with zanubrutinib 
Preliminary results from the FIH BGB-3111 study have demonstrated that zanubrutinib is well 
tolerated in patients with advanced B-cell malignancies. As of 15 December 2016, 68 patients with 
CLL/SLL (50 R/R and 18 TN) were enrolled in the Phase 1 Study. The median follow-up was 7.2 
months (range, 0-23.3). The most frequent adverse events (AEs) of any cause were bruising (35%) 
and petechiae (11%), upper respiratory tract infection (28%), fatigue (25%), cough (22%), and 
diarrhea (21%). Four serious AEs (SAEs) related to zanubrutinib were seen in 3 patients: Grade 2 
cardiac failure, Grade 2 pleural effusion, Grade 3 purpura, and Grade 3 pneumonia. The case of 
Grade 3 purpura (subcutaneous hemorrhage) was the only major bleeding event reported. Atrial 
fibrillation (Grade 3) occurred in 1 patient. One patient discontinued zanubrutinib for an AE (pleural 
effusion). As of 31 December 2016, 46 patients with WM were enrolled and evaluable for safety: 
median 2 prior therapies (range 0-8), median follow-up 8.2 months (1.4-28). The most frequent AEs 
(≥20%, all Grade 1 or 2) were upper respiratory infection (33%), contusion (28%), and constipation 
(22%). There were 3 treatment-related SAEs (Grade 2 atrial fibrillation [AF], Grade 2 headache, 
Grade 3 cryptococcal meningitis); in all 3 cases, zanubrutinib was withheld and safely resumed. 
Three patients developed AF (one Grade 1, two Grade 2), and 1 developed Grade 3 diarrhea. No 
serious hemorrhage was reported.  
Of the 21 patients enrolled in BGB-3111-1002 as of the October 2016 data cutoff, 12 patients (57%) 
had experienced a treatment-emergent adverse event (TEAE) of >Grade 2 severity. Additionally, 
18/21 (86%) of all patients had experienced a TEAE assessed by the investigator as related to 


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treatment. There had been no SAEs, AEs leading to discontinuation, or fatal AEs. 
For BGB-3111-GA101_Study_001, BGB-3111 plus obinutuzumab was well tolerated. As of 15 
December 2016, no fatal AEs occurred; only 1 AE led to treatment discontinuation (squamous cell 
carcinoma in a patient with prior squamous cell carcinoma). SAEs were reported in 25.0% of 
CLL/SLL patients and 23.1% of FL patients; there was only 1 SAE related to obinutuzumab 
(infusion-related reaction) and 1 SAE related to zanubrutinib (pneumonia). There were no AEs of 
atrial fibrillation.  
1.1.5 
Clinical Pharmacology 
The QT interval prolongation potential of zanubrutinib was evaluated in healthy volunteers in a 
thorough QT study (BGB-3111-106). Results from this study demonstrated that single oral dose of 
zanubrutinib at a therapeutic dose of 160 mg and a supratherapeutic dose of 480 mg did not have a 
clinically relevant effect on electrocardiogram (ECG) parameters, including QTc intervals and other 
ECG intervals. Because of the short half-life and no accumulation seen upon multiple-dosing, these 
results are also applicable for steady-state conditions. 
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicate that, in healthy 
volunteers, co-administration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg 
once daily for 8 days) decreased exposure of zanubrutinib by 13.5-fold for area under the plasma 
concentration-time curve from zero to infinity (AUC0-∞), and 12.6-fold for Cmax. Co-administration 
of zanubrutinib with strong CYP3A inhibitor itraconazole (200 mg once daily for 4 days) increased 
exposure of zanubrutinib by 3.8-fold for AUC0-∞, and 2.6-fold for Cmax. These results are consistent 
with the role for CYP3A isoenzymes as the principal metabolic pathway for zanubrutinib. 
Based on the in vitro study, a clinical drug-drug interaction study (BGB-3111-108) was conducted 
to assess the effect of zanubrutinib on the PK of substrates of CYP3A (midazolam), CYP2C9 
(warfarin), CYP2C19 (omeprazole), P-gp (digoxin), BCRP (rosuvastatin) using a cocktail approach. 
The study showed that zanubrutinib has no effect on CYP2C9 enzyme and BCRP activity. 
Zanubrutinib is shown to be a mild CYP3A4 and CYP2C19 inducer per FDA guidelines.  AUC0-t 
and Cmax values were approximately 47% and 30% lower, respectively, when midazolam was 
coadministered with zanubrutinib.  AUC0-t and Cmax values were approximately 36% and 20% 
lower, respectively, when omeprazole was coadministered with zanubrutinib. Repeated dosing of 


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zanubrutinib increased exposure of digoxin (P-gP substrate) with a mean increase of 11% for AUC0-
t and 34% for Cmax. 
1.2 
Rituximab 
Rituximab is a genetically engineered, chimeric murine/human monoclonal IgG1 kappa antibody 
directed against the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. 
Rituximab has an approximate molecular weight of 145 kilodalton (kD), and a binding affinity for 
the CD20 antigen of approximately 8.0 nM. Upon binding to CD20, rituximab mediates B-cell lysis, 
with possible mechanisms of lysis including complement-dependent cytotoxicity (CDC) and 
ADCC. The antibody induced apoptosis in the SU-DHL 4 human B-cell lymphoma cell line. In 
NHL patients, administration of rituximab resulted in depletion of circulating and tissue-based B 
cells. Circulating CD19-positive B cells are depleted within the first three weeks with sustained 
depletion for up to 6 to 9 months after rituximab treatment in 83% of patients. B-cell recovery 
begins at approximately 6 months, and median B-cell levels return to normal by 12 months 
following completion of treatment. Rituximab can be detectable in serum of patients 3 to 6 months 
after treatment cessation (Rituxan USPI). 
Based on population PK analysis of data from 298 non-Hodgkin lymphoma (NHL) patients who 
received rituximab once weekly or once every 3 weeks, the estimated median terminal elimination 
half-life is 22 days (range 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger 
measurable tumor lesions at pre-treatment had a higher clearance. However, dose adjustment for 
pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender have no effect on 
the PK of rituximab (Rituxan USPI). 
Most common AEs associated with rituximab treatment in clinical trials for NHL were infusion 
reaction, fever, lymphopenia, chills, infection, and asthenia. For CLL, most common AEs were 
infusion reaction and neutropenia. Severe mucocutaneous reaction, hepatitis B virus (HBV) 
reactivation, and progressive multifocal leukoencephalopathy have also been reported with 
rituximab treatments. Tumor lysis syndrome (TLS) can be associated with rituximab treatment in 
patients with NHL, with a high number of circulating malignant cells (≥ 25,000/mm3) or high tumor 
burden conferring a greater risk of TLS (Rituxan USPI). 


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Rituximab is currently approved in the US for treatment of CD20+ NHL, CLL, rheumatoid arthritis, 
and granulomatosis with polyangiitis and microscopic polyangiitis. 
1.3 
Study Rationale 
Signaling via an aberrantly activated B-cell receptor is known to play a critical role in the 
pathogenesis of B-cell malignancies by promoting survival and clonal expansion of malignant B-
cells. Treatment with inhibitors of BTK such as ibrutinib has demonstrated responses in patients 
with various B-cell malignancies including CLL/SLL, MCL, DLBCL, FL, MZL, and WM. 
Rituximab, an anti-CD20 monoclonal antibody, is widely used in the treatment of CD20+ B-cell 
malignancies, both as a component of combination regimens and as single agent, with anti-tumor 
activity of rituximab dependent in part on ADCC. Phase 2 experiences with ibrutinib in combination 
with rituximab have demonstrated that the combinations are active, lack overlapping toxicity, and 
can be combined at full monotherapy doses of the respective agents (Burger et al 2014, Fowler et al 
2015, Wang et al 2016). 
Zanubrutinib, compared to ibrutinib, is a more potent, more specific second-generation BTK 
inhibitor that has demonstrated a well-tolerated and acceptable safety profile in the ongoing global 
and China Phase 1 studies (BGB-3111-AU-003 and BGB-3111-1002). Furthermore, compared to 
ibrutinib, zanubrutinib is more selective against off-target kinases including ITK, and is associated 
with less interference of the ADCC effect induced by anti-CD20 antibodies in pre-clinical studies. 
In preclinical xenograft models, zanubrutinib has also demonstrated good combination activity with 
rituximab. 
In light of the preliminary efficacy and safety data of the ongoing global and China Phase 1 studies 
of zanubrutinib (BGB-3111-AU-003 and BGB-3111-1002) in B-cell malignancies, the encouraging 
data of combination ibrutinib and rituximab, and demonstration of combination activity for 
zanubrutinib and rituximab in preclinical models, the preliminary efficacy as well as safety, 
tolerability, and PK of zanubrutinib in combination with rituximab for non-Hodgkin lymphoma in 
Chinese patients will be explored in this study. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, the Declaration of Helsinki and any applicable regulatory requirement. 


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2 
OBJECTIVES  
All primary and secondary objectives will evaluate zanubrutinib plus rituximab in patients with 
relapsed/refractory (R/R) non-germinal center B-cell-like (GCB) DLBCL, R/R FL, and R/R MZL. 
2.1 
Primary Objective 
 To evaluate efficacy, as measured by overall response rate (ORR) by investigator 
2.2 
Secondary Objectives 
 To evaluate efficacy, as measured by the following: 
o Duration of response as determined by investigator 
o Progression-free survival as determined by investigator 
o Overall survival 
o Rate of complete response or complete metabolic response as determined by 
investigator 
o Time to response as determined by investigator 
 Safety and tolerability 
2.3 
Exploratory Objectives 


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3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
 Overall response rate (ORR) measured by investigator 
3.2 
Secondary Endpoints 
 Duration of response as determined by investigator 
 Progression-free survival as determined by investigator 
 Overall survival 
 Rate of complete response or complete metabolic response as determined by investigator 
 Time to response as determined by investigator 
 Safety and tolerability of zanubrutinib in combination with rituximab as evaluated by the 
incidence and severity of AEs, clinical laboratory abnormalities, deaths and cause of death 
3.3 
Exploratory Endpoints 
 
4 
STUDY DESIGN 
This is a multicenter open-label study evaluating the safety and efficacy of zanubrutinib 160 mg 
twice daily in combination with rituximab in the following patients: 
Cohort 1 (n=20): relapsed/refractory non-GCB DLBCL 


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Cohort 2 (n=20): relapsed/refractory FL or MZL 
Rituximab will be administered at 375 mg/m2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on 
Day 1 of Cycles 4, 6, 8, 10. 
Zanubrutinib will be administered at 160 mg orally twice daily. Zanubrutinib will be administered at 
least 30 minutes prior to the initiation of the rituximab infusion. 
Treatment with zanubrutinib may be continued until disease progression or an unacceptable drug-
related toxicity occurs. Rituximab is continued for a total of 8 doses or until disease progression or 
an unacceptable drug-related toxicity. Patients may withdraw from study treatment due to an 
adverse event, disease progression, withdrawal of consent. For patients still on study drug at the 
time of study closure and continuing to benefit from study drug, the Sponsor will make study drug 
available for continued treatment in a long-term extension study. 
The continuous safety evaluation of this study will be performed by a Safety Monitoring Committee 
(SMC) as outlined in the SMC charter.  
Safety evaluation by the SMC will be performed after 6 patients have completed at least 1 cycle (28 
days) of study treatment, and approximately every 6 months to review ongoing safety thereafter or 
according to the progress of study and necessity. Enrollment will be held during the SMC 
evaluation period (after 6 patients have enrolled) until the SMC has approved re-opening of the trial. 
 
 
 
 
 
 
 
 
4.1 
Duration of Study 
The total duration of this study is expected to be approximately 3 years, assuming an expected 
enrollment duration of 12 months and completed study treatment for a total of 24 months after the 
last enrolled patient. All patients in the study will receive zanubrutinib and rituximab for Cycles 1 to 
10, then single agent zanubrutinib for up to 2 years total treatment from Cycle 1 Day 1, until disease 


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progression, unacceptable toxicity or death, withdrawal of consent, or the study is terminated by the 
Sponsor for final analysis. Patients continuing to benefit after study closure will be given the 
opportunity to continue to receive single agent zanubrutinib on a long-term extension study.  
 
5 
STUDY POPULATION 
Approximately 40 patients will be enrolled. 
5.1 
Inclusion Criteria 
Patients may be enrolled on study only if they meet all the following criteria: 
1. Age ≥ 18 years at time of signing of informed consent. 
2. Measurable disease by computed tomography (CT) or positron emission tomography 
(PET)/CT or magnetic resonance imaging (MRI), defined as ≥ 1 nodal lesion that is > 1.5 
cm in the longest diameter, or ≥ 1 extra-nodal lesion (eg, hepatic nodules) that is > 1 cm in 
the longest diameter. 
3. Availability of archival or a fresh tumor tissue sample from an evaluable core or excisional 
biopsy (paraffin embedded block or 10-15 unstained formalin-fixed, paraffin-embedded 
[FFPE] slides) to meet the requirement of biomarker analysis  
4. Patients meet the following criteria: 
a. Cohort 1: R/R non-GCB DLBCL 
i. Histologically confirmed non-GCB DLBCL per Hans criteria (Hans et al 
2004) with non-transformed disease 
ii. 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 CR or PR to therapy for non-GCB DLBCL or 
disease progression within 6 months after completion of the most recent 
therapy for non-GCB DLBCL) 


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iii. Must have received at least one standard anthracycline ± rituximab-based 
treatment (eg, R- CHOP) or CVP+/- R for DLBCL 
b. 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 CR or 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). 
5. Laboratory parameters as specified below: 
a. Hematologic: Platelet count ≥ 75 x 10^9/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 (Hgb) 
> 8 g/dL within 7 days of study entry. 
b. Hepatic: Total bilirubin ≤ 2x upper limit of normal (ULN) unless documented 
Gilbert’s syndrome; aspartate aminotransferase (AST)/serum glutamic-oxaloacetic 
transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvic 
transaminase (SGPT) ≤ 3x ULN. 
c. Renal: Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault 
equation based on ideal body weight or as measured by nuclear medicine scan or 
24-hour urine collection) 
d. International normalized ratio and activated partial thromboplastin time (aPTT) ≤ 
1.5x ULN. Patients with anti-phospholipid syndrome, acquired von Willebrand 
disease, factor inhibitors or on vitamin K antagonist may be enrolled after discussion 
with the Medical Monitor. 
6. Left ventricular ejection fraction (LVEF) ≥ 50%. 
7. Life expectancy ≥ 6 months. 


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8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 
9. Female patients of childbearing potential must practice 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. These methods include the following: 
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with the inhibition of ovulation 
i. Oral, intravaginal or transdermal 
b. Progestogen-only hormonal contraception associated with the inhibition of ovulation 
i. Oral, injectable, implantable 
c. An intrauterine device  
d. Intrauterine hormone-releasing system  
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment, starting the day 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). Total sexual 
abstinence should only be used as a contraceptive method if it is in line with the 
patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration 
of exposure to investigational medicinal product, and withdrawal are not acceptable 
methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without 
spermicide) is not considered a highly effective method of contraception and if used, 
this method must be used in combination with another acceptable method listed 
above. 


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10. Male patients are eligible if vasectomized or if they agree 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. 
11. Able to provide written informed consent and can understand and comply with the 
requirements of the study. 
5.2 
Exclusion Criteria 
1. Known central nervous system lymphoma or leukemia. 
2. Histological confirmed gastric mucosa-associated lymphoid tissue (MALT) type MZL. 
3. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. 
4. Clinically significant cardiovascular disease including the following: 
a. Myocardial infarction within 6 months before screening 
b. Unstable angina within 3 months before screening 
c. New York Heart Association class III or IV congestive heart failure  
d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, 
ventricular fibrillation, torsades de pointes) 
e. QT interval corrected using Fridericia’s formula (QTcF) > 480 msecs based on 
Fredericia’s formula 
f. History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place 
g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic 
blood pressure > 105 mm Hg at screening 
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. 


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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 BTK inhibitor treatment. 
10. Requires ongoing treatment with a strong CYP3A inhibitor or inducer (see Appendix 5). 
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:  
a. 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. 
b. Chemotherapy or radiotherapy within 4 weeks. 
c. Monoclonal antibody within 4 weeks. 
d. Investigational therapy within 4 weeks. 
e. Chinese patent medicine with anti-neoplastic intent within 4 weeks. 
14. Not recovered from toxicity of any prior anti-cancer therapy to ≤ Grade 1, except for 
alopecia, ANC, Hgb and platelets. For ANC, Hgb and platelets, see Inclusion criterion #5.  
15. 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. 
16. 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. 
17. Major surgery within 4 weeks prior to first dose of study treatment. 


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18. Active fungal, bacterial and/or viral infection requiring systemic therapy. 
19. Known infection with human immunodeficiency virus (HIV), or serologic status reflecting 
active hepatitis B or C infection as follows: 
a. Presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibody 
(anti-HBcAb). Patients with presence of anti-HBcAb, but absence of HBsAg, are 
eligible if HBV DNA is < 500 IU/mL; anti-viral therapy will be started before the 
first dose of study drug, and maintained throughout the study treatment with monthly 
monitoring for HBV reactivation. 
b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV 
antibody are eligible if HCV RNA is undetectable (<15 IU/mL).  
See Section 7.3.6.5 and Table 4 for more information. 
20. Pregnant or lactating women. 
21. Underlying medical conditions that, in the investigator’s opinion, will render the 
administration of study drug hazardous or obscure the interpretation of toxicity or AEs. 
22. Concurrent participation in another therapeutic clinical trial. 
 
6 
STUDY TREATMENTS 
6.1 
Study Treatment  
All patients will receive zanubrutinib in combination with rituximab from Cycles 1 to 10, followed 
by zanubrutinib monotherapy starting at Cycle 11. 
6.2 
Study Treatment Preparation and Dispensation 
6.2.1 
Packaging and Labeling 
Supplies of zanubrutinib capsules will be provided in a child resistant, high-density polyethylene 
(HDPE) bottle with induction seal and bottle label. Rituximab will be provided in vials containing 
solution for infusion.  
The contents of the label will be in accordance with all applicable regulatory requirements. 


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6.2.2 
Handling and Storage 
The study drugs will be dispatched to a study center only after receipt of the required documents in 
accordance with applicable regulatory requirements and the Sponsor’s procedures. The investigator 
or pharmacist/designated personnel is responsible for maintaining the drug supply inventory and 
acknowledging receipt of all study drug shipments. All study drugs must be stored in a secure area, 
with access limited to the investigator and authorized study center personnel, and kept under 
physical conditions per the product label requirements. 
Study drug must be dispensed or administered according to procedures described herein. Only 
patients enrolled in the study may receive study drug, in accordance with all applicable regulatory 
requirements. Only authorized study center personnel may supply or administer study drug. 
6.2.3 
Compliance and Accountability 
Compliance, as well as the information provided by the patient and/or guardian, will be assessed by 
the investigator and/or study personnel at each patient visit.  
The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed and used by each patient. This information must be captured in the source document at 
each patient visit. The investigator is responsible for study drug accountability, reconciliation, and 
record maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study center personnel must maintain study drug accountability records throughout the 
course of the study. This person will document the amount of study drug received from the Sponsor, 
the amount supplied, and/or administered to and returned by patients, if applicable. 
6.2.4 
Disposal and Destruction 
After completion of the study, and following final drug inventory reconciliation by the site monitor, 
the study site will destroy or return all unused study drug supplies. 
6.3 
Patient Numbering and Treatment Assignment 
6.3.1 
Patient Numbering 
Patients will be identified by a patient number. Each patient enrolled in this study will receive a 
unique patient number which will be assigned when the patient is screened or enrolled in the study. 
Patient will be assigned in chronological order starting with the lowest number. Once a patient 


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number has been assigned to a patient, it cannot be re-assigned to any other patient. 
6.3.2 
Treatment Blinding 
This is an open-label study. 
6.4 
Dosage and Administration 
6.4.1 
Zanubrutinib 
Zanubrutinib will be dispensed by the study center personnel to patients at scheduled study visits to 
ensure adequate drug supply for administration at home throughout the treatment phase. The 
investigator is to instruct the patient to take the study drug exactly as prescribed. Patients will be 
requested to bring their unused medication, including empty bottles, to the center at each visit. All 
dosages prescribed and dispensed to the patient and all dose changes including reason for dose 
changes during the study must be recorded on the appropriate electronic case report form (eCRF). 
Zanubrutinib will be administered as two 80-mg capsules by mouth twice a day (160 mg twice a 
day) with or without food. Patients will take zanubrutinib with water at approximately the same 
time every day, approximately 12 hours apart, ± 2 hour time window. Zanubrutinib capsules should 
not be opened, broken, or chewed at any time. 
On days where both study drugs are administered, zanubrutinib will be given first and 30 minutes 
later the infusion of rituximab will be initiated. 
 
 
The investigator or his/her designee must instruct the patient not to self-administer the study drug 
prior to the office visit on those days. 
6.4.2 
Rituximab 
Rituximab will be administered at 375 mg/m2 on Cycle 1 Days 1, 8, 15, 22, and on Day 1 of Cycles 
4, 6, 8, 10. 
For the infusion rate, please refer institutional standard. For additional information, please refer to 
the drug label. 
Rituximab can cause severe, fatal infusion reactions. Patients should be pre-medicated with an 


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antihistamine and acetaminophen prior to each rituximab dosing. Institute medical management (eg, 
glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions is provided as 
needed. Depending on the severity of the infusion reaction and the required interventions, rituximab 
should be temporarily discontinued in the event of an infusion reaction. Infusion can be resumed at 
a minimum 50% reduction in rate after symptoms have resolved. 
6.5 
Dose Interruption and Modification 
The guidelines set forth in Table 1 should be followed for dose interruption or modification of 
zanubrutinib for hematologic (Section 6.5.1) or nonhematologic (Section 6.5.2) toxicities. 
Table 1. 
Zanubrutinib Dose Reduction Levels for toxicity 
Dose Level 
Zanubrutinib Dose 
0 (starting dose) 
160 mg twice daily 
-1 
80 mg twice daily 
-2 
80 mg once daily 
Zanubrutinib may be restarted upon resolution of toxicity and per investigator discretion if held for 
a maximum of 28 consecutive days. If, in the investigator’s opinion, it is in the patient’s best 
interest to restart treatment after > 28 days, then written approval must be obtained from the 
Sponsor’s medical monitor. 
6.5.1 
Zanubrutinib Dose Reductions for Hematologic Toxicity 
Dosing will be held for individual patients under any of the following conditions, based on 
investigator assessment of study-drug relatedness: 
 Grade 4 neutropenia (lasting > 10 days, however earlier interruption is acceptable if 
medically indicated)  
 Grade 4 thrombocytopenia (lasting > 10 days, however earlier interruption is acceptable if 
medically indicated) 
 ≥ Grade 3 thrombocytopenia associated with bleeding 
 ≥ Grade 3 febrile neutropenia 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery of 
the toxicity to ≤ Grade 1 or baseline. If the same event reoccurs, patients will restart at 1 dose level 


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lower upon recovery of the toxicity to ≤ Grade 1 or baseline. A maximum of 2 dose reductions will 
be allowed. Patients with ≥ Grade 3 thrombocytopenia associated with significant bleeding 
requiring medical intervention will be discontinued from study treatment. 
Asymptomatic treatment-related lymphocytosis should not be considered an AE. Patients with 
treatment-related lymphocytosis should remain on study treatment and continue with all 
study-related procedures. 
6.5.2 
Zanubrutinib Dose Reductions for Nonhematologic Toxicity 
For nonhematological toxicities ≥ Grade 3, other than hypertension adequately controlled with oral 
medication or asymptomatic laboratory events (laboratory events indicating liver or renal 
dysfunction will not be considered asymptomatic laboratory events), suspected to be related to study 
drug treatment, study drug will be held until recovery to ≤ Grade 1 or baseline, and then restarted at 
original dose level. If the event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1 or 
baseline and restarted at Level -1. If the event recurs at ≥ Grade 3 at level -1, drug will be held until 
recovery to ≤ Grade 1 or baseline and restarted at level -2. If the event recurs at ≥ Grade 3, the 
patient will be discontinued from study treatment. For patients experiencing atrial fibrillation that is 
symptomatic and/or incompletely controlled: after the atrial fibrillation is adequately controlled the 
study drug may be restarted at either the original dose or dose level-1, per discretion of the treating 
investigator. Zanubrutinib should be permanently discontinued for any intracranial hemorrhage 
events occur.  
6.5.3 
Dose Modifications for Rituximab 
No dose reductions for rituximab are allowed. A 28-day cycle length should be maintained, if 
possible. A rituximab dose delay of up to 5 days is acceptable from cycle 4. 
Severe, including fatal, infusion reactions can occur with rituximab; therefore, discontinue 
rituximab infusion and provide medical treatment for Grade 3 or 4 infusion reactions. For less 
severe infusion reactions, interrupt the infusion or slow the infusion rate. Refer to the rituximab 
prescribing information for dose withholding or discontinuation in response to specific toxicities 
associated with rituximab. 


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6.6 
Concomitant Medications and Non-Drug Therapies 
6.6.1 
Prior Therapy 
The inclusion criteria (Section 5.1) specifies that patients should have received prior systemic 
therapy.  
6.6.2 
Concomitant Therapy 
All concomitant medications, taken from 28 days prior to first dose of zanubrutinib, will be 
recorded in the eCRF with indication, dose information and dates of administration. 
6.6.2.1 
Permitted Medications 
Patients with high tumor burden should be monitored closely and prophylactic measures, including 
allopurinol or rasburicase, may be instituted per institutional standards. Tumor lysis syndrome has 
not been currently reported with zanubrutinib treatment, but has been reported in some cases with 
rituximab. 
Bisphosphonate use is permitted if the patient has already been taken it for 3 or more months and on 
a stable dose.  
Corticosteroid courses of limited duration (2 weeks or less) and dose (<20 mg prednisone per day, 
or equivalent) are permitted, if used to treat a concomitant (non-cancer) medical condition, with the 
exception of glucocorticoids used for management of rituximab-related infusion reaction.  
Patients with hematologic malignancies, particularly those having received prior lymphodepleting 
chemotherapy or having prolonged corticosteroid exposure, are pre-disposed to opportunistic 
infections as a result of disease and treatment-related factors. In patients with a high risk for 
opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP), prophylaxis should be 
considered as per institutional standards. 
6.6.2.2 
Prohibited Medications 
Patients should not receive other anticancer therapy (cytotoxic, biologic, or hormone other than for 
replacement) while on treatment in this study.  
Other anticancer therapy should not be administered until disease progression (as per clinical 
practice standards at the study center), unmanageable toxicity, or no further clinical benefit occurs 


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which requires permanent discontinuation of the study drug.  
Chinese patent medicine for treatment of cancer are not allowed on study. Chinese herbal 
medications in the use of anticancer treatment is prohibited.  
Live vaccines are prohibited during Screening and while on study treatment. 
6.6.3 
Potential Interactions Between the Study Drugs and Concomitant Medications 
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers (refer 
to Appendix 5 for a list of these medications) and grapefruit juice and Seville oranges should be 
used with caution as they may affect the metabolism of zanubrutinib. If at all possible, patients are 
encouraged not to use strong/moderate CYP3A inhibitors and inducers and should consider using 
alternative agents. If these agents are used, follow the dose modification table in Table 2. The 
medical monitor should be consulted in these situations. Please refer to the FDA Drug Development 
and Drug Interactions: Table of Substrates, Inhibitors and Inducers 2019 for a more complete list. 
Clinical drug-drug interaction study (BGB-3111-104) (refer to BGB-3111 Investigator’s Brochure) 
indicated that zanubrutinib is a mild inducer of CYP3A4 and CYP2C19. Narrow therapeutic index 
drugs that are metabolized by CYP3A4 (alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should 
be used with caution, as zanubrutinib may decrease the plasma exposures of these drugs. Since 
blood levels and effectiveness of drugs that are substrates for CYP3A (eg, steroidal contraceptives) 
may be reduced by CYP3A inducers, if patients are using hormonal contraceptives such as birth 
control pills or devices, a second barrier method of contraception (eg, condoms) is recommended to 
be used. The coadministration of oral P-gp substrates with a narrow therapeutic index (eg, digoxin) 
should be used with caution as zanubrutinib may increase their concentrations. 


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Table 2. Dose Modification Table for Zanubrutinib When Co-Administered With 
Strong/Moderate CYP3A Inhibitors or Inducers 
CYP3A 
Co-administered Drug 
Recommended use 
Inhibition 
Strong CYP3A inhibitor (eg, ketoconazole, 
conivaptan, clarithromycin, indinavir, 
itraconazole, lopinavir, ritonavir, telaprevir, 
posaconazole, voriconazole) 
80 mg once daily 
Moderate CYP3A inhibitor (eg, 
erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil, 
aprepitant, imatinib, grapefruit products) 
80 mg twice daily 
Induction 
Strong CYP3A inducer (eg, carbamazepine, 
phenytoin, rifampin, St. John’s wort) 
Avoid concomitant 
use; Consider 
alternative agents with 
less induction 
potential. 
Moderate CYP3A inducer (eg, bosentan, 
efavirenz, etravirine, modafinil, nafcillin) 
160 mg twice daily, 
use with caution; 
Monitor for potential 
lack of efficacy. 
Abbreviation: CYP3A, cytochrome P450, family 3, subfamily A. 
 
6.6.4 
Surgery and Procedures 
Susceptibility to bleeding has been observed with BTK inhibitors. Study treatment with 
zanubrutinib should be held for 3 days pre- and 7 days after surgery depending upon the type of 
surgery and the risk of surgery-related bleed. Rituximab should also be interrupted, if applicable. 
6.7 
End of Treatment 
All patients, regardless of reason for discontinuation of study treatment, will undergo an End of 
Treatment (EOT) visit within 7 days of discontinuing study drug. The reason for discontinuation 
from treatment will be recorded on eCRF. If a patient underwent study drug interruption > 7 days, 
before decision of permanent treatment discontinuation, an EOT visit can be done within the 
interval of 30 ± 3 days after the last dose of study drug, combining assessments at both EOT and 
Safety Follow-up visits. 
Permanent treatment discontinuation is defined as cessation of study drug administration. Safety 
follow-up will be performed per Section 6.8.1. 


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The primary reasons that require patients to permanently discontinue study treatment are as follows: 
 AE or intercurrent illness: Any intolerable AE that cannot be ameliorated by use of adequate 
medical intervention or that, in the opinion of the investigator or medical monitor, would 
lead to undue risk if study treatment were continued. 
 Gross noncompliance with protocol: The medical monitor or investigator may request 
permanent discontinuation of study drug treatment in the event of a major protocol 
deviation, lack of cooperation, or noncompliance. 
 Development of disease progression confirmed by investigator and medical monitor 
 Need for long-term administration of prohibited concomitant therapy 
 Death 
 Loss to follow-up 
 Sponsor discontinuation of study: The Sponsor reserves the right to terminate the study 
anytime as described in Section 6.9. The Sponsor will terminate this study following 
completion of the study objectives, or earlier if deemed necessary. 
 Patient decision: Patients may permanently discontinue study treatment anytime for any 
reason. Following study drug discontinuation, patients should have protocol required safety 
follow-up assessments 30 ±3 days after the last dose of study drug or immediately before 
commencing new anti-cancer treatment, which occurs first, unless the patient specifically 
declines further follow-up. 
6.8 
Follow-up Phase 
6.8.1 
Safety Follow-up 
All patients who discontinue study treatment will have a Safety Follow-up Visit 30 days (±3 days) 
after the last dose of study drug (zanubrutinib or rituximab, whichever occurs later); or prior to the 
start of new anticancer therapy, whichever occurs first. The investigator or his/her designee will also 
continue to collect information on new anticancer therapy given after the last dose of study drug. A 
laboratory assessment is only required if the patient has an ongoing laboratory abnormality at the 


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previous visit that the investigator considered to be related to study drug. If the patient is unable to 
return to the clinic and no laboratory assessment is necessary, the investigator or his/her designee 
will contact the patient or guardian to collect this information.  
6.8.2 
Efficacy Follow-up 
Disease status for patients who discontinue from study drug for reason(s) other than progressive 
disease (eg, AE) will be assessed radiographically by the same imaging modality as the Treatment 
Period. Tumor imaging will be performed every 12 weeks (± 7 days) since Cycle 1 Day 1, until 
progressive disease, withdrawal of consent, death, lost to follow-up, or End of Study, whichever 
occurs first.  
6.8.3 
Survival Follow-up 
Following completion of the Safety follow-up phase, every effort should be made to follow patients 
via phone contact (with patient’s guardian, if applicable) for survival approximately once every 3 
months until patient death or study termination by the Sponsor. The investigator or his/her designee 
will also continue to collect information on new anti-cancer therapy given after the last dose of 
study drug until data cutoff for final analysis. 
6.9 
End of Study 
For patients who continue to benefit from zanubrutinib treatment at the time of study closure, single 
agent zanubrutinib at the most recent tolerated dose may be continued after 2 years on study. 
Premature discontinuation from the study (including all follow-up visits) will occur under the 
following circumstances: 
 Patient withdrew consent 
 Death  
 Other 
Patients may voluntarily withdraw consent from the study at any time. 
6.10 Loss to Follow-up 
Every reasonable effort should be made to contact any patient apparently lost to follow-up during 
the study to complete study-related assessments, record outstanding data, and retrieve study drug. 


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Following unsuccessful telephone contact, an effort to contact the patient by mail using a method 
that provides proof of receipt should be attempted. Alternate contacts are permissible if the patient 
is not reachable (eg, primary care providers, referring physician, relatives). Such efforts should be 
documented in the patient’s source documents. 
If all efforts fail to establish contact, the patient will be considered lost to follow-up. 
7 
STUDY ASSESSMENTS 
7.1 
Study Procedures 
7.1.1 
Screening  
A signed written informed consent form must be obtained from the patient prior to any study-
specific procedures or assessments. Rescreening of patients will not be allowed, but laboratory 
parameters which do not meet the inclusion criteria may be re-tested within the screening window 
(Day -28 to Day -1).  
Procedures and assessments to be performed during the Screening window (Day -28 to Day -1): 
 Informed consent 
 Demographic 
 Medical history and disease history including date of NHL diagnosis; date of last recurrence; 
prior treatments for NHL including chemotherapy, radiotherapy; dates of prior NHL 
treatments; stage of disease; International Prognostic Index (IPI) score at screening (One 
point each is allocated for age> 60years, stage III/IV disease, increased lactate 
dehydrogenase (LDH), ECOG performance status >2, >2 extra-nodal site involvement); and 
previous Epstein–Barr virus (EBV)-encoded RNA (EBER) result (if available) 
 Inclusion/Exclusion Criteria 
 Concomitant medications within 28 days prior to first dose of zanubrutinib 
 CT with contrast and PET/CT of neck, chest, abdomen, and pelvis. PET/CT may be used in 
lieu of a CT with contrast only if the CT of the PET/CT has been performed with diagnostic 
quality and contrast is administered. Total body MRI is allowed if contraindicated to CT 
with contrast. If scans were conducted within 30 days of the first dose of study treatment, 
then those scans are acceptable for screening. 


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 PET scan for patients with non-GCB DLBCL in cohort 1 while only patients with FL in 
cohort 2. If scan was conducted within 30 days of the first dose of study treatment, then that 
scan is acceptable for screening. 
 ECOG performance status 
 Vital signs including temperature, blood pressure, pulse, respiratory rate 
 Physical examination 
 Adverse events 
 12-lead ECG 
 Echocardiogram (ECHO) or multigated acquisition scan (MUGA), if not performed within 
90 days of first day of Screening 
 Complete blood count (CBC) with differential 
 Comprehensive serum chemistry panel (Refer to Section 7.3.6.2) 
 HBsAg, hepatitis B surface antibody (HBsAb), HBcAb, hepatitis C virus antibody 
(HCVAb), further testing by polymerase chain reaction (PCR) to assess HBV DNA level 
may be performed for determination of study eligibility as per the Inclusion/Exclusion 
Criteria. 
 Coagulation parameters (prothrombin time [PT], aPTT, international normalized ratio 
[INR]) 
 Urinalysis 
 HIV 
 Serum pregnancy test (only in women of childbearing potential)  
 Archival tumor tissue and/or a fresh tumor biopsy (10 to 15 unstained FFPE slides) to meet 
the requirement of biomarker analysis.  
 Bone marrow aspirate and biopsy (immunohistochemistry [IHC]), if not performed within 
60 days of first dose of study drug 
Refer to the Schedule of Assessments (Appendix 2) for additional details. 
The following eCRFs must be completed for screen-fail patients: 
 Screening Phase Disposition page (include the reason for not starting treatment) 
 Informed consent 


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 Demographics 
 Serious adverse events 
 Inclusion/Exclusion criteria 
7.1.2 
Cycle 1 Day 1 (minus 3-day window) 
Procedures and assessments to be performed on Day 1 of Cycle 1 are listed below. A minus 3-day 
window is allowed for these assessments except where indicated. 
 ECOG performance status 
 Vital signs including temperature, blood pressure, pulse, respiratory rate 
 ECG 
 Height and weight 
 Physical examination 
 Adverse events 
 Concomitant medications 
 CBC with differential  
 Comprehensive serum chemistry panel (Refer to Section 7.3.6.2) 
 Urinalysis (In case where screening lab assessment for eligibility is completed within 72 
hours of study drug administration, the urinalysis does not need to be performed again for 
C1D1.) 
 Study drug administration (Cycle 1 Day 1 only) 
 
 
 
 
 
 
Refer to the Schedule of Assessments (Appendix 2) for further details. 
7.1.3 
Day 1 of Cycle 2 and All Subsequent Cycles (± 3-day window) 
Procedures and assessments to be performed on Day 1 of Cycle 2 and all subsequent cycles include: 
 ECOG performance status 
 Vital signs including temperature, blood pressure, pulse, respiratory rate 
 Weight 


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 Physical examination 
 Adverse events 
 Concomitant medications 
 CBC with differential 
 Comprehensive serum chemistry panel (Refer to Section 7.3.6.2) 
 Urinalysis 
 Study drug administration 
 
 
 
 
 
 
Refer to the Schedule of Assessments (Appendix 2) for further details. 
7.1.4 
End of Treatment 
Procedures and assessments to be performed within 7 days after last dose of study drug, (If patient 
underwent study drug interruption > 7 days, before the decision of permanent treatment 
discontinuation, the EOT visit can be done within the interval of 30 ± 3 days after the last dose of 
study drug, combining assessments at both EOT and safety Follow-up visits): 
 ECOG performance status 
 Vital signs including temperature, blood pressure, pulse, respiratory rate 
 Weight 
 Physical examination 
 Adverse events 
 Concomitant medications 
 CBC with differential 
 Comprehensive serum chemistry panel (Refer to Section 7.3.6.2) 
 Urinalysis 
 CT with contrast of neck, chest, abdomen, and pelvis for confirmation of progressive 
disease, if progressive disease is the reason for discontinuation of treatment. PET/CT may be 
used in lieu of a CT with contrast only if the CT of the PET/CT has been performed with 
diagnostic quality and contrast is administered. Tumor imaging for EOT does not have to be 


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performed if the most recent tumor imaging was performed within the previous 6 weeks. 
 Serum pregnancy test 
 PET scan for confirmation of progressive disease, if progressive disease is reason for 
discontinuation of treatment, for patients with non-GCB DLBCL in cohort 1 while only 
patients with FL in cohort 2. 
 Core or excisional tumor biopsy, if an accessible lesion is present, or a 10 mL blood 
collection for patients who discontinued treatment due to progressive disease. 
Refer to the Schedule of Assessments (Appendix 2) for further details. 
7.1.5 
Safety Follow-up 
Procedures and assessments to be performed at the Safety Follow-up Visit (30 ± 3 days after last 
dose of study drug (zanubrutinib or rituximab, whichever occurs later) or immediately before 
commencing new anti-cancer treatment, whichever occurs first): 
 Vital signs including temperature, blood pressure, pulse, respiratory rate 
 Physical examination 
 ECOG performance status 
 12-lead ECG 
 Adverse events 
 Concomitant medications 
 CBC with differential 
 Comprehensive serum chemistry panel (Refer to Section 7.3.6.2) 
 Urinalysis 
Refer to the Schedule of Assessments (Appendix 2) for further details. 
7.1.6 
Survival Follow-up 
Following completion of the Treatment and Safety Follow-up phases of the study, every effort 
should be made to contact patients approximately every 3 months for anti-tumor treatment after 
EOT and survival status. 


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7.2 
Efficacy Assessments 
7.2.1 
Imaging Studies 
7.2.1.1 
CT With Contrast 
Tumor assessment by CT with contrast of neck, chest, abdomen, and pelvis will be performed at 
protocol specified time points (Refer to Appendix 2). Total body MRI is allowed if CT with contrast 
is contraindicated. PET/CT may be used in lieu of a CT with contrast only if the CT of the PET/CT 
has been performed with diagnostic quality and contrast is administered. 
CT scan slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
Clinical suspicion of disease progression at any time will require a physical examination and 
radiological confirmation to be performed promptly, rather than waiting for the next scheduled 
tumor assessment. In the case of an unscheduled or delayed tumor assessment for any reason, 
subsequent tumor assessments must be performed per the original plan schedule from baseline. 
Response assessment for ORR will be by CT scan and categorized as per the Lugano Classification 
(Appendix 3). 
7.2.1.2 
PET 
Tumor assessment by PET will be performed at Screening, Week 24, Week 48, and at CR or 
progressive disease suspected clinically or radiographically (Refer to Appendix 2) for sites with 
PET scanning capability for patients with non-GCB DLBCL and FL until progressive disease, 
withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first. 
Response assessment for ORR will be by PET scan and categorized as per the Lugano Classification 
(Appendix 3). 
7.2.2 
Bone Marrow Aspirate and Biopsy 
Bone marrow aspirate and biopsy will be required at Screening, if not performed within 60 days of 
first dose of study drug. Repeat bone marrow aspirate and biopsy are required at the time of CR for 
confirmation of response if baseline marrow examination is positive for NHL involvement. 
7.2.3 
Archival or Fresh Tumor Collection 
Archival or a fresh tumor sample (paraffin embedded block or 10-15 unstained FFPE slides) will be 
collected at Screening to meet the requirement of biomarker detection. Additionally, an optional 


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tumor biopsy will be obtained at EOT for accessible tumor if reason for treatment discontinuation is 
progressive disease. An optional tumor biopsy will also be collected for accessible tumor from 
patients who fail to achieve PR or better after at least 6 months of study treatment. See Section 7.4.1 
for more information. 
7.3 
Safety and Tolerability Assessments 
Safety assessments should be performed at all visits by the investigator throughout the study. Safety 
assessments will consist of monitoring all AEs and SAEs, regular monitoring of blood tests, urine 
tests, vital signs, weight, performance status, and physical examinations. For schedule of study 
visits, refer to the Schedule of Assessments (Appendix 2). 
7.3.1 
Adverse Events 
Record adverse events that occurred during screening both in the medical history case report form 
and the patient’s clinical record. 
Collect nonserious AE information from the time of first dose of study drug. Information on all 
SAEs (regardless of relatedness) will be collected from the time of signed informed consent. The 
AE reporting period is defined in Section 9.4. 
All treatment-related AEs and SAEs will be followed until resolution or stabilization. The accepted 
regulatory definition for an AE is provided in Section 9.1.1. Important additional requirements for 
reporting SAEs are explained in Section 9. 
7.3.2 
Physical Examination, Vital Signs, Height, and Weight 
Physical examination, vital signs (sitting blood pressure, heart rate, respiratory rate, body 
temperature), and weight will be performed at each study visit. Height (cm) is determined at 
screening only. 
A complete physical exam includes an assessment of systems per standard of care at the study site 
and as clinically indicated by symptoms.  
Assessment of vital signs and a focused physical examination on the first day of cycle 1 may be 
skipped if performed within 7 prior days. Physical examination will include an examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 


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back, lymph nodes, extremities, and a basic nervous system evaluation. A complete or targeted 
physical examination, vital signs (sitting blood pressure, pulse rate, body temperature, and 
respiratory rate), and weight will be performed at each study visit. To the extent feasible, blood 
pressure will be taken on the same arm throughout the study. Patients must be resting in a sitting 
position for 10 minutes prior to obtaining vital signs. If blood pressure is > 150/100 mmHg in a 
patient without a history of hypertension, or increased by > 20 mmHg (diastolic) from baseline 
measurement in a patient with a previous history of hypertension, the assessment should be repeated 
in 10 minutes for confirmation. Height in centimeters (cm) and body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes) will be measured. Weight will be measured on 
Day 1 of each treatment cycle.  
7.3.3 
Medical and Cancer History 
Review any medical and cancer history any time after obtaining informed consent, including 
presence or absence of disease related constitutional symptoms. Clinically significant medical 
history findings (eg, previous diagnoses, diseases or surgeries) not pertaining to the study 
indication, started before signing the informed consent, and considered relevant for the patient’s 
study eligibility will be collected and captured in the eCRF. Clinically significant is defined as any 
events, diagnoses or laboratory values requiring treatment, follow-up or the presence of signs or 
symptoms that require medical intervention. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. 
Other background information including history of disease, including the date of initial diagnosis 
and current disease status, staging, and sites of disease (see Appendix 4). Prior 
medications/significant non-drug therapies and demographic data (gender, date of birth [or age] and 
race/ethnicity) will also be collected. The investigator will obtain the patient's medical history at the 
Screening visit. Medical history will include all active conditions, and any conditions diagnosed 
within the prior 10 years that are considered to be clinically significant by the investigator. 
Significant findings that were present prior to the signing of the informed consent must be included 
in the relevant medical history/current medical conditions page on the patient’s eCRF. 
7.3.4 
ECOG Performance Status 
ECOG performance status (Table 3) will be assessed at the Screening Visit, Day 1 of each treatment 


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cycle, End of Treatment Visit, and at the Safety Follow-up Visit.  
Table 3. 
ECOG Performance Status 
Grade 
Performance 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
Abbreviation: ECOG, Eastern Cooperative Oncology Group 
 
7.3.5 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed in triplicate at screening. Patients should be 
in the semi-recumbent or supine position. The Cycle 1 and Safety Follow-up ECGs should be 
performed pre-dose.  
7.3.6 
Laboratory Evaluations 
Screening blood tests performed within 3 days of the first study drug administration do not need to 
be repeated on Cycle 1 Day 1. Abnormal laboratory values will constitute AEs only if they are 
associated with clinical signs or symptoms that are clinically significant and/or require therapy, and 
should be recorded on the AEs eCRF. In addition, isolated abnormal laboratory values that are 
considered clinically significant (eg, cause study discontinuation or constitutes in and of itself an 
SAE) should be recorded on the AEs eCRF. 
7.3.6.1 
Hematology 
CBC with differential is required to be performed every visit during the treatment phase. CBC 
includes hemoglobin, hematocrit, reticulocyte, platelet count, red blood cell count, white blood cell 
count with differential including neutrophils (including bands), lymphocytes, monocytes, 


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eosinophils, and basophils. In the event of neutropenia or thrombocytopenia, these assessments will 
be conducted as frequently as the investigator feels it necessary until toxicity resolves to ≤ Grade 2. 
7.3.6.2 
Clinical Chemistry and Immunoglobulins 
Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen 
(or urea), creatinine, calcium, phosphate/phosphorus, magnesium, total bilirubin, total protein, 
albumin, ALT, AST, LDH, and alkaline phosphatase. In the event of ≥ Grade 3 clinical chemistry 
toxicity, these assessments will be conducted as frequently as the investigator feels it necessary until 
toxicity resolves to ≤ Grade 2. Total immunoglobulins will be obtained every 6 months, including 
IgG, IgM, IgA. 
7.3.6.3 
Coagulation 
Coagulation studies including PT, INR, and aPTT will be performed at Screening. Repeat testing 
may also be performed as clinically indicated during the Treatment Period including for those 
patients on anticoagulation therapy as approved by the medical monitor. 
7.3.6.4 
Urinalysis 
Urinalysis will be performed at screening, and at every visit during the treatment period and EOT, 
using a urine dipstick. Urine microscopy will be performed if the urine dipstick is abnormal. The 
assessment includes: pH, glucose, protein, ketones, bilirubin, blood, and specific gravity. If the 
urine protein is ≥ 2+ by dipstick, a 24-hour urine for total protein and creatinine will be obtained 
and evaluated. 
7.3.6.5 
Hepatitis B and Hepatitis C Testing 
Hepatitis B/C serologic markers and/or viral load will be tested at screening. The hepatitis B testing 
includes HBsAg, HBcAb, and HBsAb as well as HBV DNA by PCR if the patient is negative for 
HBsAg but HBcAb positive (regardless of HBsAb status). The hepatitis C testing includes HCV 
antibody as well as HCV RNA by PCR if the patient is HCV antibody positive. Patients with 
positive HBsAg and/or HBV DNA ≥ 500 IU/mL or detectable level of HCV RNA (≥ 15 IU/mL) are 
not eligible. Patients who are HBsAg negative and HBcAb positive must initiate the anti-viral 
therapy before the first dose of study treatment and undergo monthly HBV DNA screening by PCR. 
Resumption of study drug in patients whose HBV reactivation resolves should be discussed with, 
and approved by, physicians with expertise in managing hepatitis B and the medical monitor. 


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Patients positive for HCV antibody but negative for HCV RNA (<15 IU/mL) must undergo monthly 
HCV RNA screening. Patients with known HIV are excluded from the study. Patients with detected 
HCV RNA should stop study drug and anti-viral therapy should be initiated. The medical monitor 
should be informed of any suspected hepatitis B or hepatitis C reactivation. 
Table 4 below, shows how the results for HBV, and HBV testing at screening relate to Inclusion and 
Exclusion criteria. 
Table 4. 
Active Hepatitis B or HCV Infection (Detected Positive by Polymerase Chain 
Reaction)  
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA < 500 IU/mL 
and 
anti-viral therapy is started prior to first 
dose of study treatment and throughout the 
study treatment 
and 
Perform monthly monitoring of HBV DNA 
HBsAg (-) and HBcAb (+) 
HBV DNA ≥ 500 IU/mL1 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not-detected” (<15 IU/mL) 
 
Perform monthly monitoring of HCV RNA  
Antibody (+) 
HCV RNA Detected1 
 Abbreviation: IU, International unit; HBcAb, Hepatitis B core antibody; HBsAg, Hepatitis B surface antigen; HBV, 
hepatitis B virus; HCV, hepatitis C virus 
 Note: Please refer to Section 7.3.6.5 above. 
 
7.3.6.6 
Pregnancy Test 
A serum pregnancy test will be performed at Screening and EOT for women of childbearing 
potential. Any female patient who is pregnant will not be eligible for the study. Patients must have a 
negative serum pregnancy test at Screening. Subsequent tests may be urine tests, and should be 
performed as clinically indicated. A patient who has a positive pregnancy test result at any time 
after initiation of study treatment will be immediately withdrawn from participation in the study.  


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7.4 
Other Assessments  
7.4.1 
Biomarker Analysis 
Patients who have DLBCL must have archival tumor tissues or agree to a tumor biopsy for 
confirmation of the DLBCL subtype and further genetic analysis. Either a FFPE block with tumor 
tissue (preferred) or 10 to 15 unstained slides must be sent to the central laboratory (to meet the 
requirement of biomarker analysis) to conduct exploratory biomarker analysis such as DNA panel 
sequencing, IHC and gene expression profile (GEP) to confirm the DLBCL subtype. Other 
biomarkers will also be assessed, including but not limited to EBV status, myelocytomatosis 
(MYC)/B-cell lymphoma (BCL) 2/BCL6 rearrangement and expression, etc. Pathology and IPI 
information will be collected from the site, if available.  
Patients who have FL and MZL must have archival tumor tissues or agree to a tumor biopsy for 
biomarker genetic analysis such as DNA panel sequencing. Either a FFPE block with tumor tissue 
(preferred) or 10 to 15 unstained slides must be sent to the central laboratory (to meet the 
requirement of biomarker analysis). 
 
 
 
 
 
 
Please refer to Lab Manual for more details. 
8 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. Site 
audits may be made periodically by the Sponsor’s or the contract research organization’s (CRO’s) 
qualified compliance auditing team, which is an independent function from the study team 
responsible for conduct of the study. 


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8.1 
Data Collection 
Data required by the protocol will be entered into the eCRFs in an electronic data capture (EDC) 
system that is compliant with all regulatory requirements.  
Data collection in the eCRF must follow the instructions described in the eCRF Completion 
Guidelines (eCCGs). The investigator has ultimate responsibility for the collection and reporting of 
all clinical data entered in the eCRF. The investigator or designee as identified on Form FDA 1572 
must sign the completed casebooks to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available in 
any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
8.2 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file which includes all database modifications) will be 
followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies and completeness. 
During the course of the study, a study monitor (CRA) will make site visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records and ensure that the study 
is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs for 
completeness, clarity and cross checking with source documents is required to monitor the progress 
of the study. Direct access to source data is also required for inspections and audits, and will be 
carried out giving due consideration to data protection and medical confidentiality. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
Version 18.1 or higher. Concomitant medications will be coded using the World Health 


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Organization Drug Dictionary. Concomitant diseases/medical history will be coded using the 
MedDRA® Version 18.1 or higher. 
8.3 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of 
this study. Such audits/inspections can occur at any time during or after completion of the study. If 
an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of his/her personnel 
to the auditor/inspector to discuss findings and any relevant issues. 
9 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  
9.1 
Adverse Events 
9.1.1 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of an AE include: 
 Worsening of a chronic or intermittent pre-existing condition including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse outcome. 
 New condition(s) detected or diagnosed after study drug administration even though it may 
have been present before the start of the study.  
 Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 


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(eg, hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In these instances, all patient identifiers will be blinded on the copies of the medical 
records prior to submission to the Sponsor. 
9.1.1.1 
Assessment of Severity  
The investigator will assess the intensity for each AE and SAE reported during the study. When 
applicable, AEs and SAEs should be assessed and graded based upon the National Cancer Institute-
Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE Version 4.03). 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)  
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL  
 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or life-
threatening [Grade 4]), whereas seriousness is classified by the criteria based on the regulatory 
definitions. Seriousness serves as the guide for defining regulatory reporting obligations from the 
Sponsor to applicable regulatory authorities. 
An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is 
defined as “serious” when it meets one of the pre-defined outcomes as described in Section 9.2. 


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9.1.1.2 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence of 
each AE or SAE. The investigator will use his/her clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapies, other 
risk factors, and the temporal relationship of the event to the study drug should be considered and 
investigated. The investigator will also consult the IB, for marketed products, in the determination 
of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the Sponsor. However, it is very important that the investigator always 
makes assessment of causality for every SAE prior to transmission of the SAE report/eCRF to the 
Sponsor since the causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality in light of follow-
up information, amending the SAE report/eCRF accordingly. 
Investigators must also systematically assess the causal relationship of AEs to study drug (including 
any other non-study drugs, radiation therapy, etc.) using the following definitions: 
• Related: There is clear evidence to suggest a causal relationship that there is reasonable temporal 
relationship; the positive of de-challenge result (When necessary the positive of re-challenge result); 
the occurrence of AE that could be attributed to the pharmacological effect of study treatment.  
• Probably related: This causality assessment will be applied for AE that is regarded by the 
investigator as highly positive related to the study treatment that: There is reasonable temporal 
relationship; the occurrence of AE could not be explained by the patient’s medical history, 
concurrent medical condition, or other the patient’s signs or symptoms; the positive of de-challenge 
result; the positive of re-challenge result.  
• Possibly related: There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug). However, the influence of other 
factors may have contributed to the AE (eg, the patient’s clinical condition, other concomitant AEs).  
• Unlikely related: There is little evidence to suggest there is a causal relationship. There is another 
reasonable explanation for the AE.  


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• Not rrelated: An AE will be considered “not related” to the use of the product if any of the 
following tests are met: 
o 
An unreasonable temporal relationship between administration of the product and the onset 
on the AE (eg, the AE occurred either before, or too long after administration of the 
product for it to be considered product-related);  
o 
 A causal relationship between the product and the AE is biologically implausible (eg, 
death as a passenger in an automobile accident);  
o 
A clearly more likely alternative explanation for the AE is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related AE).  
The causality for cases assessed with 5-point scale will be mapped to 2-point scale during aggregate 
safety data analysis according to the BeiGene latest mapping rule. 
9.1.1.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient and 
provide further information to the Sponsor or designee on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. Once resolved, the appropriate AE or SAE eCRF 
page(s) will be updated. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare professionals. 
The Sponsor or designee may request that the investigator performs or arranges for the conduct of 
supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or 
causality of the AE or SAE. The investigator is obligated to assist. If a patient dies during 
participation in the study or during a recognized follow-up period, the Sponsor will be provided 
with a copy of any post-mortem findings, including histopathology. 


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New or updated information will be recorded on the originally completed SAE report/eCRF, with 
all changes signed and dated by the investigator. The updated SAE report/eCRF should be re-sent to 
the Sponsor or designee within the time frames outlined in Section 9.7.  
9.1.2 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, CBC, coagulation) or other abnormal assessments 
(ECGs, X rays, vital signs) that are judged by the investigator as clinically significant will be 
recorded as AEs or SAEs. This includes clinically significant abnormal laboratory findings or other 
abnormal assessments that are present at baseline and significantly worsen during the study. 
However, clinically significant abnormal laboratory findings or other abnormal assessments that are 
present at the start of the study and do not worse will not be reported as AEs or SAEs. The 
definition of clinically significant is left to the judgment of the investigator; in general, these are 
events that result in clinical signs or symptoms, require active medical intervention, or lead to dose 
interruption or discontinuation. 
Asymptomatic treatment-related lymphocytosis should not be considered an AE. 
9.1.3 
Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE. The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including 
clarifications). 
9.2 
Serious Adverse Events  
An SAE is any untoward medical occurrence that, at any dose: 
 Results in death. 
 Is life threatening.  
NOTE: The term “life threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it was more severe. 
 Requires hospitalization or prolongation of existing hospitalization. 


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NOTE: In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred, or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an SAE. 
 Results in disability/incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions, but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is considered a significant medical AE by the investigator based on medical judgement (eg, 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
The following are NOT considered SAEs: 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
 Hospitalization for social/convenience considerations 
 Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience 
9.3 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any adverse drug event, the specificity 


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or severity of which is not consistent with those noted in the current protocol and/or Investigator’s 
Brochure. This refers to any AE that has not been previously observed (eg, included in the 
Investigator’s Brochure), rather than from the perspective of such an event not being anticipated 
from the pharmacological properties of the product. 
9.4 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events 
9.4.1 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of zanubrutinib or 90 days after the last dose of rituximab, 
whichever is longer. Patients with an ongoing AE that leads to treatment discontinuation will be 
followed until either the event resolves, the investigator assesses the event as stable, or the patient is 
lost to follow-up. After this period, the investigator should report any AE/SAEs that are believed to 
be related to prior study drug treatment. 
9.4.2 
Eliciting Adverse Events 
The investigator or designee will inquire about AEs by asking the following standard questions: 
 How are you feeling?  
 Have you had any medical problems since your last visit?  
 Have you taken any new medicines since your last visit?  
All AEs and SAEs will be recorded in the source documents and eCRFs. 
9.5 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events  
9.5.1 
Diagnosis versus Signs and Symptoms  
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF (and SAE 
report, as applicable), rather than the individual signs and symptoms (eg, record only hepatitis rather 
than elevated transaminases, bilirubin or jaundice). However, if a constellation of signs and/or 


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symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual AE should be recorded as an SAE or AE on the eCRF (and SAE report, if 
applicable). If a diagnosis is subsequently established, it should replace the individual signs and/or 
symptoms as the AE term on the eCRF (and SAE report, if applicable), unless the signs/symptoms 
are clinically significant. 
9.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other AEs (eg, clinical sequelae or a cascade of AEs) should 
be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as the SAE or AE on the eCRF (and SAE report, 
if applicable). However, if a patient initially has a non-serious AE, and it subsequently becomes an 
SAE, both AEs should be reported separately on the eCRF. The onset date of the non-serious AE 
should be recorded as the start date of the non-serious AE. The onset date of the SAE should be 
recorded as the start date when the non-serious AE becomes an SAE. 
9.5.3 
Persistent or Recurring Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such AEs should only be recorded once on the AE eCRF (and SAE report, if 
applicable). If a persistent AE worsens in grade, it should be recorded as a new AE on the eCRF 
(and a stop date should be recorded in the previous AE).  
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent AEs should be recorded separately on the eCRF (and SAE report, 
if applicable).  
9.5.4 
Disease Progression  
Disease progression is expected in this study population, and the term “disease progression” should 
not be reported as an AE term. When disease progression is identified, the AE that identifies the 
disease progression should be reported as the AE term. For instance, a patient with pleural effusion 
presents with shortness of breath. The cause of the shortness of breath is a pleural effusion resulting 
from disease progression. The AE term should be reported as “pleural effusion” instead of disease 
progression or metastasis to lungs. If a patient has a seizure that is determined to be associated with 
a brain metastasis, the term “seizure” should be recorded as the AE instead of disease progression or 


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brain metastasis. If a patient experiences multi-organ failure due to disease progression, the term 
“multi-organ failure” should be reported as the AE instead of disease progression. Deaths that are 
assessed by the investigator as solely due to disease progression should be recorded on the Study 
Completion or Early Discontinuation eCRF as efficacy data. They should not be reported as an 
SAE. A patient death not solely due to disease progression as assessed by the investigator should be 
reported as an SAE immediately, regardless of relationship to study drug. 
If there is any uncertainty regarding whether an AE is due to disease progression, it should be 
reported as an AE. 
9.5.5 
Death 
When recording a death as an SAE, the AE that caused or contributed to fatal outcome should be 
recorded as the single medical concept. If the cause of death is unknown and cannot be ascertained 
at the time of reporting, record “unexplained death.” 
9.6 
Recording of Adverse Events and Serious Adverse Events 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the Sponsor or designee. In these instances, all patient identifiers will be blinded on the copies of the 
medical records prior to submission to the Sponsor or designee. When a SAE occurs, it is the 
responsibility of the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) relative to the event. The investigator will then record all 
relevant information regarding an SAE form. It is not acceptable for the investigator to send 
photocopies of the patient’s medical records to the Sponsor or designee in lieu of completion of the 
appropriate SAE form. However, there may be instances when copies of medical records for certain 
cases are requested by the Sponsor or designee. In this instance, all patient identifiers will be 
redacted on the copies of the medical records prior to submission to the Sponsor or designee. 
9.7 
Prompt Reporting of Serious Adverse Events  
9.7.1 
Time Frame for Submission of Serious Adverse Events 
Serious adverse events will be reported promptly to the Sponsor or designee within 24 hours once 


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the investigator determines that the event meets the protocol definition of a SAE (Table 5). 
Table 5 
Timeframe for Reporting Serious Adverse Events to the Sponsor or Designee 
Type 
Initial Report 
Document  
Follow-up SAE 
Report  
Document  
All SAEs  
Within 24 hours 
of first 
knowledge of the 
AE  
SAE form 
As expeditiously 
as possible  
Updated SAE 
form  
 
 
9.7.2 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the Sponsor or designee within 24 hours as outlined in Section 9.7.1. The SAE report 
form will always be completed as thoroughly as possible with all available details of the SAE, e-
signed by the investigator (or designee) and forwarded to the Sponsor within the designated time 
frames. If the investigator does not have all the information regarding an SAE, he/she will not wait 
to receive additional information before notifying the Sponsor of the event and will complete the 
form. The form will be updated when additional information is received. 
The investigator will always provide an assessment of causality at the time of the initial report as 
described in Section 9.1.1.2. 
If the EDC system is nonoperational, facsimile transmission of the paper SAE form is the preferred 
backup method to transmit this information to the project contact for SAE receipt. In rare 
circumstances and in the absence of facsimile equipment, notification by email is acceptable, with a 
copy of the paper SAE form sent by overnight mail. Initial notification via the telephone does not 
replace the need for the investigator to complete and sign the paper SAE form within the time 
frames outlined in Section 9.7.1. After the EDC becomes operational again, the investigator will 
enter the information in the EDC system. 
The Sponsor or designee will provide a list of project contacts for SAE receipt, fax numbers, 
telephone numbers, and mailing addresses.  


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9.7.3 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the Sponsor or designee in accordance with the 
procedures detailed in Section 9.7.2. The Sponsor has a legal responsibility to notify, as appropriate, 
both the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation. Prompt notification of SAEs by the investigator to the appropriate project 
contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards the 
safety of other patients are met. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
This protocol is being filed under an Investigational New Drug (IND) protocol amendment with the 
United States FDA. Once active, a given SAE may qualify as an IND safety report if the SAE is 
both attributable to the study drug and unexpected. In this case, all investigators included in the IND 
(and associated INDs for the same compound) will receive an expedited investigator safety report, 
identical in content to the IND safety report submitted to the FDA. 
Expedited investigator safety reports are prepared according to the Sponsor’s policy and are 
forwarded to investigators as necessary. The purpose of the report is to fulfill specific regulatory 
and GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, revised 
Investigator’s Brochure) from the Sponsor, the responsible person according to local requirements is 
required to promptly notify his/her IRB or IEC.  
9.8 
Serious Adverse Events Related to Study Participation 
A SAE considered related to study participation (eg, procedures, invasive tests, a change in existing 
therapy), even if it occurs during the pre-or post-treatment period, will be reported promptly to the 
Sponsor or designee (Section 9.7). 
9.9 
Pregnancy Reporting 
If a female patient or the partner of a male patient becomes pregnant while receiving zanubrutinib or 
within 90 days of the last dose of zanubrutinib, or a female patient pregnant while receiving 


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rituximab or within 12 months after the last dose of rituximab, a pregnancy report form should be 
completed and expeditiously submitted to the Sponsor or designee to follow up with the patient. 
Information on the status of the mother and child will be forwarded to the Sponsor. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature 
termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as a SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drug 
should be recorded and reported as a SAE. 
A serum pregnancy test will be performed at Screening and EOT in women of childbearing 
potential. Any female patient who is pregnant will not be eligible for the study. A urine or serum 
pregnancy test must be performed if any woman suspects that she has become pregnant during the 
study. 
9.9.1 
Action to be Taken and Reporting if a Pregnancy Occurs  
A patient who has a positive pregnancy test result at any time after the study drug administration 
will be immediately withdrawn from participation in the study. 
The investigator or his/her designee will collect pregnancy information on any female patient or a 
female partner of a male patient who becomes pregnant while participating in this study. The 
investigator or his/her designee will record pregnancy information on the appropriate form and 
submit it to the Sponsor or designee within 2 weeks of learning of a patient’s or male patient’s 
female partner’s pregnancy. The patient or male patient’s female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor or designee.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE, and will 
be followed.  
A spontaneous abortion is always considered to be a SAE and will be reported as described 


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previously. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study drug by the investigator will be reported to the Sponsor or designee. 
While the investigator is not obligated to actively seek this information in former patients, he/she 
may learn of a SAE through spontaneous reporting. 
9.10 Post-Study Adverse Events and Serious Adverse Events  
A post-study AE or SAE is defined as any AE that occurs after the AE/SAE detection reporting 
period. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will notify 
the Sponsor or designee. 
9.11 Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards and Ethics Committees  
The Sponsor will promptly assess all SAEs against cumulative study drug experience to identify and 
expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs and 
IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the Sponsor will assess the 
expectedness of the SAEs using the following reference documents: 
 BGB-3111 Investigator’s Brochure  
 Local prescribing information for rituximab  


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10 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
All statistical analyses will be performed by the Sponsor or designee after the study is completed 
and the database is locked and released. 
Details of the statistical analyses will be included in a separate statistical analysis plan (SAP). 
10.1 Sample Size 
Total sample size for the study will be approximately 40 patients, 20 for each cohort. There will be 
no hypothesis testing for study endpoints, thus the sample size is not based on the statistical power 
calculation. 
10.1.1 
Analysis Sets  
The Safety Analysis Set includes all patients who received at least 1 dose of study drug. The Safety 
Analysis Set will be used for all efficacy and safety analyses. 
All patients for whom valid zanubrutinib PK can be estimated and no important protocol deviations 
affecting PK will be included in the PK Analysis Set on an as treated basis. Similarly, patients for 
whom valid rituximab PK can be estimated and no important protocol deviations affecting PK will 
be included in the PK Analysis Set on an as treated basis. For exploratory parameters, all patients 
for whom can be estimated on with evaluable data will be included in the summaries. 
10.1.2 
Interim Analysis 
No interim analysis is planned for this study.  
10.1.3 
Withdrawal 
Patients who withdraw from the study will not be replaced. 
10.1.4 
Pharmacokinetics 
Plasma and serum samples for analysis of zanubrutinib and rituximab respectively will be collected 
at the time points described in Section 7.1 and Schedule of Assessments (Appendix 2). 
Plasma zanubrutinib and serum rituximab concentrations will be summarized and displayed in 
tabular format. 


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Additional analyses such as population PK analysis may be performed in conjunction with data 
from other studies and the results from such analyses may be reported separately from the clinical 
study report (CSR). 
10.2 Efficacy Data Analysis 
Response assessment for disease status-based efficacy endpoints (ORR, CR, CMR, PFS, time to 
response [TTR] and DOR) will be performed per the Lugano Classification (Cheson et al 2014).  
10.2.1 
Primary Efficacy Endpoint 
The primary endpoint of the study is ORR by investigator. ORR will be calculated as crude 
proportion of number of patients who achieve PR or higher as best response. The estimate of ORR 
with 95% exact confidence interval will be presented in each cohort.  
10.2.2 
Secondary Efficacy Endpoints 
CR and CMR will be analyzed using the same methods applied for ORR analysis. Listings for time 
to event secondary efficacy endpoints (PFS, DOR, overall survival [OS] and TTR) will be 
generated. The distribution of time to event secondary efficacy endpoints will be estimated where 
applicable.  
10.3 Safety Data Analysis 
10.3.1 
Adverse Event 
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified into 
standardized medical terminology using the MedDRA®. AEs will be coded to the MedDRA® 
(Version 18.1 or higher) lower level term closest to the verbatim term. The linked MedDRA® 
preferred term and primary system organ class are also captured in the database. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose date of study drug up to 30 days following discontinuation 
of zanubrutinib or 90 days following discontinuation of rituximab, whichever comes later; or 
initiation date of new anticancer therapy, if it occurs prior to the other two dates. Only those AEs 
that were treatment-emergent will be included in summary tables. All AEs, treatment-emergent or 
otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 


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system organ class and preferred term. A patient will be counted only once by the highest severity 
grade according to the NCI-CTCAE Version 4.03 within a system organ class and preferred term, 
even if the patient experienced more than 1 TEAE within a specific system organ class and 
preferred term. The number (percentage) of patients with TEAEs will also be summarized by 
relationship to the study drug. The treatment-related AEs include those events considered by the 
investigator to be related, possibly or probably related, unlikely related to study drug or with 
missing assessment of the causal relationship. SAEs, deaths, TEAEs ≥ Grade 3, related TEAEs, and 
TEAEs that led to treatment discontinuation, dose reduction or dose interruption will be 
summarized. 
10.3.2 
Laboratory Assessments 
CBC and serum chemistry values will be evaluated for each laboratory parameter. Abnormal 
laboratory values will be flagged and identified as those outside (above or below) the normal range. 
Reference (normal) ranges for laboratory parameters will be included in the clinical study report 
(CSR). Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n [%] for categorical variables) for laboratory parameters and 
their changes from baseline will be calculated. Laboratory values will be summarized by visit and 
by worst post-baseline visit. 
Laboratory parameters that are graded in NCI-CTCAE Version 4.03 will be summarized by CTCAE 
grade. In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading 
in both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
10.3.3 
Electrocardiogram 
All ECG parameters, including the QT interval corrected for heart rate (QTc), will be listed for each 
patient. 
10.3.4 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by visit for 
all visits. Vital signs will be listed by patient and visit. 


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10.3.5 
Extent of Exposure 
Extent of exposure to zanubrutinib in combination with rituximab will be calculated for each 
patient. Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received, duration of exposure (days), cumulative total dose received per patient (mg), dose 
intensity (mg/day) and relative dose intensity (%), as appropriate. 
The number (percentage) of patients with dose reductions, dose interruption, and drug 
discontinuation will be summarized with the respective reasons, as appropriate. The cycle in which 
the first dose reduction/interruption occurred will be summarized using descriptive statistics. 
Frequency of dose reductions and interruptions will be summarized descriptively, as appropriate. 
Patient data listings will be provided for all dosing records. 
10.3.6 
Physical Examination 
Physical examination results will be listed. 
10.3.7 
Other Safety Endpoints 
ECOG performance status will be summarized. Pregnancy test and viral serology will be listed. 
10.4 Explorative Endpoint Analyses 
11 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
11.1 Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to the 
appropriate regulatory agency before the study is initiated at a study center in that country. 


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11.2 Investigator Responsibilities 
11.2.1 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the Declaration of 
Helsinki International Conference on Harmonization (ICH) guidelines, and that the basic GCP 
principles, as outlined in 21 Code of Federal Regulations (CFR) 312, Subpart D, “Responsibilities 
of Sponsors and Investigators,” 21 CFR, Part 50, and 21 CFR, Part 56, are adhered to. 
Investigators and all sub-investigators must provide documentation of their financial interest or 
arrangements with BeiGene, or proprietary interests in the drug being studied. This documentation 
must be provided before the participation of the investigator and any sub-investigator. The 
Investigator and sub-investigator(s) agree to notify BeiGene of any change in reportable interests 
during the study and for 1 year following completion of the study. Study completion is defined as 
the date that the last patient has completed the protocol defined activities. 
11.2.2 Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP and all applicable regulatory requirements, 
including, where applicable, current version of the Declaration of Helsinki. 
The investigator (or Sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s informed consent form, and any other information that will be presented to potential 
patients (eg, advertisements or information that supports or supplements the informed consent) are 
reviewed and approved by the appropriate IEC/IRB. The investigator agrees to allow the IEC/IRB 
direct access to all relevant documents. The IEC/IRB must be constituted in accordance with all 
applicable regulatory requirements. The Sponsor will provide the investigator with relevant 
document(s)/data that are needed for IEC/IRB review and approval of the study. Before the study 
drug(s) can be shipped to the study center, the Sponsor must receive copies of the IEC/IRB 
approval, the approved informed consent form, and any other information that the IEC/IRB has 
approved for presentation to potential patients. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has approved 
for presentation to potential patients is amended during the study, the investigator is responsible for 
ensuring the IEC/IRB reviews and approves, where applicable, these amended documents. The 


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investigator must follow all applicable regulatory requirements pertaining to the use of an amended 
informed consent form including obtaining IEC/IRB approval of the amended form before a new 
patient consents to take part in the study using this version of the form. Copies of the IEC/IRB 
approval of the amended informed consent form/other information and the approved amended 
informed consent form/other information must be forwarded immediately to the Sponsor. 
11.2.3 Informed Consent 
The investigator is responsible for obtaining written informed consent from all patients participating 
in this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study is given and before performing any study-related procedures. The investigator must utilize 
an IRB/IEC-approved consent form for documenting written informed consent. Before patient 
participation begins, each informed consent will be appropriately signed and dated by the patient or 
the patient’s legally authorized representative and the person obtaining consent. 
Informed consent will be obtained before the patient can participate in the study. The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
11.2.4 Investigator Reporting Requirements 
The investigator (or Sponsor, where applicable) is responsible for reporting SAEs to the IEC/IRB, 
in accordance with all applicable regulations. Furthermore, the investigator may be required to 
provide periodic safety updates on study conduct at the study center and notification of study 
closure to the IEC/IRB. Such periodic safety updates and notifications are the responsibility of the 
investigator and not of the Sponsor. 
11.2.5 Confidentiality 
Information on maintaining patient confidentiality in accordance to individual local and national 
patient privacy regulations must be provided to each patient as part of the informed consent form 
(ICF) process, either as part of the ICF or as a separate signed document (eg, in the US, a site-
specific Health Insurance Portability and Accountability Act [HIPAA] consent may be used). The 
investigator must assure that the patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only patient initials (if allowed), date of 


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independent central review, and an identification code (ie, not names) should be recorded on any 
form or biological sample submitted to the Sponsor, IRB, or laboratory. The investigator must keep 
a screening log showing codes, names, and addresses for all patients screened and for all patients 
enrolled in the trial.  
The Investigator agrees that all information received from BeiGene, including but not limited to the 
IB, this protocol, case report forms (CRFs), the investigational new drug, and any other study 
information, remain the sole and exclusive property of BeiGene during the conduct of the study and 
thereafter. This information is not to be disclosed to any third party (except employees or agents 
directly involved in the conduct of the study or as required by law) without prior written consent 
from BeiGene. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the public 
domain. 
11.2.6 Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the principal investigator or 
sub-investigator within a reasonable time period after data collection. This also applies to records 
for those patients who discontinue the study early. If a patient withdraws from the study, the reason 
must be noted in the appropriate eCRF. If a patient is withdrawn from the study because of a 
treatment-limiting AE, thorough efforts should be made to clearly document the outcome. 
The eCRFs exists within an EDC system with controlled access managed by BeiGene or its 
authorized representative for this study. Study staff will be appropriately trained in the use of eCRFs 
and applications of electronic signatures before being given access to the EDC system. Original data 
and any changes of data will be recorded using the EDC system, with all changes tracked by the 
system and recorded in an electronic audit trail. The investigator attests that the information 
contained in the eCRFs is true by providing an electronic signature within the EDC system. After 
final database lock, the investigator will receive a copy of the patient data for that site on CD-ROMs 
for archiving the data at the study site. 
11.2.7 Drug Accountability 
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability of 


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all used and unused study drug. This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition), patient dispensing records and returned or destroyed study 
product. Dispensing records will show quantities received from BeiGene and quantities dispensed to 
patients, including lot number, date dispensed, patient identifier number, patient initials (if allowed), 
and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction in order to ensure that it complies with BeiGene requirements. At the end of the 
study, following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet BeiGene’s requirements for disposal, arrangements will be made 
between the site, BeiGene or its representative to destroy or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
11.2.8 Inspections 
The investigator should understand that source documents for this trial should be made available to 
appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, or to 
regulatory authority or health authority inspectors. 
11.2.9 Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators ascertain they will apply due 
diligence to avoid protocol deviations. 
11.3 Sponsor Responsibilities 
11.3.1 
Protocol Modifications 
Protocol modifications to reduce immediate risk to study patients, may be initiated only by 
BeiGene. All protocol modifications must be submitted to competent authorities according to local 
requirements and to the IRB/IEC together with, if applicable, a revised model ICF in accordance 
with local requirements. Written documentation of competent authorities (as applicable according to 
local requirements) and to IRB/IEC and required site approval must be obtained by the Sponsor 


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before changes can be implemented. 
Information on any change in risk and /or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming willingness to remain in the trial. 
11.3.2 
Study Report and Publications 
A CSR will be prepared and provided to the regulatory agency(ies). BeiGene will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study 
Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, objective, 
and clinically meaningful manner that is consistent with good science, industry and regulatory 
guidance, and the need to protect the intellectual property of BeiGene (Sponsor), regardless of the 
outcome of the study. The data generated in this clinical trial are the exclusive property of the 
Sponsor and are confidential. Since this is a multicenter study, the first publication or disclosure of 
study results shall be a complete, joint multicenter publication or disclosure coordinated by the 
Sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors (ICMJE) Uniform 
Requirements for Manuscripts or stricter local criteria (ICMJE 2013).  
Each investigator agrees to submit all manuscripts abstracts, posters, publications and presentations 
(both oral and written) to the Sponsor prior to submission or presentation in accordance with the 
clinical study agreement. This allows the Sponsors to protect proprietary information, provide 
comments based on information from other studies that may not yet be available to the investigator, 
and ensure scientific and clinical accuracy. Each investigator agrees that, in accordance with the 
terms of the clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings in advance of the publication/presentation.  
11.4 Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction with 
the investigator or study center personnel, as appropriate: 


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 Return of all study data to the Sponsor 
 Data queries 
 Accountability, reconciliation, and arrangements for unused study drug(s) 
 Review of study records for completeness 
 Return of treatment codes to the Sponsor 
 Shipment of PK samples to assay laboratories 
In addition, the Sponsor reserves the right to suspend or prematurely discontinue this study either at 
a single study center or at all study centers at any time for reasons including, but not limited to, 
safety or ethical issues or severe non-compliance. If the Sponsor determines such action is needed, 
the Sponsor will discuss this with the investigator (including the reasons for taking such action) at 
that time. When feasible, the Sponsor will provide advance notification to the investigator of the 
impending action prior to it taking effect. 
The Sponsor will promptly inform all other investigators and/or institutions conducting the study if 
the study is suspended or terminated for safety reasons, and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action. If required 
by applicable regulations, the investigator must inform the IEC/IRB promptly and provide the 
reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the Sponsor. In addition, 
arrangements will be made for all unused study drug(s) in accordance with the applicable Sponsor 
procedures for the study.  
Financial compensation to investigators and/or institutions will be in accordance with the agreement 
established between the investigator and the Sponsor. 
11.5 Records Retention and Study Files 
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. These documents should be 
classified into at least the following 2 categories: (1) Investigator’s study file, and (2) patient 


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clinical source documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB/IEC, 
and governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs) would include (although not be limited to) the 
following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, x-ray, pathology and special assessment reports, 
consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (eg, audit 
or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and personnel. Where permitted by local 
laws/regulations or institutional policy, some or all of these records can be maintained in a format 
other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be exercised 
before such action is taken. The investigator must assure that all reproductions are legible, are a true 
and accurate copy of the original, and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an 
acceptable backup of these reproductions and that an acceptable quality control process exists for 
making these reproductions. 
The Sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional requirements or 
local laws or regulations, or the Sponsor’s standards/procedures; otherwise, the retention period will 
default to 15 years. 
The investigator must notify the Sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of the records 
in the event the investigator leaves the study center. 


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If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store these 
in sealed containers outside of the site so that they can be returned sealed to the investigator in case 
of a regulatory audit. When source documents are required for the continued care of the patient, 
appropriate copies should be made for storage outside of the site. 
Biological samples remaining after this study may be retained in storage by the Sponsor for a period 
up to 2 years. 
11.6 Provision of Study Results and Information to Investigators 
When the CSR is completed, the Sponsor will provide the major findings of the study to the 
investigator.  
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s). 
The Sponsor will not routinely inform the investigator or patient the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will be undetermined at such an early stage of research. 
11.7 Information Disclosure and Inventions 
All information provided by the Sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) is the sole property of the Sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial property 
rights which are conceived or reduced to practice by the study center personnel during the course of 
or as a result of the study are the sole property of the Sponsor, and are hereby assigned to the 
Sponsor. 
If a written contract for the conduct of the study which includes ownership provisions inconsistent 
with this statement is executed between the Sponsor and the study center, that contract’s ownership 
provisions shall apply rather than this statement. 
All information provided by the Sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) will be kept by the investigator and other 


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study center personnel. This information and data will not be used by the investigator or other study 
center personnel for any purpose other than conducting the study. 
These restrictions do not apply to: 
 Information which becomes publicly available through no fault of the investigator or study 
center personnel. 
 Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study. 
 Information which is necessary to disclose in order to provide appropriate medical care to a 
patient. 
 Study results which may be published as described in Section 11.3.2. 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
11.8 Joint Investigator/Sponsor Responsibilities 
11.8.1 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
Investigator’s source documentation in order to verify the data recorded in the CRFs for 
consistency. 
The monitor is responsible for routine review of the CRFs at regular intervals throughout the study 
to verify adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them. The monitor should have access to any patient records needed to verify the 
entries on the CRFs. The investigator agrees to cooperate with the monitor to ensure that any 
problems detected during these monitoring visits are resolved. 
11.8.2 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Sponsor or its designee immediately. The investigator agrees to 


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provide to representatives of a regulatory agency or BeiGene access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 


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12 
REFERENCES 
 
BeiGene Investigator’s Brochure, Zanubrutinib (BGB-3111). Edition 6, February 2019. 
Blum KA. B-cell receptor pathway modulators in NHL. Hematology Am Soc Hematol Educ Program. 
2015;82-91. 
Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with 
high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10):1090-99. 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2013;369(1):32-42. 
Castillo JJ, Palomba ML, Advani R, et al. Ibrutinib in Waldenström macroglobulinemia: latest evidence and 
clinical evidence. Ther Adv Hematol. 2016;7(4):179-86. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 
2014;32(27):3059-68. 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 
4.03. U. S. Department of Health and Human Services, Food and Drug Administration. 2010. 
Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of 
therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100(1):77-86. 
Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab-refractory 
Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicenter, 
phase 3 trial. Lancet Oncol. 2017;18(2):241-250. 
Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. U. S. Department of Health and Human Services, Food and Drug Administration. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling
/ucm093664.htm. Accessed 21 February 2019. 
Fowler N, Nastoupil L, de Vos S, et al. Ibrutinib plus rituximab in treatment-naive patients with follicular 
lymphoma: results from a multicenter, phase 2 study. Blood. 2015;126:470. 
Gayko U, Fung M, Clow F, et al. Development of the Bruton’s tyrosine kinase inhibitor ibrutinib for B cell 
malignancies. Ann N.Y. Acad Sci. 2015;1358:82-94. 
Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large 
B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282. 
IMBRUVICA® (ibrutinib) [prescribing information]. Sunnyvale, CA: Pharmacyclics LLC; Janssen Biotech, 
Inc., 2018. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the Conduct, Reporting, 
Editing, and Publication of Scholarly Work in Medical Journals. Updated August 2013. Available at: 
http://www.icmje.org 
Naymagon L, Abdul-Hay M. Novel agents in the treatment of multiple myeloma: a review about the future.  
J Hematol Oncol. 2016;9(1):52-72. 


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Qiu Y, Kung HJ. Signaling network of the Btk family kinases. Oncogene. 2000;19(49):5651-61. 
Rituxan® (rituximab) [prescribing information]. South San Francisco, CA: ; Biogen and Genentech, Inc., 
2018.  
Tam CS, Grigg AP, Opat S, et al. The BTK inhibitor, BGB-3111, is safe, tolerable, and highly active in 
patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. 
2015;126:832. 
Tucker DL, Rule SA. Ibrutinib for mantle cell lymphoma. Future Oncol. 2016;12(4):477-91. 
Ujjani CS, Jung SH, Pitcher B, et al. Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously 
untreated follicular lymphoma: Alliance A051103. Blood. 2016;128(21):2510-16. 
Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle 
cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016;17(1):48-56. 
Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large 
B cell lymphoma. Nat Med. 2015;21(8):922-6. 
Young RM, Staudt LM. Targeting pathological B cell receptor signaling in lymphoid malignancies. Nat Rev 
Drug Discov. 2013;12(3):229-43. 


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13 
APPENDICES 
Appendix 1. 
Signature of Investigator 
 
PROTOCOL 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) 
PROTOCOL NO: 
 
BGB-3111-213 
 
This protocol is a confidential communication of BeiGene (Beijing) Co., Ltd. I confirm that I have 
read this protocol, I understand it, and I will work in accordance with this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and that 
are consistent with good clinical practices and the applicable laws and regulations. Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will be 
published or disclosed without prior written approval from BeiGene (Beijing) Co., Ltd. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the center in which the study will be conducted. Return the signed copy to the contract research 
organization (CRO). 
 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
Signature of Investigator: 
_______________________________   Date:  _____________ 
 
Printed Name: 
_______________________________ 
 
Investigator Title: 
_______________________________ 
 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 


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Appendix 2. 
Schedule of Assessments 
Screening 1 
Treatment Period 
Safety Follow-up 2 
Survival/Efficacy 
Follow-up 3 
Cycle 1 
Cycle 2 and 
additional cycles  
(every 28 ± 3 days) 
EOT 4 
Days 
-28 to -1 
1 5 
1 5  
 
30 ± 3 days 
after last dose of 
study drug 
 
Informed consent 6 
x 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
Demographic/Medical history/ 
Disease staging/Prior 
medications/IPI score/EBV 
infection 7 
x 
 
 
 
 
 
Vital signs 8 
x 
x 
x 
x 
x 
 
Height and weight 9 
x 
x 
x 
x 
x 
 
Physical examination 
x 
x 
x 
x 
x 
 
ECOG performance status 
x 
x 
x 
x 
x 
 
12-lead ECG 10 
x 
x 
 
 
x 
 
Review adverse events 11 
x 
x 
x 
x 
x 
 
Review concomitant medications 12 
x 
x  
x 
x 
x 
 
CBC with differential 13 
x 
x 5 
x 5 
x 
x 
 
Serum chemistry panel 13 
x 
x 5 
x 5 
x 
x 
 
Coagulation parameters 14 
x 
 
 
 
 
 
Urinalysis 15 
x 
x 
x 
x 
 
 
Immunoglobulins 
 
x 16 
x 16 
 
 
 
Hepatitis B and C 17 
x 
 
 
 
 
 


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Screening 1 
Treatment Period 
Safety Follow-up 2 
Survival/Efficacy 
Follow-up 3 
Cycle 1 
Cycle 2 and 
additional cycles  
(every 28 ± 3 days) 
EOT 4 
Days 
-28 to -1 
1 5 
1 5  
 
30 ± 3 days 
after last dose of 
study drug 
 
HIV 
x 
 
 
 
 
 
Pregnancy test 18 
x 
 
 
x 
 
 
Tumor tissue collection for 
biomarker study 19 
x 
 
When patient fails to 
achieve partial 
response (PR) or 
better after at least 6 
months of study 
treatment 
x 
 
 
Blood collection for biomarker 
study 20 
x 
 
When patient fails to 
achieve partial 
response (PR) or 
better after at least 6 
months of study 
treatment 
x 
 
 
CT or PET/CT or MRI 21, 22 
x 
Week 12, then every 12 weeks, ± 7 days 
x 22 
 
x 22 
PET 23 
x 
Week 24, Week 48, clinical CR or progressive 
disease suspected clinically or by CT (MRI if 
CT contraindicated) 
 
 
x 
ECHO or MUGA 24 
x 
 
 
 
 
 
Bone marrow aspirate/biopsy 25 
x 
For confirmation of CR if baseline marrow is 
positive for NHL 
 
 
 
Survival status 
 
 
 
 
 
x 
Zanubrutinib administration 
 
orally twice daily, continuously 
 
 
Rituximab administration 
 
Days 1, 8, 15, 22 of Cycle 1, then Day 1 of Cycles 4, 6, 8, 
and 10 
 
 
  
 
 
  
 
 
 


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Screening 1 
Treatment Period 
Safety Follow-up 2 
Survival/Efficacy 
Follow-up 3 
Cycle 1 
Cycle 2 and 
additional cycles  
(every 28 ± 3 days) 
EOT 4 
 
Abbreviation: CBC, complete blood count; CT, computed tomography; EBV, Epstein–Barr virus; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, 
Eastern Cooperative Oncology Group; EOT, end of treatment; IPI, International Prognostic Index; MRI, magnetic resonance imaging; MUGA, multigated 
acquisition scan; PET, positron emission tomography. 
1  
All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of 
assessments. Screening procedures may be performed up to 28 days prior to first dose of treatment. If CT and PET scans were conducted within 30 days of 
the first dose of study treatment, then those scans are acceptable for screening. 
2  
The mandatory Safety Follow-up Visit should be conducted 30 days (±3 days) after the last dose of study therapy (zanubrutinib or Rituximab, whichever is 
later) or before the initiation of a new treatment, whichever comes first.  
3  
Following completion of the Safety follow-up phase, every effort should be made to follow patients for survival approximately once every 3 months until 
patient death or study termination by the Sponsor. For patients who discontinue study treatment for reason other than progressive disease, disease status 
should be captured every 12 weeks (± 7 days) until progressive disease, withdrawal of consent, death, lost to follow-up, end of study or study termination by 
Sponsor, whichever occurs first. 
4  
When patients go off treatment, they will need to undergo EOT visit within 7 days of last dose of study drug. If patient underwent study drug interruption > 7 
days, before decision of EOT, EOT visit can be done within the interval of 30 ± 3 days after last dose of study drug, combining assessments at both EOT and 
safety Follow-up visits.   
5  
In Cycle 1, tests may be performed 3 days prior to Day 1 of the cycle. In Cycle 2 and beyond, tests may be performed within a 3-day window of Day 1 of the 
cycle.  
6  
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed as part of routine clinical management are 
acceptable in lieu of a screening test if performed within the specified timeframe (eg, within 28 days prior to Cycle 1 Day 1). Assign baseline number when 
the study informed consent is signed. 
7  
Includes history for the primary diagnosis (date of NHL diagnosis and last recurrence, stage, and biopsy details), treatment of NHL including prior systemic, 


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radiation treatment. Date of last prior cancer treatment must be documented. Radiographic studies performed prior to study entry may be collected for review 
by the investigator. Report complete medication history for 28 days prior to the Screening visit (Visit 1). Disease staging should be recorded as per criteria in 
Appendix 4. Collect IPI score at screening (One point each is allocated for age>60years, stage III/IV disease, increased LDH, ECOG performance status >2, 
>2 extra-nodal site involvement) and previous EBER result (if available). 
8  
Vital signs to include temperature, blood pressure, pulse, respiratory rate. 
9  
Height (cm) is determined at Screening only. 
10  At each time point listed, triplicated 12-lead ECG will be performed by qualified site personnel after the patient has rested in a semi-recumbent or supine 
position for at least 5 minutes. Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the patient’s medical 
chart and the second copy will be kept in the study file for retrospective collection by the Sponsor if necessary. 
11  Adverse experiences and laboratory safety measurements will be graded per NCI-CTCAE version 4.03. All adverse experiences, whether gradable by 
CTCAE or not, will also be evaluated for seriousness. AE and SAE will be reported until 30 days after the last dose of zanubrutinib, or 90 days after the last 
dose of rituximab, whichever occurs later. See Section 9 for details regarding the reporting of AEs. 
12  All Concomitant Medications within 28 days prior to first study treatment and until 30 days after the last dose of study treatment should be recorded in the 
CRFs. Any new anti-cancer therapy, if taken after treatment discontinuation, will also be recorded. 
13  
If screening lab assessment for eligibility is completed within 3 days of study drug administration, they do not need to be performed again for C1D1. Re-
screening of patients will not be allowed, but laboratory parameters which do not meet the inclusion criteria may be re-tested within the Screening window 
(Day -28 to Day -1). In Cycle 2 and beyond, laboratory assessments can be done within 48 hours of the visit and do not necessarily need to be on the day of 
the visit. 
14  Coagulation parameters (PT, INR, aPTT) should be determined at Screening and during study treatment as clinically indicated.  
15  Urinalysis will be performed at screening, every visit during the treatment period and EOT. In case where screening lab assessment for eligibility is 
completed within 72 hours of study drug administration, the urinalysis does not need to be performed again for C1D1. The testing includes pH, glucose, 
protein, ketones, bilirubin, blood, and specific gravity. If urine protein is ≥2+ by dipstick, a 24-hour urine for total protein and creatinine will be obtained 
and evaluated. 
16  Total immunoglobulins will be obtained every 6 months, including IgG, IgM, IgA. 
17  Testing will be performed at Screening and includes Hepatitis C virus (HCV) antibody, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(HBsAb), and Hepatitis B core antibody (HBcAb). Patients who are HBcAb positive at Screening must not be enrolled until further testing by PCR to assess 
Hepatitis B viral load for determination of study eligibility as per Inclusion/Exclusion Criteria (See Section 5.2 and Section 7.3.6.5). 
18  Serum pregnancy test (only in women of childbearing potential) at screening and at EOT. Patients must have a negative serum pregnancy test at Screening. 
Subsequent tests may be urine tests and should be performed as clinically indicated. 
19  Archival or newly obtained tumor tissue from a core or excisional biopsy will be collected (paraffin block or 10-15 unstained FFPE slides) to meet the 
requirement of biomarker analysis at Screening. Optional tumor biopsy will be obtained at EOT for accessible tumor if reason for treatment discontinuation 
is progressive disease. Optional tumor biopsy will also be collected for accessible tumor from patients who fail to achieve partial response (PR) or better 
after at least 6 months of study treatment.  
20  Blood samples (10 ml) will be collected at screening. In addition, blood samples will be collected from patients who fail to achieve partial response (PR) or 
better after at least 6 months of study treatment. Another 10 ml blood sample will be obtained at EOT if the reason for treatment discontinuation is 
progressive disease. 
21  Tumor imaging (CT with contrast of neck, chest, abdomen and pelvis, and PET/CT) will be performed within 28 days prior to the first dose of study drug 


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treatment. Any qualified imaging assessments already completed during the regular work-up of the patient are accepted within 28 days prior to start of 
treatment, including before signing the main study informed consent form, and can be considered as the Screening/baseline image for this study. Imaging 
timing should follow calendar days and should not be adjusted for treatment delays. Tumor assessments by CT with contrast should be performed at 
Screening, Week 12, then every 12 weeks (± 7 days) until progressive disease, withdrawal of consent, death, lost to follow-up, or end of study, whichever is 
earlier. Target and non-target lesions must be identified at the time of Screening and the same lesion(s) must be re-assessed by investigator at each time point 
in a consistent manner in accordance with the Lugano Classification (Cheson et al 2014). The same diagnostic modality must be used throughout the study. 
PET/CT can be performed in lieu of a CT with contrast only if the CT is performed with diagnostic quality and contrast is administered. Total body MRI 
may be substituted for CT if CT with contrast is contraindicated.  
22  Tumor imaging for EOT does not have to be performed if the most recent tumor imaging was performed within the previous 6 weeks. For patients who 
discontinue study treatment for reason other than progressive disease, tumor imaging will be performed every 12 weeks (± 7 days) until progressive disease, 
withdrawal of consent, death, lost to follow-up, or end of study, whichever occurs first. 
23  Tumor assessment by PET scan will be performed at Screening, Week 24, Week 48, progressive disease suspected clinically or by CT (MRI if CT 
contraindicated), and CR suspected clinically or by CT (MRI if CT contraindicated), for sites with PET scanning capability. For patients with diagnosis of 
MZL, PET scan is not required at Screening or on study treatment. 
24  ECHO or MUGA is required at Screening unless performed within 90 days of first day of Screening (Visit 1). 
25  Bone marrow aspirate and biopsy will be performed at Screening, if not performed within 60 days of first dose of study drug. Bone marrow aspirate and 
biopsy will also be required for confirmation of CR if baseline marrow was positive by NHL. 
26  
. 
 
 
 








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Source: Cheson BD, Fisher RJ, Barrington SF, et al.  J Clin Oncol 2014;32(27):3059-67. 
Abbreviation: CT, computed tomography; FDG, fluorodeoxygluose; IHC, immunohistochemistry; LDi, longest transverse diameter of a lesion; PPD, cross 
product of the longest transverse diameter of a lesion and perpendicular diameter; SDi, shortest axis perpendicular to the longest transverse diameter of a lesion; 
SPD, sum of the product of the perpendicular diameters for multiple lesions; 5PS, 5-point scale. 
*A score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant lesions: 
Up to six of the largest dominant nodes, nodal masses, and extra-nodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be 
from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs 
(eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Non-measured lesions: Any disease not selected as measured, 
dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extra-nodal sites not selected 
as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is 
any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extra-nodal sites (eg, GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
Splenomegaly defined as vertical spleen length > 13 cm for purposes of the CT reads. 
PET 5-point scale (Deauville Criteria): 
 
1: no uptake above background 
 
2. uptake ≤ mediastinum 
 
3. uptake > mediastinum but ≤ liver 
 
4. uptake moderately > liver 
 
5. uptake markedly higher than liver and/or new lesions 
 
X. new areas of uptake unlikely to be related to lymphoma 


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Appendix 4. 
Non-Hodgkin Lymphoma Staging 
Stage 
Involvement 
Extra-nodal (E) Status 
I 
One node or a group of adjacent nodes 
Single extra-nodal lesion without nodal 
involvement 
II 
Two or more nodal groups on the same side of 
the diaphragm 
Stage I or II by nodal extent with limited 
contiguous extranodal involvement 
II bulky* 
II as above with bulky disease 
Not applicable 
III 
Nodes on both sides of the diaphragm; nodes 
above the diaphragm with spleen involvement 
Not applicable 
IV 
Additional non-contiguous extra-lymphatic 
involvement 
Not applicable 
Source: Cheson BD, Fisher RJ, Barrington SF, et al.  J Clin Oncol 2014;32(27):3059-67. 
Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue. 
*Bulky disease defined as a single nodal mass of 10 cm or greater than a third of the transthoracic diameter at 
any level of thoracic vertebrae as determined radiographically. 
 


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Appendix 5. 
CYP3A Inhibitors and Inducers 
Strong CYP3A Inhibitors 
Antibiotics:  clarithromycin, telithromycin, troleandomycin 
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals:  boceprevir, telaprevir 
Other:  cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease inhibitors:  indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Moderate CYP3A Inhibitors 
Antibiotics:  ciprofloxacin, erythromycin 
Antifungals: fluconazole, clotrimazole 
Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir 
Calcium channel blockers:  diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib, crizotinib 
Food products:  grapefruit juice (citrus paradisi juice) 
Herbal medications:  Schisandra sphenanthera 
Others:  amiodarone, aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
Strong/Moderate CYP3A Inducers 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s 
wort (hypericum perforatum), enzalutamide, mitotane, bosentan, efavirenz, etravirine, modafinil 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers.  
Abbreviation: CYP3A, cytochrome P450, family 3, subfamily A. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information and Summary of 
Product Characteristics to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
For a more complete list, please refer to the FDA Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers List (FDA 2019). 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-213 
Study Protocol 
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) 
 
Date: 
11-Sep-2020 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE 
Author:  
 
                
 
 
 
Signature 
Date:  ______________ 
 
 
 
 
 
Approval 
 
 
 
 
 
 
 
Signature 
Date:  ______________ 
 
 
 
 
 
 
 
 
Signature 
Date:  ______________ 
Signature 
Date:  ______________ 


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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5 
1 
INTRODUCTION 
6 
2 
STUDY OVERVIEW 
6 
3 
STUDY OBJECTIVES 
7 
3.1 
Primary Objective 
7 
3.2 
Secondary Objectives 
7 
3.3 
Exploratory Objectives 
7 
4 
STUDY ENDPOINTS 
7 
4.1 
Primary Endpoint 
7 
4.2 
Secondary Endpoints 
7 
4.3 
Exploratory Endpoints 
8 
5 
SAMPLE SIZE CONSIDERATIONS 
8 
6 
STATISTICAL METHODS 
8 
6.1 
Analysis Sets 
8 
6.2 
Data Analysis General Considerations 
9 
6.2.1 
Definitions and Computations 
9 
6.2.2 
Handling of Missing Data 
9 
6.2.3 
Adjustment for Covariates 
10 
6.2.4 
Multiplicity Adjustment 
10 
6.2.5 
Data Integrity 
10 
6.3 
Patient Characteristics 
10 
6.3.1 
Patient Disposition 
10 
6.3.2 
Protocol Deviations 
10 
6.3.3 
Demographic and Other Baseline Characteristics 
11 
6.3.4 
Disease History 
11 
6.3.5 
Prior Anticancer Drug Therapies 
12 
6.3.6 
Prior and Concomitant Medications 
12 
6.3.7 
Medical History 
12 
6.4 
Efficacy Analysis 
12 
6.4.1 
Primary Efficacy Endpoint 
13 
6.4.2 
Secondary Efficacy Endpoints 
13 
6.4.2.1 
Rate of complete response or complete metabolic 
response by investigator 
13 
6.4.2.2 
Progression Free Survival by investigator 
13 
6.4.2.3 
Duration of response by investigator 
14 
6.4.2.4 
Time to response by investigator 
14 
6.4.2.5 
Overall Survival 
15 
6.4.3 
Subgroup Analyses 
15 
6.5 
Safety Analyses 
15 
6.5.1 
Extent of Exposure 
15 
6.5.2 
Adverse Events 
17 
6.5.3 
Laboratory Values 
20 


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6.5.4 
Vital Signs 
21 
6.5.5 
Physical Examination 
21 
6.5.6 
Electrocardiograms 
21 
6.5.7 
Eastern Cooperative Oncology Group 
21 
6.5.8 
Other Safety Endpoints 
21 
6.6 
Pharmacokinetics analyses 
21 
6.7 
Biomarker/Pharmacodynamic Analyses 
22 
6.8 
Other Analyses 
22 
7 
INTERIM ANALYSIS 
22 
8 
CHANGES IN THE PLANNED ANALYSIS 
22 
9 
REFERENCES 
22 
10 
APPENDIX 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AEs 
adverse events 
AESI 
adverse event of special interest 
BOR 
best overall response 
CMR 
complete metabolic response 
CR 
complete response 
CT 
computed tomography 
DLBCL 
diffuse large B-cell lymphoma 
FL 
follicular lymphoma 
GCB 
germinal center B-cell-like 
MedDRA 
medical dictionary for regulatory activities 
MZL 
marginal zone lymphoma 
NCI CTCAE 
national cancer institute common terminology criteria for adverse 
events 
ORR 
overall response rate 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PT 
preferred term  
R/R 
relapsed/refractory 
SMC 
safety monitoring committee 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
 
 
 


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1 
INTRODUCTION 
The purpose of this statistical analysis plan is to describe the detailed plan for data analysis in 
evaluation of safety and efficacy of zanubrutinib (BGB-3111) in combination with rituximab for 
BGB-3111-213. The focus of this statistical analysis plan is for the planned final analysis specified 
in the study protocol. This document is based on the protocol version 2.0 dated 28-MAR-2019.  
Any changes made to the planned analyses that are in the protocol prior to database lock will be 
identified and documented in statistical analysis plan and clinical study report. The changes made 
to the planned analyses after database lock will be only documented in the clinical study report. 
2 
STUDY OVERVIEW 
This is a multicenter open-label study evaluating the safety and efficacy of zanubrutinib 160 mg 
twice daily in combination with rituximab in the following patients: 
• Cohort 1 (planned: n=20): relapsed/refractory (R/R) non-germinal center B-cell-like (GCB) 
diffuse large B-cell lymphoma (DLBCL) 
• Cohort 2 (planned: n=20): R/R follicular lymphoma (FL) or R/R marginal zone lymphoma 
(MZL) 
Rituximab will be administered at 375 mg/m2 intravenously on Cycle 1 Days 1, 8, 15, 22, and on 
Day 1 of Cycles 4, 6, 8, 10. 
Zanubrutinib will be administered continuously at 160 mg orally twice daily since Day 1 of Cycle 
1. Zanubrutinib will be administered at least 30 minutes prior to the initiation of the rituximab 
infusion. One cycle will be 28 days. 
Treatment with zanubrutinib may be continued for up to 2 years total treatment, until disease 
progression or an unacceptable toxicity occurs. Rituximab is continued for a total of 8 doses or 
until disease progression or an unacceptable toxicity. Patients may withdraw from study treatment 
due to an adverse event, disease progression, or withdrawal of consent. For patients still on study 
drug at the time of study closure and continuing to benefit from study drug, the sponsor will make 
zanubrutinib monotherapy available for continued treatment in a long-term extension study.   
The continuous safety evaluation of this study will be performed by a Safety Monitoring 
Committee (SMC) as outlined in the SMC charter.  
Pharmacokinetics blood sampling for zanubrutinib will be performed at: (1) pre-dose on Cycle 1 
Day 1; (2) 2 hours (± 30 minutes) after zanubrutinib dosing on Cycle 1 Day 1; (3) pre-dose on 
Cycle 4 Day 1; and (4) 2 hours (± 30 minutes) after zanubrutinib dosing on Cycle 4 Day 1. 
Pharmacokinetics blood sampling for rituximab will be performed at (1) pre-dose on Cycle 1 Day 
1; (2) within 30 minutes after end of infusion on Cycle 1 Day 1; (3) pre-dose on Cycle 4 Day 1; 
(4) within 30 minutes after end of infusion on Cycle 4 Day 1.  


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3 
STUDY OBJECTIVES 
All primary and secondary objectives will evaluate zanubrutinib plus rituximab in patients with 
R/R non-GCB DLBCL, R/R FL, and R/R MZL. 
3.1 
Primary Objective  
• To evaluate efficacy, as measured by overall response rate by investigator. 
3.2 
Secondary Objectives  
• To evaluate efficacy, as measured by the following: 
o Duration of response as determined by investigator 
o Progression-free survival as determined by investigator 
o Overall survival 
o Rate of complete response or complete metabolic response as determined by 
investigator 
o Time to response as determined by investigator 
• Safety and tolerability 
3.3 
Exploratory Objectives 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
• Overall response rate (ORR) measured by investigator 
4.2 
Secondary Endpoints 
Efficacy: 
• Duration of response as determined by investigator 
• Progression-free survival (PFS) as determined by investigator 


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• Overall survival 
• Rate of complete response (CR) or complete metabolic response (CMR) as determined by 
investigator 
• Time to response as determined by investigator 
Safety: 
• Safety and tolerability of zanubrutinib in combination with rituximab as evaluated by the 
incidence and severity of adverse events (AEs), clinical laboratory abnormalities, deaths 
and cause of death 
4.3 
Exploratory Endpoints 
5 
SAMPLE SIZE CONSIDERATIONS 
Total sample size for the study will be approximately 40 patients, 20 for each cohort. There is no 
pre-specified hypothesis for the study endpoints, thus the sample size is not based on the statistical 
power calculation. 
6 
STATISTICAL METHODS 
6.1 
Analysis Sets 
The Safety Analysis Set includes all patients who received at least 1 dose of study drug 
(zanubrutinib or rituximab). The Safety Analysis Set will be used for all efficacy and safety 
analyses. 
A summary of analysis sets for all patients will provide the number and percentage of patients in 
each analysis set. 


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6.2 
Data Analysis General Considerations 
6.2.1 
Definitions and Computations 
Study drug: Study drugs for this study are zanubrutinib and rituximab. Study treatment for this 
study is zanubrutinib in combination with rituximab. 
Study day: Study day will be calculated in reference to the date of the first dose of any study 
drug.  For assessments conducted on or after the date of the first dose of study drug, study day 
will be calculated as (assessment date – date of first dose of study drug + 1).  For assessments 
conducted before the date of the first dose of study drug, study day is calculated as (assessment 
date – date of first dose of study drug). There is no study day 0.  
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings. Study day and any corresponding durations will be presented based on the 
imputations specified in Appendix A. 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the first dose of study drug. 
All calculations and analyses will be conducted using SAS version 9.4 or higher. 
6.2.2 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the statistical analysis 
plan. Missing dates or partially missing dates will be imputed conservatively for 
prior/concomitant medications/procedures, diagnosis, prior therapy/response to prior therapy, 
subsequent anti-cancer therapies, adverse events and deaths as provided in Analysis Details 
Specification document for analyses that require the date values. Specific rules for handling of 
missing or partially missing dates for prior/concomitant medications/procedures, diagnosis, prior 
therapy/response to prior therapy, subsequent anti-cancer therapies, adverse events, and deaths 
are provided in Appendix A. 
When summarizing categorical variables, patients with missing data are generally included in the 
denominator to calculate percentages unless otherwise specified. When needed, the category of 
“Missing” is created and the number of patients with missing data is presented.  
When summarizing continuous variables, patients with missing data are not included in 
calculations unless otherwise specified. 
No imputation of AE grades will be performed. Treatment-emergent adverse events (TEAEs) with 
missing Common Terminology Criteria for Adverse Events (CTCAE) grade will only be 
summarized in the all-grades column. 
If the assessment of the relationship of an AE to study treatment is missing, then the AE is assumed 
to be related to the study treatment in the safety analysis summary. No imputation will be done in 
the AE listings. 
By-visit summary of variables with missing data will use only non-missing data, not imputed one, 
unless otherwise specified. Unscheduled visits will not be included in by-visit summaries.    


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6.2.3 
Adjustment for Covariates 
Not applicable. 
6.2.4 
Multiplicity Adjustment 
No formal hypothesis testing is planned for this study. Adjustment for multiplicity is not 
planned. 
6.2.5 
Data Integrity 
Before any pre-specified statistical analysis begins, the integrity of the data should be reviewed 
to assure fit-for-purpose. The data set for analysis should be an accurate and complete 
representation of the patients' relevant outcomes from the clinical database. All essential data 
should be complete and reviewed up to database lock date. Critical consistency checks and 
appropriate source data verification should be complete according to the final data extraction 
plan. 
6.3 
Patient Characteristics 
Patient characteristics will be summarized by disease type and overall based on safety analysis set, 
unless otherwise specified. 
6.3.1 
Patient Disposition 
The following patient disposition information will be summarized for all enrolled patients: 
• Number of patients enrolled  
• Number of treated patients 
• Number (%) of treated patients who discontinued study treatment  
• Reason for study treatment discontinuation  
• Number (%) of treated patients who discontinued study  
• Reason for study discontinuation 
The number (%) of patients still receiving treatment and still in the study at database lock will 
also be summarized. 
Study follow-up time will be defined as the time from first dose date to the death date or end of 
study date (whichever occurs earlier) for patients discontinued from study, or the database cutoff 
date for ongoing patients. Study follow-up time will be estimated by median and range. 
6.3.2 
Protocol Deviations 
Study conduct and protocol deviations will be monitored during this study by the clinical research 
organization (Parexel) and the sponsor (BeiGene). The clinical research organization will assess 
potential protocol deviations as minor or major according to the protocol deviation specification 
in this study and review them with BeiGene study team. The major protocol deviations are defined 
as those that are likely to have a major impact on the patient’s rights, safety, well-being, and/or on 
the validity of data for analysis. The final determination of important protocol deviations (culled 


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from the list of major protocol deviations) will be made by the BeiGene’s medical team, using the 
criteria for important protocol deviation described in the ICH E3 guidelines before the database 
lock. Important protocol deviations will be summarized by deviation category. Listing will also be 
provided. 
6.3.3 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics including the following will be summarized using 
descriptive statistics:  
• Age (years) and age categorized (years) as <65, ≥65  
• Sex 
• Race 
• Eastern cooperative oncology group performance status (categorical) 
• Height (cm) and weight (kg) 
• Body mass index (in kg/m2) 
• Body surface area (in m2) 
• Hepatitis B core antibody status 
A listing of demographic and other baseline characteristics will be provided. 
6.3.4 Disease History  
Disease history and baseline disease characteristics including followings will be summarized by 
descriptive statistics:  
• Time since initial diagnosis to first dose of study drug (months) 
• Disease stage at study entry (I, II, II bulky, III, IV) 
• International prognostic index (low, low intermediate, high intermediate, and high for non-
GCB DLBCL and MZL patients) and FL international prognostic index (low, intermediate, 
and high for FL patients) 
• Time from last disease progression to first dose of study drug (months) 
• Bone Marrow Involvement (yes, no, indeterminate) 
• Epstein–Barr virus-encoded RNA (positive, negative, not available) 
• Hemoglobin 
• Neutrophils 
• Platelets 
• Lactate dehydrogenase 
• Prior transplant  
• Prior radiotherapy  


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A listing of disease history and characteristics will be provided. 
6.3.5 
Prior Anticancer Drug Therapies  
Prior therapy for lymphoma including following information will be summarized and listed:  
• Number of prior lines of therapy 
• Prior anticancer drug therapy and category 
• Duration of last line therapy (months) 
• Best response to last line therapy 
• Time from end of last line therapy to first dose of study drug (months) 
6.3.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes version Sep 2018 B3 or later and will be further classified to the appropriate 
anatomical therapeutic chemical code.  
Prior medications are defined as medications that started before the first dose date. Concomitant 
medications are defined as medications that (1) started before the first dose of study drug and were 
continuing at the time of the first dose of study drug, or (2) started on or after the date of the first 
dose of study drug up to 30 days following last dose of zanubrutinib or 90 days following last dose 
of rituximab, whichever comes later; or initiation of a new anticancer therapy, if it occurs prior to 
the other two dates. For the purpose of determining if a medication should be noted as a 
concomitant medication, the imputation rules stated in Appendix A and Analysis Details 
Specification document will be used.  
The number (%) of patients reporting prior medications and the number (%) of patients reporting 
concomitant medications will be summarized by anatomic therapeutic chemical medication class 
Level 2 and World Health Organization drug dictionary preferred name. A listing of prior and 
concomitant medications will be provided. 
6.3.7 
Medical History 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(version 18.1 or higher). The number (%) of patients reporting a history of any medical condition, 
as recorded on the electronic case report form, will be summarized by MedDRA system organ 
class (SOC) and preferred term (PT). A listing of medical history will be provided. 
6.4 
Efficacy Analysis 
Response assessment for disease status-based efficacy endpoints (ORR, CR, CMR, time to 
response, duration of response and PFS) will be performed per the Lugano Classification (Cheson 
et al 2014).  
The efficacy analysis will be performed by disease type separately. All efficacy analyses will be 
based on the Safety Analysis Set.  


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All efficacy endpoints based on Lugano Classification will be summarized based on the overall 
disease assessment results. Overall disease assessment will be based on positron emission 
tomography (PET) and computed tomography (CT) for Non-GCB DLBCL and FL patients, and 
will be based on CT for MZL patients. Besides, disease response will be summarized per CT-based 
assessment for Non-GCB DLBCL and FL patients. 
6.4.1 
Primary Efficacy Endpoint 
Overall Response Rate by investigator 
The primary endpoint of the study is ORR, defined as proportion of patients who achieved Best 
Overall Response (BOR) of partial response or higher. 
A point estimate and a 2-sided 95% exact binomial confidence interval using Clopper-Pearson 
method will be provided for ORR.  
A patient’s BOR is the best response recorded from Cycle 1 Day 1 until database lock, progressive 
disease, or start of new anticancer treatment, whichever is the earliest. Responses recorded after 
initiation of new anticancer treatment will not be considered for best overall response. Response 
rate is a crude proportion of patients with best overall responses in corresponding response 
categories. 
Patients without postbaseline tumor assessment will be considered as non-responders. The number 
and proportion of patients who achieved each BOR category will be calculated.  
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 Rate of complete response or complete metabolic response by investigator 
Rate of CR or CMR is defined as the proportion of patients whose BOR met CR or CMR criteria 
among all patients in the safety analysis set. 
Rate of CR or CMR will be analyzed using the same methods applied for ORR analysis. A point 
estimate and a 2-sided 95% exact binomial confidence interval using the Clopper-Pearson method 
will be provided for rate of CR or CMR. 
6.4.2.2 Progression Free Survival by investigator 
PFS is defined as the time (in months) from the first dose date of study drug to the date of 
progressive disease (PD) or death (due to any cause), whichever occurs first: 
PFS = (The earlier of disease progression or death date – first dose date of study drug +1) / 30.4375. 
PFS will be right-censored for patients who met one of the following conditions: 1) no baseline 
and/or postbaseline disease assessments; 2) starting a new anticancer therapy before PD or death; 
3) death or PD immediately after more than 6 months since last disease assessment; and 4) alive 
without documentation of disease progression. For such patients, the primary analysis of PFS will 
be right-censored according to the convention described in Table 1 which is based on the Food 
and Drug Administration Guidance for Industry, “Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics” (2018) and references within the guidance document. 




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6.4.2.5 Overall Survival  
Overall survival is defined as the time (in months) from the date of first study dose to the date of 
death due to any cause. Patients who remained alive as of the database lock or discontinuation of 
the study (discontinued study due to reasons other than “Death”) will be censored at the last date 
the patient was known to be alive on or before database lock. The analysis methods for overall 
survival will be the same as those for PFS. 
6.4.3 
Subgroup Analyses 
Primary endpoint will be summarized by disease type in the following subgroups defined by 
baseline demographic and disease characteristics, as appropriate (i.e. when there is sufficient 
number of patients in the subgroup, otherwise relevant subgroups may be combined): sex, age 
group (< 65 vs. ≥ 65), eastern cooperative oncology group performance status (0 vs. ≥ 1), disease 
stage at study entry (I/II/II bulky vs. III/IV), International prognostic index (low vs low 
intermediate/high intermediate/high for non-GCB DLBCL and MZL patients; low vs 
intermediate/high for FL patients), number of prior lines of therapy (1 vs. ≥2).  The aforementioned 
demographic and disease characteristics and their respective categories are subject to change, if 
warranted, to better represent the data. Subgroup analysis of ORR will be presented in forest plots. 
6.5 
Safety Analyses 
All safety analyses will be based on the safety analysis set. Safety analysis will be summarized by 
disease type and overall, unless otherwise specified. 
The study set up a SMC. The SMC monitors safety data according to the SMC charter (Appendix 
C) throughout the study.  
6.5.1 
Extent of Exposure 
Extent of exposure to the zanubrutinib will be summarized descriptively with respect to the 
following: 
• Number of cycles received: defined as duration of exposure (days)/28  
• Duration of exposure (months): defined as the duration from the date of the first dose to 
the end of treatment decision date for patients discontinued zanubrutinib treatment, or the 
data cutoff date for ongoing patients. 
• Number (%) of patients in each category of duration of exposure  
• Cumulative dose administered (g): defined as the cumulative dose of zanubrutinib received 
during the treatment period  
Note: If the actual dose received during a period is unknown (e.g. diary not returned, and 
no other information can be used), it will be considered as the study drug was administered 
as prescribed conservatively. 


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• Actual dose intensity (mg/day): defined as the cumulative dose (in mg) received by a 
patient divided by the duration of treatment (in days), where duration of treatment is 
calculated as latest exposure record ending date - first dose date + 1. 
Note: For patients who are ongoing at the data cutoff, the actual dose intensity is calculated 
based on study drug administration records prior to data cutoff as the cumulative dose (in 
mg) received by a patient prior to the data cutoff divided by the duration from first dose 
date to the end date of the last zanubrutinib administration record. 
• Relative dose intensity: defined as the ratio of the actual dose intensity (mg/day) to the 
planned dose intensity in percentage. Planned dose intensity is 320 mg/day. 
• Number (%) of patients with dose reduction, drug interruption and dose missed/changed  
• Number of dose reduction, drug interruption and dose missed/changed per patient 
• Reasons for dose reduction, drug interruption, dose missed/changed   
• Duration of drug interruption  
• Cycle in which the first dose reduction/drug interruption occurred 
Extent of exposure to the rituximab will be summarized descriptively with respect to the following: 
• Duration of exposure (months): defined as the duration from the date of the first dose to 
the last dose date of rituximab. 
• Number of doses received 
• Number (%) of patients received rituximab treatment by time point 
• Number (%) of patients with drug interruption, drug delay and dose missed 
• Number of drug interruption per patient 
• Reasons for drug interruption, drug delay and dose missed   
• Cycle in which the first drug interruption occurred 
For zanubrutinib, dose reduction is defined as any planned dose reduction from the original 
planned dose (160mg twice a day), regardless of reasons. Drug interruption is defined as any dose 
temporary discontinuation determined by investigator. Dose missed/changed is defined as any 
dose temporary discontinuation/change determined by the patient.  
For rituximab, drug interruption is defined as any dose temporary discontinuation due to AE. Dose 
missed is defined as any dose temporary discontinuation due to reasons other than AE.  


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For patients with drug interruption due to AE but with missing start/end date, the end date will be 
imputed with the corresponding AE stop date, the dose interruption start date will be back 
calculated based on the dosage missing reported. If the dosage is also missing, the start and stop 
date of the drug interruption will be imputed with the AE start/stop date. 
6.5.2 
Adverse Events  
Adverse Event 
AEs will be graded by the investigators using NCI CTCAE v4.03. The AE verbatim descriptions 
(investigator reported terms from the case report form) will be classified into standardized medical 
terminology using the MedDRA. Adverse events will be coded to the MedDRA (Version 18.1 or 
higher) lower level term closest to the verbatim term. The linked MedDRA PT and primary SOC 
are also captured in the database. 
A treatment-emergent adverse event is defined as an adverse event that emerges during 
treatment, having been absent pretreatment, or worsens relative to the pretreatment state, starting 
on or after the first dose of study drug up to 30 days following discontinuation of zanubrutinib or 
90 days following discontinuation of rituximab, whichever comes later; or initiation of new 
anticancer therapy, if it occurs prior to the other two dates. Worsening of an event to Grade 5 
beyond day 30 after last dose of zanubrutinib or day 90 after last dose rituximab of a treatment-
emergent adverse event is also considered a treatment-emergent adverse event. Only those AEs 
that were treatment-emergent will be included in summary tables. All AEs, treatment-emergent 
or otherwise, will be presented in patient data listings. 
Treatment-related AEs include those events considered by the investigator to be related, possibly 
related, probably related, unlikely related to study drug, or with missing assessment of the causal 
relationship.  
TEAE will be summarized based on the number (%) of patients experiencing events by MedDRA 
SOC and PT. A patient reporting the same AE more than once will be counted only once when 
calculating incidence 1) within a given SOC, and 2) within a given SOC and PT combination. For 
such cases, the maximum CTCAE toxicity grade and strongest causal relationship to study drug 
for the event will be used in the incidence calculations. 
An overall summary of TEAEs will include the number (%) of patients: 
• With at least one TEAE 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
• With at least one Grade 3 or higher TEAE 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE of 
Grade 3 or higher  
• With at least one TEAE leading to death 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
leading to death  
• With at least one serious TEAE 


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• With at least one treatment-related (related to zanubrutinib and/or rituximab) serious 
TEAE  
• With at least one TEAE leading to treatment discontinuation 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
leading to treatment discontinuation 
• With at least one TEAE leading to dose modification (dose reduction/drug interruption) of 
zanubrutinib and/or rituximab 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
leading to dose modification (dose reduction/drug interruption) of zanubrutinib and/or 
rituximab  
• With at least one TEAE leading to dose reduction of zanubrutinib (only for overall 
summary table)  
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
leading to dose reduction of zanubrutinib (only for overall summary table)  
• With at least one TEAE leading to drug interruption (only for overall summary table) of 
zanubrutinib and/or rituximab 
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE 
leading to drug interruption (only for overall summary table) of zanubrutinib and/or 
rituximab 
• With at least one TEAE of special interest TEAE  
• With at least one treatment-related (related to zanubrutinib and/or rituximab) TEAE of 
special interest TEAE  
Summaries of all above TEAEs will be provided by SOC and PT, unless otherwise specified.  
Summaries of all TEAEs, serious adverse event, Grade 3 or higher TEAEs and treatment-related 
TEAEs will also be provided by PT only. Summaries of all TEAEs will be provided by SOC, PT, 
and worst grade. 
In addition, summary of below TEAEs will be provided by SOC and PT for zanubrutinib and 
rituximab separately: 
• With at least one treatment-related TEAE (zanubrutinib and rituximab-related separately) 
• With at least one treatment-related Grade 3 or higher TEAE (zanubrutinib and 
rituximab-related respectively) 
• With at least one treatment-related serious TEAE (zanubrutinib and rituximab-related 
separately) 
• With at least one TEAE leading to zanubrutinib dose modification (dose reduction/drug 
interruption)  
• With at least one TEAE leading to rituximab interruption  
Adverse Event of Special Interest 


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AE of special interest (AESI) will be defined and summarized by AESI category name and PT for 
each of following groups: 
• All AESIs  
• Treatment-related AESIs (study treatment, zanubrutinib and rituximab related separately) 
• AESI of Grade 3 or higher 
• Serious AESIs 
• AESIs leading to treatment discontinuation  
• AESIs leading to dose modification (dose reduction/drug interruption) of any study drug 
and zanubrutinib separately, and leading to rituximab interruption  
• AESIs leading to death  
Summary of all AESIs will also be provided by worst grade. The AESI categories and detailed 
search criteria will be provided separately. 
Summary will also be provided for TEAEs related to liver, arrhythmia and diarrhea. 
Exposure-Adjusted Incidence Rates  
Exposure-adjusted incidence rate by category will also be calculated for AESIs. In calculating 
exposure-adjusted incidence rate, the analysis restricts on the occurrence of the first event per 
patient and ignores the existence of later (multiple) events as these cannot be assumed to occur 
independent of previous events. The incidence rate for a patient is derived from the duration of 
treatment exposure of that patient. A patient’s duration of exposure is given either 1) by the time 
when the first event has occurred, or the treatment had ended, whichever is earlier (non-censored 
data), or 2) by the total duration of exposure from first dose date to end of treatment date or the 
data cutoff date (whichever is earlier) in case the patient does not experience the event (censored 
data). Depending on whether a patient has an event or not, the duration of exposure enters the 
denominator in its non-censored or censored form, respectively. The exposure-adjusted incidence 
rate per event considers the first event per patient only, and the corresponding exposure time in 
the denominator: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= ∑
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,𝑖𝑖
𝑛𝑛
𝑖𝑖=1
∑
𝑡𝑡𝑒𝑒𝑒𝑒𝑒𝑒𝑛𝑛𝑛𝑛,𝑖𝑖
𝑛𝑛
𝑖𝑖=1
 
Whereby AESIevent,i represents if patient i experienced the event (1) or not (0), and tevent,i as time 
when the first AESI occurs or the treatment ends, whichever is earlier (non-censored data) or total 
duration of exposure if no event occurs (censored data). 
A summary of the number of deaths and the cause of death, classified by deaths within 30 days of 
last dose of zanubrutinib or 90 days of last dose of rituximab (whichever is later) and deaths more 
than 30 days after last dose of zanubrutinib or 90 days of last dose of rituximab (whichever is 
later), will be provided.   


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Patient data listings of deaths, all AEs, serious adverse events, treatment-related AEs, AEs of 
Grade 3 or higher, AEs that led to death, AEs that led to dose modification (reduction/interruption), 
AEs that led to treatment discontinuation, and AESIs will be provided. 
Other exploratory analysis may be performed if deemed necessary. 
6.5.3 
Laboratory Values 
All hematology, serum chemistry, coagulation, and urinalysis results for each patient will be 
presented in data listings. Actual value and change from baseline for all hematology, serum 
chemistry, and coagulation parameters will be summarized at each scheduled visit. 
Selected laboratory test results will be assigned toxicity grades using NCI CTCAE 4.03 for all 
patients. These laboratory parameters of interest are: 
Hematology 
Serum Chemistry 
Coagulation* 
Hemoglobin 
(decrease) 
Alanine 
transaminase  
(increase) 
Albumin 
(decrease) 
Activated partial 
thromboplastin time 
(increase) 
Platelets (decrease) 
Aspartate 
transaminase  
(increase) 
Sodium (increase, 
decrease) 
International Normalized 
Ratio (increase) 
White blood cell 
(increase, decrease) 
Alkaline 
Phosphatase  
(increase) 
Phosphorus 
(decrease) 
 
Absolute 
Neutrophil Count 
(decrease) 
Total Bilirubin  
(increase) 
 
Potassium 
(increase, 
decrease) 
 
Absolute 
Lymphocyte Count 
(increase, decrease) 
Creatinine 
(increase) 
Magnesium 
(increase, 
decrease) 
 
 
Calcium (increase, 
decrease) 
 
 
 
Glucose (increase, 
decrease) 
 
 
* Coagulation parameters may not be summarized if only few patients have post-baseline assessments. 
For hypocalcemia and hypercalcemia, serum calcium will be corrected using the formula: 
Corrected calcium = Serum calcium + 0.8 * (4 – serum albumin) where serum calcium is 
recorded in mg/dL and serum albumin is recorded in g/dL. 
Shift tables assessing the toxicity grade at baseline versus worst toxicity recorded post-baseline 
will be presented. A summary of the number (%) of patients with Grade 3 or higher toxicity at 
postbaseline and change of more than 2 grades from baseline will be provided separately for 
selected laboratory parameter of interest. In the summary of laboratory parameters by CTCAE 
toxicity grade, parameters with CTCAE toxicity grading in both high and low directions will be 
summarized separately. 


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Summary of urinalysis (dipstick) will be summarized at each scheduled visit. 
Listing of Grade 3 or higher laboratory values will also be provided. Box-whisker plots will be 
generated for parameters of interest.  
Hy’s Law criteria is defined with alanine aminotransferase or aspartate aminotransferase > 
3xULN and total bilirubin > 2xULN and alkaline phosphatase < 2xULN; total bilirubin and 
alkaline phosphatase were both within 28 days after alanine aminotransferase or aspartate 
aminotransferase elevation. Incidence of patients who met one or more of the Hy’s law criteria 
will be summarized. A listing of patients with alanine aminotransferase / aspartate 
aminotransferase > 3x ULN and total bilirubin > 2x ULN will be generated. 
6.5.4 
Vital Signs 
Actual value and change from baseline for all vital signs and weight will be summarized at each 
scheduled visit.  
Shift tables assessing the toxicity grade at baseline versus worst toxicity recorded post-baseline 
for systolic and diastolic blood pressure will be presented. Box-whisker plots will be generated 
for actual value and change from baseline for systolic and diastolic blood pressure. 
Vital signs will be listed by patients and visits. 
6.5.5 
Physical Examination 
Physical examination results will be listed without summary. 
6.5.6 
Electrocardiograms 
Electrocardiogram assessments will be performed at the screening, cycle 1 and safety follow-up 
visits. Patient listing for electrocardiogram data will be provided. 
6.5.7 
Eastern Cooperative Oncology Group 
Eastern cooperative oncology group performance status will be summarized and listed at each 
visit. Shift table assessing the eastern cooperative oncology group performance status at baseline 
versus worst performance status post-baseline will be presented. 
6.5.8 
Other Safety Endpoints 
Pregnancy test and viral serology will be listed. 
6.6 
Pharmacokinetics analyses 


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6.7 
Biomarker/Pharmacodynamic Analyses 
6.8 
Other Analyses 
Additional exploratory analyses may be conducted as appropriate. Any exploratory analyses that 
are performed will be appropriately titled/labeled as exploratory and will be clearly distinguished 
from planned analyses when results are reported in the Clinical Study Report. 
7 
INTERIM ANALYSIS 
No interim analysis is planned for this study.  
8 
CHANGES IN THE PLANNED ANALYSIS 
Changes made to the planned analysis are as follows: 
• The PK Analysis Set definition was updated to provide more clarity. 
9 
REFERENCES 
1. Brookmeyer, R. and Crowley, J. (1982) A confidence interval for the median survival 
time. Biometrics, 38, 29-41. 
2. Cheson, BD et al. (2014) Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin 
Oncol, 32(27):3059–3068. 
3. Food and Drug Administration Center for Drug Evaluation Research (CDER) and Center 
for Biologics Evaluation and Research (CBER) (2018). FDA Guidance for Industry: 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
https://www.fda.gov/media/71195/download 
4. Greenwood, M. (1926) The natural duration of cancer. Public health and medical 
patients, 33: 126. 


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5. Schemper, M, and Smith, T.L. (1996) A note on quantifying follow-up in studies of 
failure time. Controlled Clinical Trials, 17:343-346 
 
 
 


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10 
APPENDIX 
Appendix A: Missing Data Imputation Rule  
In general, missing or partial dates will not be imputed at data level. The following rules will apply 
for the specific analysis and summary purposes mentioned below only.   
A.1 Prior/Concomitant Medications/Procedures 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rules will be applied to 
impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to January 01 
• If only day is missing, then set to the first day of the month 
If end date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31 
• If only day is missing, then set to last day of the month 
If start date or end date of a medication is completely missing, do not impute. 
If the imputed end date > death date/last known alive date or end of study date, then set to the 
death date/last known alive date or end of study date, whichever occurs first. 
A.2 Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment emergent by default. The following rules will be applied to impute 
partial dates for adverse events: 
If start date of an adverse event is partially missing, impute as follows: 
• If both month and day are missing, then the imputed day and month will be January 01 or 
the first dosing date if they have the same year, whichever is later.  
• If only day is missing, then the imputed day will be the first day of the month or the first 
dosing date if they have the same month and year, whichever is later  
• If start date is completely missing, the imputed day will be the first dosing date as long as 
AE end date is not before the first dosing date.  
If end date of an AE is partially missing, impute as follows: 


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• If both month and day are missing, then set to December 31 
• If only day is missing, then set to last day of the month 
• If end date is completely missing, do not impute. 
If the imputed AE end date > death date/last known alive date or end of study date, then set to the 
death date/last known alive date or end of study date, whichever occurs first. 
A.3 Deaths 
In case complete death dates are not recorded, impute as follows: 
• If both month and day are missing, then the imputed month and day will be January 01 or 
the last date of patient known to be alive + 1, whichever is later. 
• If only day is missing, the death will be assumed to be on the first day of the month or the 
last date of patient known to be alive +1, whichever is later.  
A.4 Subsequent Anti-cancer Therapies 
If the start date of a subsequent anti-cancer therapy is incomplete or missing, impute as follows:  
• If both month and day are missing, then the imputed month and day will be January 01 or 
the last day of the month for the last adequate disease assessment if they have the same 
year. 
• If only day is missing, then the imputed day will be the first day of the month. 
A.5 Diagnosis 
If a diagnosis date is partially missing, impute as follows: 
• If both month and day are missing, then set to January 01 
• If only day is missing, then set to the first day of the month 
If a diagnosis date is completely missing, do not impute. 
 
A.6 Prior Therapy/Response to Prior Therapy 
If a prior therapy or response to prior therapy date is partially missing, impute as follows: 
• If only day is missing, then set to the 15th of the month or the first study drug dose date-1, 
whichever is earlier. An imputed start date can be no later than the end date and vice 
versa. 
No imputation will be performed for all other types of missing dates 
 


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Appendix B: The International Prognostic Index 
B1.  Follicular Lymphoma International Prognostic Index  
The FL international prognostic index uses five independent predictors of inferior survival:  
• age >60 years 
• hemoglobin <12 g/dL 
• serum lactate dehydrogenase >normal 
• Ann Arbor stage III/IV 
• number of involved nodal areas > 4 
The presence of 0-1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease, 
respectively. 
 
B.2 International Prognostic Index for DLBCL and MZL 
• age >60 years 
• serum lactate dehydrogenase >normal 
• Performance status 2-4 
• Stage III or IV 
• Extranodal involvement >1 site 
The presence of 0-1, 2, 3, and 4-5 adverse factors defines low, low intermediate, high intermediate 
and high-risk disease, respectively. 
 


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Appendix C: Safety Monitoring Committee Charter 
The safety monitoring committee charter is provided in a separate document.