Clinical trial NCT03145064
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Relapsed/refractory non-GCB type
Sponsor: BeiGene
Start date: 2017-06-30; Completion date: 2020-09-03
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Screening (up to 28 days); daily treatment until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow-up, or study termination from sponsor; treatment (up to 2 years), safety follow-up (30 days); survival follow-up until data cutoff for final analysis.

Detailed description:
This is a single-arm, multicenter, open-label Phase 2 study to evaluate efficacy, safety, tolerability of BGB-3111 (zanubrutinib) in participants with relapsed/refractory non-germinal center B-cell (GCB) type diffuse large B-cell lymphoma (DLBCL).

The study will enroll approximately 40 participants treated with zanubrutinib (160 milligrams \[mg\]) twice daily (BID). All participants in the study were treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the study was terminated by the sponsor for final analysis. At the time of final analysis, participants who remained on treatment were considered for participation in the extension study when eligible. A treatment cycle consisted of 28 days.

Arms: arm 1: Participants received zanubrutinib BID.
Interventions: intervention 1: Zanubrutinib
Intervention descriptions: intervention 1: Administered at a dose of 160 mg BID orally.

Protocol documents:
Prot_000.pdf: 
BeiGene (Beijing) Co., Ltd 
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Version 2.0, 16 April 2018 
 
Clinical Study Protocol 
Protocol Title:  
A Phase 2, Single arm, Multicenter, Open-label Study of 
Bruton’s Tyrosine Kinase (BTK) inhibitor BGB-3111 in subjects 
with relapsed/refractory non-GCB type Diffuse Large B cell 
lymphoma 
Protocol Number: 
BGB-3111-207   
Date of Protocol: 
 
 
16 April 2018, Version 2.0 
Study Phase: 
2 
Sponsor: 
BeiGene (Beijing) Co., Ltd  
No. 30 Science Park Road,  
                                                                 Zhong-Guan-Cun Life Science Park 
 
Changping district, Beijing 102206  
China 
 
Coordinating Investigator: 
 
 
Sponsor Medical Monitor: 
 
 
 
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. 


BeiGene (Beijing) Co., Ltd 
BGB-3111-207                                                     CONFIDENTIAL 
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Version 2.0, 16 April 2018 
SIGNATURES 
PROTOCOL TITLE: 
A Phase 2, Single arm, Multicenter, Open-label Study of Bruton’s 
Tyrosine Kinase (BTK) inhibitor BGB-3111 in subjects with relapsed/ 
refractory non-GCB type Diffuse Large B cell lymphoma 
PROTOCOL NO: 
 
BGB-3111-207 
 
____________________________________ 
 
 
___________________ 
 
 
 
 
 
Date 
Coordinating Investigator 
 
____________________________________ 
 
 
___________________ 
 
 
 
 
Date 
Sponsor Medical Monitor 
 
 


BeiGene (Beijing) Co., Ltd 
BGB-3111-207                                                     CONFIDENTIAL 
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Version 2.0, 16 April 2018 
PROTOCOL AMENDMENT RATIONALE, VERSION 2.0  
Protocol BGB-3111-207 (Version 2.0) is amended for the following reasons:  
1. To remove Cohort 2, because adequate pharmacokinetics (PK)/pharmacodynamic (PD) data 
have been obtained from other BTK studies. 
2. Sample size of Cohort 1 is reduced from 70 to 40 due to relevant adjustment in Beigene 
strategy. 
3. Remove adverse events of special interest (AESI) to align with other protocols. 
4. To clarify zanubrutinib dose reduction for non-hematologic toxicity 
5. To replace independent Data Monitoring Committee (DMC) with Safety Monitoring Committee 
(SMC). It is because that at the early stage of clinical study, we focus more on safety than on 
efficacy, so the efficacy data will not be evaluated by committee in this Phase 2 study. 
6. To revise and clarify some eligible criteria. 
In addition, some contents (including administrative information, language, and format) are 
modified to improve the clarity and consistency throughout the document. Changes were made to 
the synopsis to match changes made in the protocol body. 
Substantial Changes: 
• Replaced the compound name of BGB-3111 with its international non-proprietary name, 
zanubrutinib, throughout this document (except for reference). 
• Original Section 6.1.1 was moved in Section 1.7 (Zanubrutinib Pharmacokinetics and 
Pharmacodynamics), the wording was updated for clarification. 
• Section 2.3 (Exploratory Objective): 
• Section 3.2 (Secondary Endpoints): removed the safety endpoints related to AESI. 
• Section 3.3 and 10.1.3 (Exploratory Endpoints): 
 
  
• Section 4.1: revised the sample size as 40 subjects, clarify the treatment phase and the duration 
of the follow-up phase, and revised wording for clarification. 
• Figure 1: revised as “Safety Follow-up visit (30 ± 7 days after last dose)”. 
• Removed Cohort 2 in Figure 1 and remove the original Figure 2. 


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Version 2.0, 16 April 2018 
• Section 5.1 (Inclusion Criteria) 
o #5: updated the period of tumor tissue sample collection to within 2 years of study 
entry and removed the wording related to Cohort 2. 
o #9: revised neutrophils assessment as within 7 days of first dose of study drug 
o #10: revised platelets assessment as within 7 days of first dose of study drug 
o #14: replaced “Hemoglobin ≥ 8g/dL” with “Independent of erythropoietin (EPO) 
support or transfusion within 7 days of first dose of study drug” 
• Section 5.2 (Exclusion Criteria): in #11, replaced prophylactic entacavir with anti-HBV 
medication and clarified that patients who receive anti-HBV medication will have HBV DNA 
test every 3 cycles; in #14, removed Chinese herbal medications. 
• Section 6.1 (Study Treatment): removed wording related to Cohort 2 and revised the wording 
for clarification. 
• Section 6.2.1 (Packaging and Labeling): removed bottle number. 
• Section 6.4 (Dosage and Administration): revised to clarify that patients will take zanubrutinib 
with water at approximately the same time every day, with a minimum of 8 hours between 
consecutive doses; and removed wording related to Cohort 2. 
• Section 6.5.2 (Dose Reductions for Non-Hematologic Toxicity): updated wording for 
clarification. 
• Section 7.1 (Study Flow and Visit Schedule, Table 2), added time windows for Safety 
Follow-up Visit (30 ± 7 days) and Survival Follow-up (every 3 months ± 7 days); in #10 e, 
clarified that patients who receive anti-HBV medication will have HBV DNA test every 3 
cycles, removed the wording related to Cohort 2 and PK/PD, added a line for urine or serum 
pregnancy test, and revised the footnotes to be consistent with other sections. 
• Section 7.1, removed the original Table 3 and Table 4 because they are PK/PD related. 
• Section 7.4.5.4 (Coagulation), add activated partial thromboplastin time (screening only) for 
consistency. 
• Section 7.4.6 (Electrocardiogram), removed the wording related to PK/PD. 
• Removed the original sections of Pharmacokinetics (original in Section 7.5), Pharmacodynamic 
Biomarkers (original in Section 7.6.2), and Pharmacogenetics (original in Section 7.6.3). 


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Version 2.0, 16 April 2018 
• Section 9.1.1.1 (Period and Method of Detecting AEs and SAEs), revised wording for 
clarification. 
• Remove original Section 9.5 (Adverse Events of Special Interest) 
• Section 9.5 (Safety Monitoring Committee): replaced independent DMC with SMC, clarified 
that efficacy data will not be evaluated, and updated that early safety review will occur about 
3 months after enrollment of the 25th subject. 
• Section 10.1.2 (Secondary Endpoints): removed the safety endpoints related to AESI and PK. 
• Section 10.2.1 (Analysis Populations): removed the wording related to PK analysis. 
• Section 10.2.3 (Demographics and Other Baseline Characteristics): remove race, geographic 
region, and blastoid histology from this section. 
• Section 10.2.5.1 (Primary Efficacy Analysis); removed the hypothesis testing from this study. 
• Section 10.2.5.3 (Exploratory Efficacy Analysis): 
. 
• Removed original Section 10.2.6 (Pharmacokinetic Analysis) and original Section 10.2.7 
(Biomarker/Pharmacodynamic Data, If Applicable) 
• Section 10.3.1 (Extent of Exposure): removed “dose delay” and clarified the wording. 
• Section 10.3.2 (Adverse Events): removed the wording related to AESI. 
• Section 10.4 (Sample Size Consideration): updated the sample size as 40. 
• Section 10.6 (Other Statistical Issues): revised as “Not applicable”. 
• Section 11.4 (Study and Study Center Closure): removed the wording related to PK samples. 
 
 
 


BeiGene (Beijing) Co., Ltd 
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Version 2.0, 16 April 2018 
SYNOPSIS 
Name of Sponsor/Company: 
BeiGene (Beijing) Co., Ltd 
Name of Finished Product: 
Zanubrutinib (BGB-3111) 
Name of Active Ingredient: 
Zanubrutinib 
Title of Study:  
A Phase 2, Single arm, Multicenter, Open-label Study of Bruton’s Tyrosine Kinase 
(BTK) inhibitor BGB-3111 in subjects with relapsed/refractory non-GCB type Diffuse 
Large B cell lymphoma  
Protocol No: 
 
BGB-3111-207 
Study duration:  Screening (up to 28 days); daily treatment until 
disease progression, unacceptable toxicity or death, withdrawal of 
consent, lost to follow-up, or study termination from sponsor; 
treatment (up to 2 years), safety follow-up (30 days); survival follow-
up until data cutoff for final analysis.  
Phase:  2 
Objectives: 
Primary: 
To evaluate the efficacy of zanubrutinib at a dose of 160 mg orally (PO) twice daily (BID), in subjects with 
relapsed or refractory non-Germinal Center B cell type Diffuse Large B cell Lymphoma (non-GCB 
DLBCL) as assessed by the objective response rate according to the 2014 International Working Group in 
Non-Hodgkin’s Lymphoma (NHL) criteria (Cheson et al 2014). 
Secondary: 
To evaluate the efficacy of zanubrutinib as measured by progression free survival (PFS). 
To evaluate the efficacy of zanubrutinib as measured by duration of response (DOR). 
To evaluate the efficacy of zanubrutinib as measured by time to response (TTR). 
To evaluate the safety and tolerability of zanubrutinib at a dose of 160 mg PO BID in subjects with relapsed 
or refractory non-GCB type DLBCL. 
Exploratory: 
 
 
  
Methodology: 
This is a single-arm, multicenter, open-label Phase 2 study to evaluate efficacy, safety, tolerability of 
zanubrutinib in subjects with relapsed/refractory non-GCB type Diffuse Large B Cell Lymphoma. 
The study will enroll approximately 40 subjects treated with zanubrutinib 160mg BID.  All subjects in the 
study will be treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the 
study is terminated by the sponsor for final analysis.  At the time of final analysis, subjects who remain on 
treatment will be considered for participation in the extension study when eligible.  A treatment cycle 
consists of 28 days. 
Planned number 
of subjects: 
Approximately 40 subjects will be enrolled. 


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Study Population 
Inclusion criteria:  
1. Histologically confirmed non-germinal center diffuse large B cell lymphoma 
(DLBCL), by immunohistochemistry using the Hans algorithm,  
a. CD10- and BCL6-,  
b. CD10-, BCL6+, but MUM1+  
2. Men and women ≥ 18 years of age.  
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  
4. Measurable disease is defined as at least 1 lymph node >1.5 cm in longest diameter 
and measurable in 2 perpendicular dimensions.  
5. All subjects must provide fresh tumor biopsy or recent tumor tissue samples (within 
2 years of study entry [informed consent form signed]).  
6. Received at least one prior therapy for DLBCL that includes anthracycline based 
chemotherapy. 
7. Patient not eligible for or refuses intensive chemotherapy and hematopoietic stem 
cell transplant. 
8. Documented failure to achieve at least partial response (PR) with, or documented 
disease progression after response to, the most recent treatment regimen. 
9. Neutrophils ≥ 1 x 109/L independent of growth factor support within 7 days of first 
dose of study drug. 
10. Platelets ≥ 75 x 109/L, independent of growth factor support or transfusion within 
7 days of first dose of study drug. 
11. Creatinine clearance of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation 
or estimated glomerular filtration rate [eGFR] from the modification of diet in renal 
disease [MDRD]). 
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
upper limit of normal (ULN). 
13. Bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome, then up to 5xULN 
allowed). 
14. Independent of erythropoietin (EPO) support or transfusion within 7 days of first 
dose of study drug. 
15. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial 
thromboplastin time (APTT) ≤ 1.5 x ULN. 
16. Subjects may be enrolled who relapse after autologous stem cell transplant, at least 
6 months after transplant, subjects should have no active infections (ie, fungal or 
viral). 
17. Females of childbearing potential must agree to use highly effective forms of birth 
control throughout the course of the study and at least up to 90 days after last dose 
of study drug.  Highly effective forms of birth control can be defined as abstinence, 
hysterectomy, bilateral oophorectomy with no menstrual bleeding for up to 6 
months, intrauterine contraception, hormonal methods such as contraceptive 
injection, oral contraceptive, etc.  Males must have undergone sterilization–
vasectomy, or utilize a barrier method where the female partner utilizes the effective 
forms of birth control noted above.  
18. Life expectancy of > 3 months. 
19. Able to provide written informed consent and can understand and comply with the 
requirements of the study. 


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Exclusion criteria:  
1. Current or history of central nervous system (CNS) lymphoma. 
2. Prior exposure to a BTK inhibitor. 
3. Prior corticosteroids (at dosages equivalent to prednisone > 20 mg/day) given with 
anti-neoplastic intent within 7 days, prior chemotherapy, targeted therapy, or 
radiation therapy within 3 weeks, or antibody based therapies or Chinese anti-
cancer herbal therapies within 4 weeks of the start of study drug. 
4. Major surgery within 4 weeks of screening. 
5. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, absolute 
neutrophil count (ANC) and platelets. For ANC and platelets, please follow 
inclusion criteria #9 [neutrophils] and #10 [platelets]). 
6. History of other active malignancies within 2 years of study entry, with exception of 
(1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or 
squamous cell carcinoma of skin; (3) previous malignancy confined and treated 
locally (surgery or other modality) with curative intent. 
7. Currently active clinically significant cardiovascular disease such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by 
the New York Heart Association (NYHA) Functional Classification, or history of 
myocardial infarction within 6 months of screening. Left Ventricular Ejection 
Fraction (LVEF) is lower than 50% measured by echocardiography (ECHO) 
(AHA,2016). 
8. QTcF (Fredericia’s correction) > 450 msecs or other significant electrocardiogram 
(ECG) abnormalities including second degree atrioventricular (AV) block Type II, 
or third degree AV block.  
9. Unable to swallow capsules or having a disease significantly affecting 
gastrointestinal function such as malabsorption syndrome, resection of the stomach 
or small bowel, symptomatic inflammatory bowel disease, or partial or complete 
bowel obstruction. 
10. Uncontrolled systemic infection or infection requiring parenteral anti-microbial 
therapy. 
11. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C 
infection (detected positive by polymerase chain reaction [PCR]). 
Inclusion 
Exclusion 
HIV 
Antibody (-) 
Antibody (+) 
HBV 
HBsAg (-) 
HBsAg (+) 
HBsAg (-) 
HBcAb (+) 
HBV DNA<1000 IU/mL, 
After enrollment, check HBV DNA 
monthly or every 3 cycles for patients 
receiving anti-HBV medication to prevent 
HBV reactivation 
HBsAg(-) 
HBcAb(+)  
HBV DNA ≥1000 
IU/mL 
HCV 
Antibody (-) 
 
 
Antibody (+)  
HCV RNA<1(log10IU/mL) 
and monthly monitoring, or treatment with 
anti-HCV medication. 
Antibody(+) 
HCV RNA 
≥1(log10IU/mL) 
HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, 
hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus. 
HBV evaluation includes HBsAg, HBcAb, HBsAb. If subject is HBsAg- but 
HBcAb+ (without considering HBsAb status), will evaluate HBV DNA using PCR, 
the acceptable upper limit is 1000IU/ml, however, because different assays are used 
in different hospitals, the acceptable upper limit will be that of the upper limit at the 
hospital where the test is conducted. HCV evaluation involves the HCV Ab, if 
positive, to evaluate HCV RNA as above. 


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12. Pregnant or lactating women. 
13. Any life-threatening illness, medical condition or organ system dysfunction which, 
in the investigator’s opinion, could compromise the subject’s safety, or put the 
study at risk. 
14. On medications which are strong cytochrome P450, family 3, subfamily A 
(CYP3A) inhibitors or CYP3A inducers (Appendix 4).  
Test product, dose and mode of 
administration: 
Zanubrutinib 160 mg (two - 80 mg white opaque capsules) PO BID 
Reference therapy, dose, and 
mode of administration: 
Not applicable 
Study Treatment: 
Zanubrutinib 160 mg will be administered as two 80-mg capsules by mouth twice a day with or without 
food.  Patients will take zanubrutinib with water at approximately the same time every day, with a minimum 
of 8 hours between consecutive doses.  Treatment with zanubrutinib may be continued until disease 
progression, unacceptable toxicity, or withdrawal of consent.  At the time of final analysis, subjects who 
remain on treatment will be considered for participation in the extension study.  A treatment cycle consists 
of 28 days. 
The guidelines set forth in Table 1 should be followed for dose interruption or modification of zanubrutinib 
for hematologic, non-hematologic toxicities. 
Table 1: Zanubrutinib Dose Reduction Steps 
Dose Level 
Zanubrutinib Dose  
Starting Dose 
160 mg BID 
Dose Level -1 
80 mg BID 
Dose Level -2 
80 mg QD 
BID=twice daily; QD=once a daily 
Study drug (zanubrutinib) may be held for a maximum of 28 consecutive days. If, in the Investigator’s 
opinion, it is in the subject’s best interest to restart study drug after more than 28 days, then written approval 
to be issued by the sponsor medical monitor after request by investigator. 
Dose Modifications for Hematologic Toxicity 
Dosing will be held for individual subjects under any of the following conditions:  
• 
Grade 4 neutropenia (lasting >7days, however, earlier interruption acceptable if medically 
indicated) 
• 
Grade 4 thrombocytopenia (lasting >7days, however, earlier interruption acceptable if medically 
indicated) 
• 
≥Grade 3 febrile neutropenia 
• 
≥Grade 3 thrombocytopenia associated with bleeding 
For the first occurrence of hematologic toxicity, treatment may restart at full dose upon recovery of the 
platelet count to ≥ 75109/L, neutrophil recovery to ≥ 1109/L.  If the same event reoccurs, subjects will 
restart at one dose level lower upon recovery. A maximum of 2 dose reductions will be allowed. Subjects 


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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 (Cheson et al 2012). 
Subjects with treatment-related lymphocytosis should remain on study treatment and continue with all 
study-related procedures. 
Dose Reductions for Non-Hematologic Toxicity  
For non-hematological toxicities ≥ Grade 3, other than hypertension that is 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 the original dose level. If the 
event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1 or baseline and restarted at Dose 
Level -1.  If the event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1or baseline and 
restarted at Dose Level -2.  If the event recurs at ≥ Grade 3 at Dose Level -2, the subject will be 
discontinued from study treatment. For subjects experiencing atrial fibrillation that is symptomatic and/or 
incompletely controlled: after 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. 
Concomitant Therapy and Clinical Practice: 
Prohibited Concomitant Therapy 
During study treatment, subjects are prohibited from receiving any anticancer therapy, including but not 
restricted to chemotherapy, immunotherapy, corticosteroids (at dosages equivalent to >20mg/day of 
prednisone), experimental therapy, radiotherapy, and Chinese herbal medications are prohibited.  
Corticosteroid courses (at dosages equivalent to prednisone >20mg/day) of limited duration (2 weeks or 
less) are permitted, if used to treat a concomitant (non-cancer) medical condition. Bisphosphonates that have 
been in steady use for over 3 months are permitted.  
Drugs known to prolong the QT/QTc interval are prohibited  
In accordance with the Food and Drug Administration (FDA) Guidance for Industry:  E14 Clinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 
Drugs known to prolong QT interval should be avoided, it they have to be prescribed, it has to be agreed to 
by the sponsor’s medical monitor. A link to a list of drugs with QTc prolongation potential is provided 
through the https://crediblemeds.org/, and is also provided in Appendix 2. 
Concomitant Use of CYP3A Inhibiting Drugs  
The primary metabolic pathway for zanubrutinib involves the cytochrome P450, family 3, subfamily A 
(CYP3A) isoform.  Strong CYP3A4 inhibitors or strong inducers must be avoided.  If no alternative 
treatment is available, zanubrutinib should be stopped for the duration of CYP3A4 inhibitor or inducer 
usage; subjects should be closely monitored for potential toxicities with temporary interruption of 
zanubrutinib.If the subject requires treatment with moderate CYP3A4 inhibitors or inducers, the medical 
monitor should be consulted for potential toxicity (see Appendix 4). 


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Criteria for Evaluation: 
Response will be evaluated based on investigator review using the 2014 International Working Group in 
Non-Hodgkin’s Lymphoma (NHL) criteria (Appendix 3).  Patient will receive a positron emission 
tomography (PET) and contrast computed tomography (CT) at screening, after 12 and 24 weeks of therapy, 
and at suspected complete remission. Contrast CT alone will be performed at weeks 36, 48, and thereafter, 
once every 16 weeks. Response will be assessed on the basis of radiological evaluations.  Bone marrow 
biopsy will be required for confirmation of complete response ([CR] at first occurrence of radiological and 
clinical evidence of CR) in subjects with bone marrow tumor involvement prior to study drug. 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 radiological assessment. 
The safety of this study will be monitored by a Safety Monitoring Committee (SMC), its organization and 
detailed execution will be written in the SMC charter.  The SMC will evaluate safety data, and advise 
accordingly. Subjects will be evaluated for AEs (all grades, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03 [NCI CTCAE v. 4.03]) and serious AEs (SAEs).  
Subjects who, at time of progression, have an ongoing AE that leads to treatment discontinuation will be 
followed until the event resolves, the investigator assesses the event as stable, the subject is lost to follow-
up, or the subject starts a different anti-tumor therapy. 
A significant safety event (SSE) is defined as any of the following: 
• 
General toxicity (NCI CTCAE V.4.03):  Grade 3 and Grade 4 AEs, SAEs. 
• 
Any adverse event that requires dose interruption, reduction or discontinuation of the study drug. 
• 
A subject’s death. 
In the case of major toxicity concerns, the SMC can recommend to modify the trial conduct. 
Endpoints: 
Primary Endpoint: 
The primary endpoint of the study is the rate of objective response, defined as the achievement of either a 
partial response (PR) or complete response (CR) by the 2014 modification of the International Working 
Group on Non-Hodgkin’s lymphoma (NHL) Criteria (Cheson et al 2014) (Appendix 3) at any time on study 
drug. 
Secondary Endpoints 
Efficacy: 
• 
Progression free survival (PFS): defined as time from first dose of zanubrutinib until first 
documentation of progression (by IWG on NHL criteria) or death, whichever comes first 
• 
Duration of response (DOR) is defined as the time from the date that the response criteria are first met 
to the date that progressive disease (PD) is objectively documented or death, whichever occurs first. 
• 
Time to response (TTR) is defined as the time from first dose of zanubrutinib to documentation of a 
response. 
Safety: 
• 
To evaluate the safety and tolerability of zanubrutinib, as defined by: 
o The incidence and severity of treatment-emergent adverse events (TEAEs), SAEs and treatment-
related AEs according to NCI CTCAE v4.03 
o The incidence, severity, timing, and causation of adverse events leading to study drug 
discontinuation. 


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Exploratory Endpoints: 
•
Statistical Methods: 
Populations: 
The Safety Population includes all subjects who received any dose of zanubrutinib.  This will be the 
population for the efficacy and safety analyses.   
The Per-Protocol Population (PP) includes subjects who received any dose zanubrutinib and had no major 
protocol deviations.  Criteria for exclusion from the PP will be determined and documented before the 
database lock for the primary analysis.  This will be the secondary analysis population for efficacy analysis 
Primary Efficacy Analysis: 
The ORR in this study is estimated as 35%, which is deemed a clinical meaningful improvement.   
Two-sided Clopper-Pearson 95% confidence interval (CI) of ORR will be constructed to assess the 
precision of the rate estimate. No hypothesis testing will be done. 
Best overall response (BOR) is defined as the best response recorded from the start of zanubrutinib until 
data cut or start of new anti-neoplastic treatment.  Subjects with no post-baseline response assessment (due 
to any reason) will be considered non-responders for BOR.  The proportion and its corresponding Clopper-
Pearson 95% CI for each of the response categories (CR, PR, stable disease [SD], and PD) will be 
presented. 
The primary efficacy analysis will be conducted no later than 12 months after the first dose of the last 
subject, and will be based on the safety population. 
Secondary Efficacy Analysis:  
Kaplan-Meier (KM) method will be used to estimate progression event-free curves and corresponding 
quartiles (including the median).  A two-sided 95% CIs of median, if estimable, will be constructed with a 
generalized Brookmeyer and Crowley method.  The PFS at 6 and 12 months, defined as the percentages of 
subjects in the analysis population who remain alive and progression-free at the specified time points, will 
be estimated using the KM method along with the corresponding 95% CI constructed using Greenwood’s 
formula.   
The PFS censoring rule will follow FDA Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007). 
Time to event variables (DOR and TTR) will be similarly analyzed using the KM method as described 
above.  The KM estimates of DOR and TTR will be plotted over time. 
Sensitivity analysis will be performed for primary and secondary endpoints in the PP population. 
Exploratory Efficacy Analysis: 
Safety Analysis: 
Drug exposure will be summarized, including duration, dosage, and dose intensity.   
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA) terms and graded according to the NCI CTCAE v.4.03.  All treatment emergent AEs (TEAEs) 
will be summarized.  A TEAE is defined as an AE that had an onset date on or after the first dose of study 
drug up to 30 days following study drug discontinuation or was worsening in severity from baseline 


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(pretreatment).  Serious adverse events, deaths, TEAEs with Grade 3 or above, and TEAEs that led to 
treatment discontinuation, dose reduction or dose interruption will be summarized. 
Multiple occurrences of the same event will be counted once at the maximum severity within a system organ 
class (SOC) and preferred term (PT). 
Clinical laboratory data with values outside of the normal ranges will be identified.  Select laboratory data 
will be summarized by grade.  Vital signs will also be summarized by visit.  
Sample Size: 
Approximately 40 subjects will be enrolled. The precision of the estimated ORR is used in the sample size 
calculation. Assuming an ORR of 35%, the 95% exact confidence interval will be 20.6% to 51.7%. 
 
 


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TABLE OF CONTENTS 
SIGNATURES ...........................................................................................................................2 
PROTOCOL AMENDMENT RATIONALE, VERSION 2.0 ..................................................3 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................14 
LIST OF TABLES ...................................................................................................................17 
LIST OF APPENDICES ..........................................................................................................17 
LIST OF FIGURES .................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
1 
INTRODUCTION .......................................................................................................22 
1.1 
Current Status of Diffuse Large B cell Lymphoma Care ................................22 
1.2 
Zanubrutinib .....................................................................................................24 
1.3 
Non-Clinical Data ............................................................................................24 
1.4 
Zanubrutinib global Phase 1 Clinical Experience ............................................25 
1.5 
Zanubrutinib in Relapsed or Refractory DLBCL global clinical trial .............25 
1.6 
Zanubrutinib Phase I clinical trial in China .....................................................25 
1.7 
Zanubrutinib Pharmacokinetics and Pharmacodynamics ................................26 
1.8 
Zanubrutinib in non-GCB Diffuse Large B Cell Lymphoma ..........................27 
2 
OBJECTIVES ..............................................................................................................28 
2.1 
Primary Objective ............................................................................................28 
2.2 
Secondary Objective ........................................................................................28 
2.3 
Exploratory Objective ......................................................................................28 
3 
STUDY ENDPOINTS .................................................................................................28 
3.1 
Primary Endpoint .............................................................................................28 
3.2 
Secondary Endpoints .......................................................................................29 
3.3 
Exploratory Endpoints .....................................................................................29 
4 
STUDY DESIGN.........................................................................................................29 
4.1 
Summary of Study Design ...............................................................................29 
5 
STUDY POPULATION ..............................................................................................32 
5.1 
Inclusion Criteria .............................................................................................32 
5.2 
Exclusion Criteria ............................................................................................33 
6 
STUDY TREATMENTS .............................................................................................35 
6.1 
Study Treatment ...............................................................................................35 
6.2 
Study Treatment Preparation and Dispensation ...............................................35 
6.2.1 
Packaging and Labeling ....................................................................35 
6.2.2 
Handling and Storage ........................................................................35 
6.2.3 
Compliance and Accountability ........................................................36 
6.2.4 
Disposal and Destruction ...................................................................36 


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6.3 
Subject Numbering and Treatment Assignment ..............................................36 
6.3.1 
Subject Numbering ............................................................................36 
6.3.2 
Treatment Assignment .......................................................................36 
6.3.3 
Treatment Blinding ............................................................................36 
6.4 
Dosage and Administration..............................................................................36 
6.5 
Dose Interruption and Modification.................................................................37 
6.5.1 
Dose Reductions for Hematologic Toxicity ......................................37 
6.5.2 
Dose Reductions for Non-Hematologic Toxicity ..............................38 
6.6 
Concomitant Medications and Non-Drug Therapies .......................................38 
6.6.1 
Permitted Medications .......................................................................38 
6.6.2 
Prohibited Medications ......................................................................39 
6.6.3 
Medications to be used with Caution ................................................39 
6.7 
Discontinuation of treatment and premature withdrawal.................................40 
6.7.1 
Discontinuation of treatment .............................................................40 
6.7.2 
Early Termination ..............................................................................40 
7 
STUDY ASSESSMENTS ...........................................................................................41 
7.1 
Study Flow and Visit Schedule ........................................................................41 
7.2 
Subject Demographics/Other Baseline Characteristics ...................................47 
7.2.1 
Demography ......................................................................................47 
7.2.2 
Medical History .................................................................................47 
7.2.3 
Other Baseline Characteristics ..........................................................47 
7.3 
Efficacy ............................................................................................................48 
7.3.1 
Physical Examination ........................................................................48 
7.3.2 
Radiological Tumor Assessment .......................................................48 
7.3.3 
Bone Marrow Assessment .................................................................49 
7.3.4 
Endoscopy .........................................................................................49 
7.4 
Safety ...............................................................................................................49 
7.4.1 
Adverse Events ..................................................................................49 
7.4.2 
Physical Examination, Vital Signs, Height, and Weight ...................50 
7.4.3 
ECOG Performance Status ................................................................50 
7.4.4 
Echocardiogram .................................................................................50 
7.4.5 
Laboratory Evaluations .....................................................................50 
7.4.6 
Electrocardiogram .............................................................................52 
7.5 
Biomarkers .......................................................................................................52 
7.5.1 
Predictive Biomarkers .......................................................................52 
7.6 
Appropriateness of Measurements ...................................................................53 
8 
DATA HANDLING AND QUALITY ASSURANCE ...............................................54 
8.1 
Data Collection ................................................................................................54 
8.2 
Data Management/Coding ...............................................................................54 
8.3 
Quality Assurance ............................................................................................55 
9 
SAFETY MONITORING AND REPORTING...........................................................56 
9.1 
Adverse Events ................................................................................................56 
9.1.1 
Definitions and Reporting .................................................................56 


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9.1.2 
Laboratory Test Abnormalities ..........................................................59 
9.1.3 
AE due to disease progression ...........................................................60 
9.1.4 
Adverse Events Secondary to Prior Events .......................................60 
9.1.5 
Recurrent Adverse Events .................................................................60 
9.1.6 
Death ..................................................................................................61 
9.2 
Serious Adverse Events ...................................................................................61 
9.2.1 
Definitions .........................................................................................61 
9.2.2 
Reporting ...........................................................................................62 
9.3 
Pregnancies ......................................................................................................64 
9.3.1 
Time Point for Collecting Pregnancy Information. ...........................64 
9.3.2 
Action to be Taken and Reporting if a Pregnancy Occurs ................64 
9.4 
Lack of Efficacy ...............................................................................................65 
9.5 
Safety Monitoring Committee .........................................................................65 
10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .........................66 
10.1 
Primary, Secondary and Exploratory Study Endpoints ...................................66 
10.1.1 
Primary Endpoint ...............................................................................66 
10.1.2 
Secondary Endpoints .........................................................................66 
10.1.3 
Exploratory Endpoints .......................................................................66 
10.2 
Statistical Analysis ...........................................................................................67 
10.2.1 
Analysis Populations .........................................................................67 
10.2.2 
Subject Disposition ............................................................................67 
10.2.3 
Demographics and Other Baseline Characteristics ...........................67 
10.2.4 
Prior and Concomitant Therapy ........................................................67 
10.2.5 
Efficacy Analyses ..............................................................................68 
10.3 
Safety Analyses ................................................................................................69 
10.3.1 
Extent of Exposure ............................................................................69 
10.3.2 
Adverse Events ..................................................................................70 
10.3.3 
Laboratory Analyses ..........................................................................70 
10.3.4 
Vital Signs .........................................................................................71 
10.3.5 
Electrocardiogram .............................................................................71 
10.4 
Sample Size Consideration ..............................................................................71 
10.5 
Interim Analysis ...............................................................................................71 
10.6 
Other Statistical Issues .....................................................................................71 
11 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .........72 
11.1 
Regulatory Authority Approval .......................................................................72 
11.2 
Investigator Responsibilities ............................................................................72 
11.2.1 
Good Clinical Practice .......................................................................72 
11.2.2 
Ethical Conduct of the Study and Ethics Approval ...........................72 
11.2.3 
Informed Consent ..............................................................................73 
11.2.4 
Investigator Reporting Requirements ................................................73 
11.2.5 
Confidentiality ...................................................................................73 
11.2.6 
Case Report Forms ............................................................................74 
11.2.7 
Drug Accountability ..........................................................................74 
11.2.8 
Inspections .........................................................................................74 


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11.2.9 
Protocol Adherence ...........................................................................75 
11.3 
Sponsor Responsibilities ..................................................................................75 
11.3.1 
Protocol Modifications ......................................................................75 
11.3.2 
Study Report and Publications ..........................................................75 
11.4 
Study and Study Center Closure ......................................................................76 
11.5 
Records Retention and Study Files ..................................................................77 
11.5.1 
Study Files and Retention of Records ...............................................77 
11.6 
Provision of Study Results and Information to Investigators ..........................78 
11.7 
Information Disclosure and Inventions ............................................................78 
11.8 
Joint Investigator/Sponsor Responsibilities .....................................................79 
11.8.1 
Access to Information for Monitoring ...............................................79 
11.8.2 
Access to Information for Auditing or Inspections ...........................79 
12 
REFERENCES ............................................................................................................80 
13 
APPENDICES .............................................................................................................82 
 
LIST OF TABLES 
Table 1  
Zanubrutinib Dose Reduction Steps ...................................................................... 37 
Table 2  
Study Assessment and Procedure Schedule for Study BGB-3111-207 ............... 42 
Table 3  
Revised Ann Arbor Staging Classificationa ........................................................... 47 
Table 4  
HBV, HCV, and HIV Testing for Inclusion/Exclusion ......................................... 52 
Table 5  
Timeframe for Reporting Serious Adverse Events to the Sponsor ..................... 62 
 
LIST OF APPENDICES 
Appendix 1 
Signature of Investigator ......................................................................................... 83 
Appendix 2 
Medications which are known to prolong the QT interval and/or induce 
Torsades de pointes to be avoided .......................................................................................... 84 
Appendix 3 
Revised criteria for response assessment of lymphoma (Cheson et al) ............... 86 
Appendix 4 
Prohibited Medications (CYP3A Inhibitors and CYP3A Inducers) ................... 90 
Appendix 5 
Medications to be Used with Caution..................................................................... 91 
Appendix 6 
ECOG Performance Status ..................................................................................... 92 
 
LIST OF FIGURES 
Figure 1 
Schema for Study BGB-3111-207 ........................................................................... 31 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
activated B-cell 
ADCC 
antigen-dependent cell-mediated cytotoxicity 
AEs 
adverse events 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
ATP 
adenosine triphosphate 
AUC 
area under the plasma concentration-time curve 
AV 
atrioventricular 
BCR 
BID 
B-cell receptor 
twice a day 
BOR 
best overall response 
BP 
blood pressure 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
CERT 
Center for Education and Research on Therapeutics 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CYP 
cytochrome 
CYP3A 
cytochrome P450, family 3, subfamily A 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DLBCL 
diffuse large B cell lymphoma 
DOR 
duration of response 
EC 
expansion cohort 


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ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
eGRF 
EGFR 
estimated glomerular filtration rate  
epithelial growth factor receptor 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FGR 
Garden-Rasheed feline sarcoma viral (v-fgr) oncogene homolog 
GCB 
GCP 
Germinal center B-cell type 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
HDL 
hepatitis C virus 
high density lipoprotein 
HDPE 
high density polyethylene 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
50% maximum inhibitory concentration 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IND 
investigational new drug 
INR 
international normalized ratio 
IPI 
International Prognostic Index 
IRB 
ITK 
JAK3 
KM 
Institutional Review Board 
interleukin-2-inducible T cell kinase 
Janus kinase 3 
Kaplan-Meier 
LCK 
lymphocyte-specific protein tyrosine kinase 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LVEF 
left ventricular ejection fraction 


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MCL 
mantle cell lymphoma 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for 
Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NTI 
narrow therapeutic index 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PLCβ2 
PO 
phospholipase C-beta-2 
per os (orally) 
PP 
per-protocol population 
PR 
partial response 
PT 
preferred term or prothrombin time 
RBCs 
red blood cells 
R-CHOP 
rituximab-cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP) 
SAEs 
serious adverse events 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SOPs 
standard operating procedures 
SSE 
significant safety event 
TEAEs 
treatment emergent adverse events 
TEC 
tyrosine kinase expressed in hepatocellular carcinoma 
TLS 
tumor lysis syndrome 
TTR 
time to response 


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ULN 
upper limit of normal 
WBCs 
white blood cells 
WHO-DD 
World Health Organization Drug Dictionary 
zanubrutinib 
BGB-3111 
 
 


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1 
INTRODUCTION 
1.1 
Current Status of Diffuse Large B cell Lymphoma Care 
In 2012, there were 386,000 new non-Hodgkin’s lymphoma (NHL) patients diagnosed worldwide, 
at an incidence rate of 5.1/100,000 population, in the same year, there were 200,000 deaths from the 
illness (GLOBOCAN 2012). In 2016, 72,580 new NHL patients will be diagnosed in the US, with 
20,150 dying from the disease, 5 years survival has already risen to 70.7%. Diffuse large B cell 
lymphoma (DLBCL) made up 37% of NHL patients (Morton et al 2006). In China, the incidence of 
non-Hodgkin’s lymphoma is 5 /100,000 population, contributing 65,000 new cases a year; DLBCL 
makes up 40% of the new cases. The median age for diagnosis is 60-70 years, with a slight 
preponderance of males.  
DLBCL is the most common type of NHL, morphologically, it consists of large cells with nuclei 
larger than that of macrophages,  the lymphoma cells express the B cell antigens CD19+, CD20+, 
CD22+, CD79a+, and often are CD45+, but have to be CD3-, subgroups can be CD63+ (primary 
cutaneous B cell lymphoma, leg type), CD5+ (CD5 + DLBCL), CD10+ (GCB subtype), CD138+ 
(plasmablastic differentiation), CD30+ (which could be either CD30 + DLBCL or PMBL or 
Hodgkin’s lymphoma), IRF/MUM1+ (ABC type), BCL2 and BCL6 can be positive or negative in 
the GCB and non-GCB subtypes. There are many subtypes of DLBCL, defined by the organ in 
which DLBCL is located at diagnosis, age of the patient, associated infectious agent, and also by 
overlap with Burkitt’s lymphoma or Hodgkin’s disease (Xie et al 2015). In 2000, gene expression 
profiling (GEP) separated the morphologically similar DLBCLs into different types, the most 
common being the germinal center type (GCB) with genes akin to germinal center B cells, and the 
non-GCB or activated B cell (ABC) type, with genetic pathways in alignment with activated 
peripheral blood B cells. The GCB type enjoys a significantly superior 12 years survival of 60-75%, 
in contrast to 25-40% for the non-GCB type after first line treatment with standard immuno-
chemotherapy of rituximab, cyclophosphamide, doxorubicin, prednisolone (R-CHOP) (Alizadeh et 
al 2000). GEP is costly and difficult to execute clinically. In 2004, the Hans algorithm based on 
immunohistochemical markers was developed for simplified subtype differentiation (Hans et al, 
2004).  Both GEP and the Hans algorithm were separately demonstrated to correlate with the 
International Prognostic Index (IPI), and immunohistochemistry (IHC) is still in the mainstream for 
diagnosis in the present day (Agarwa et al, 2016). Many algorithms have been developed for 
subtyping of DLBCL, however, for this phase II trial, the Hans algorithm will be used (Gifford et al 
2016). 


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About 10-15% of DLBCLs are so called double and triple hit lymphomas (de Jonge et al 2016), 
there is a fundamental t(8;14) with c-myc over-expression, and concurrent abnormalities / over-
expression of bcl-2, and/or bcl-6; this poor prognosis group has a significantly inferior survival of 
only 35% at 2years after R-CHOP (Barrans et al, 2010), over and above that would be expected 
from the IPI score. CARD11 mutations detected in 11% of DLBCL impacts the CBM complex of 
BCL10, CARD11, and MALT1, A30(inhibitor of CBM complex) mutations occur in 30%, 18% 
DLBCL tumors have CD79B ITAM region mutations, all can impact B cell receptor pathway drug 
efficacy. In a clinical study of 187 Korean DLBCL patients, CD79B mutation was found in 16 cases 
(8.5%), of whom 11cases also carried the MYD88 mutation; and MYD88 with L265P mutation was 
detected in 19.3% of cases, but neither mutation seemed to have an impact on disease outcome. 
However, Toll like receptor antagonists have demonstrated efficacy in vitro, and have been 
advanced into clinical trials to rectify the purported resistance to BTK inhibitors from such 
mutations. 
DLBCL patients are staged according to the Ann Arbor classification, just under a third of patients 
have stage I or II disease (ie, disease confined to 1 side of the diaphragm) at diagnosis, a third 
present with bulky disease (> 7.5 cm), about 40% have extranodal involvement, 20% have marrow 
involvement, although neither staging nor B symptoms (weight loss, fever, night sweats) have been 
definitively linked to prognosis. An international prognostic score (IPI) was developed in 1993 in 
the pre-rituximab era, and is still applicable in the present day, although it has been simplified and 
modified in the post rituximab era. One point each is allocated for age>60yrs, stage III/IV disease, 
increased lactate dehydrogenase (LDH), ECOG performance status >2, >2 extranodal site 
involvement, patients are thus stratified into 3 risk groups of very good (0 points), good (1 or 2 
points), and poor (3-5 points), with respective 5 year disease free and overall survival rates of 
94%/94%, 80%/80%, and 53%/55% (Zelenetz et al 2016).  IPI scores have also been modified for 
geriatric patients, and patients with central nervous system involvement which will not be needed 
for the present clinical trial. 
Since 2004, R-CHOP has become first line therapy for DLBCL patients, with 3yr overall survival 
(OS) rates ranging from 59% to 91%, depending on the IPI scores. Unfortunately, 30-40% of 
patients will eventually relapse and require salvage treatment. The patients are then practically 
divided into a group amenable to intensive treatment, followed by bone marrow transplantation 
(Camicia et al 2015), and a left over group not amenable to such treatment for varying reasons, most 


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commonly, age over 65yrs, and these patients are to receive more moderate therapy.  Regimens for 
relapsed and refractory disease can be more intense and toxic, and has to be  followed by bone 
marrow rescue, regimens such as DHAP (dexamethasone, cisplatin, cytarabine), ESHAP (VP-16, 
cytarabine, cisplatin, methylprednisolone), GEMOX (gemcitabine and oxaliplatin), ICE (ifosfamide, 
carboplatin, etoposide), all with or without rituximab, these regimens often incur significant 
morbidity in themselves. For those who are not candidates for intensive treatment, regimens 
recommended include bendamustine, brentuximab vedotin (if CD30+), GEMOX, lenalidomide, 
often with rituximab, there is no definitive recommended regimen that has been show to superior to 
all others. 
When patients relapse, it can be as a result of original tumor heterogeneity, with positive selection 
for subclones carrying intrinsic genetic or epigenetic resistance mechanisms, treatment induced, or 
through interaction of the tumor with its micro- environment. BTK inhibitors can play a significant 
role in the control of the non-GCB type DLBCLs, which demonstrated activation of the B-cell 
receptor (BCR) pathway and downstream NKB activation. BTK inhibitors have demonstrated 
efficacy in the proof of concept study in non-GCB DLBCL patients, with a good toxicity profile, 
and quality of life.  Zanubrutinib is a best in class BTI inhibitor, and will hopefully open up a new 
era of B-cell malignancy control.  
1.2 
Zanubrutinib  
Zanubrutinib (also known as BGB-3111) is a novel second generation small molecule oral BTK 
inhibitor, which forms an irreversible covalent bond at Cys481 within the adenosine triphosphate 
(ATP) binding pocket of the BTK protein.  Zanubrutinib is highly potent against BTK; however, as 
opposed to ibrutinib, zanubrutinib has significantly less epithelial growth factor receptor 
(EGFR)/Janus kinase 3 (JAK3)/ tyrosine kinase expressed in hepatocellular carcinoma 
(TEC)/interleukin-2-inducible T cell kinase (ITK) inhibitory activity, thus potentially reducing the 
side effects seen with ibrutinib and allowing increased exposure with potentially improved efficacy.  
1.3 
Non-Clinical Data 
Zanubrutinib inhibits BTK with a 50% maximum inhibitory concentration (IC50) of 0.3 nanomolar 
(nM) in biochemical assays.  Cellular assays confirmed that zanubrutinib inhibited B-cell receptor 
(BCR) aggregation-triggered BTK autophosphorylation, and blocked downstream phospholipase C-
beta-2 (PLCβ2) signaling in mantle cell lymphoma (MCL) cell lines.  Zanubrutinib potently and 
selectively inhibited cellular growth of several MCL cell lines (REC-1, Mino and JeKo-1) and 
activated B-cell (ABC) type of diffuse large B-cell lymphoma (DLBCL) cell line TMD8, with IC50s 
from 0.36 nM to 20 nM, while inactive in many other hematologic cancer cell lines.  In vivo studies 
showed that zanubrutinib induced dose-dependent anti-tumor effects against REC-1 MCL 
xenografts engrafted either subcutaneously or systemically in mice.  Zanubrutinib was more 


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selective than ibrutinib for inhibition of kinase activity of BTK vs. EGFR, Garden-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 
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 antigen-dependent cell-mediated cytotoxicity (ADCC).  Zanubrutinib was shown 
to be at least 10-fold weaker than ibrutinib in inhibiting rituximab-induced ADCC, consistent with 
zanubrutinib being a more selective BTK inhibitor, with much weaker ITK inhibition activity than 
ibrutinib in both biochemical and cellular assays, thus preventing the potential for antagonism with 
rituxan that has been seen pre-clinically with other BTK inhibitors. 
1.4 
Zanubrutinib global Phase 1 Clinical Experience 
The first-in-human study with zanubrutinib, which was designed to look at safety and 
pharmacokinetics in subjects with B-cell lymphoid malignancies, started in Australia in August 
2014.  As of 28 February 2016, a total of 95 subjects have been enrolled; 25 subjects in dose 
escalation and 70 subjects into one of the four dose expansion cohorts (ECs); dosing in EC included 
57 subjects receiving 160 mg twice daily and 13 subjects receiving 320 mg daily.  A total of 57 
subjects are considered fully evaluable for efficacy and safety, defined as having been enrolled for 
at least 12 weeks prior to the latest data cut-off date (21 January 2016).  
Median follow-up is 212 days (range 10-492).  The maximum tolerated dose (MTD) was not 
reached.  Zanubrutinib was well tolerated; in 82% of subjects no drug-related AEs of ≥ Grade 2 
were reported within the first 12 weeks of therapy.  As of the cut-off date, only 3 subjects 
discontinued zanubrutinib due to adverse events (AEs), including 2 subjects due to complications 
related to refractory underlying malignancy and 1 patient due to worsening of bronchiectasis.  Six 
subjects (11%) experienced a Grade >3 toxicity believed by the investigator to be related to 
zanubrutinib, including 5 cases of transient neutropenia and 1 case of Grade 3 hypertension.  Grade 
1 or 2 toxicities reported, regardless of attribution, with an incidence of greater than 15%, include 
petechiae/ contusion/ bruising (39%), diarrhea (28%), cough (28%), upper respiratory infection 
(26%), fatigue (23%), rash (18%), and constipation (18%). 
1.5 
Zanubrutinib in Relapsed or Refractory DLBCL global clinical trial 
Up until June 10th, 2016, in subjects that are fully evaluable for safety and efficacy, 15 cases were 
diagnosed as DLBCL, 7 (47%) patients have attained response to treatment. 
1.6 
Zanubrutinib Phase I clinical trial in China 
The IND package for zanubrutinib was approved by the CFDA in February of 2016. Phase I clinical 
trial (BGB-3111-1002）was initiated in July 2016, 2 dose schedules of 320 mg QD or160 mg BID 


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were tested, with evaluation of pharmacokinetics, safety, and tolerability in Chinese B cell 
lymphoma patients.  By the end of October, 2 groups of 21 patients, 11 on 160 mg BID, and the rest 
on 320mg QD, had all passed the one month DLT evaluation period, including 16 males and 5 
females, ranging in age between 35-72 years, including 9 chronic lymphocytic leukemia (CLL)/ 
small lymphocytic lymphoma, 6 cases follicular lymphoma, 2 cases each of MCL, marginal zone 
and Waldenstrom’s macroglobulinemia. Up until October 27th, 2016, zanubrutinib related adverse 
events > Grade 3 included one Grade3 and 2 Grade 4 neutropenia，the remaining were all Grade 2 
AEs, including 1 neutropenia, 1 anemia, 2 asymptomatic QTcF prolongation and 1 upper respiratory 
tract infection. So far, 5 patients have had their first 12-week evaluation, all have attained partial 
response, 3 CLL, 1 Waldenstom macogloulinemia, and 1 follicular lymphoma.  Zanubrutinib 
induced physiological lymphocytosis, which was correlated with concurrent decrease in 
lymphadenopathy. 
1.7 
Zanubrutinib Pharmacokinetics and Pharmacodynamics 
The pharmacokinetic data of zanubrutinib has been based on 76 B cell lymphoma patients, 1113 
serum samples. These patients received doses between 40 to 320mg daily, when given as a single 
dose, at steady state, the maximum observed plasma concentration (Cmax) and area under the plasma 
concentration time curve (AUC)0-24h increase was linear. Absorption of zanubrutinib is rapid with 
median time to maximum plasma concentration of 2 hours. The terminal elimination half-life is 
approximately 5 hours at 320 mg daily. Clearance and distribution is 136L/h and 300L respectively.  
At 80 mg/d of zanubrutinib, drug exposure (Cmax and AUC0-24h）approximated ibrutinib dosed at 
560mg/day。The free drug ratio between zanubrutinib and ibrutinib were 5.8% and 2% 
respectively，therefore, theoretically zanubrutinib dosed at 40mg/day would attain equivalent free 
drug exposure (Cmax and AUC0-24h） to Ibrutinib given at 560mg/day. In the 320 mg QD and 160 
mg BID groups，the zanubrutinib steady state free drug exposure (Cmax and AUC0-24h）are 646 
ng/mL and 2,704 ng/mL*h, or 282 ng/mL and 3,006 ng/mL*h respectively. In zanubrutinib global 
phase I clinical trial, plasma exposure on18 Korean patients dosed at 160 mg BID were similar to 
Caucasians. 
Full occupancy of BTK in peripheral blood mononuclear cells was achieved in all subjects in the 
study, while occupancy in lymph node tissue was assessed only at 160 mg twice daily and 320 mg 
daily.  At the 160 mg BID dose, full BTK occupancy was observed at trough exposure periods, 
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 indications at all tested 
dose levels; thus, a minimum effective dose cannot be established at this time.  Conversely, there is 
now extensive experience at the 160 mg twice daily and 320 mg daily; both schedules show a high 
level of activity without compromise of the tolerability profile as compared to lower doses of 


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zanubrutinib.  Therefore, 160 mg PO BID is selected as the recommended Phase 2 dose based on 
sustained target occupancy, high rates of objective response in multiple histologies, and a favorable 
safety and tolerability profile. 
Cytochrome P450, family 3, subfamily A (CYP3A) was the major CYP isoform responsible for 
zanubrutinib metabolism.  Zanubrutinib is a moderate inhibitor for CYP2C8 (IC50 = 4.03 µM), 
CYP2C9 (IC50 = 5.69 µM) and CYP2C19 (IC50 = 7.80 µM) while the IC50s for other CYP isozymes 
are all larger than 10 µM.  Zanubrutinib is not a time-dependent CYP inhibitor of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A.  Drug-drug interactions between 
zanubrutinib and CYP2C8, CYP2C9, and CYP2C19 substrates would be dependent on final plasma 
levels obtained in humans at therapeutic doses.  Zanubrutinib is not an inducer of human CYP1A2, 
CYP2B6 but have weak CYP3A induction potential at concentration equal or higher than 3 µM in 
primary human hepatocytes.  For this reason, caution must be used when using strong CYP3A 
activators as in Appendix 4.  
In the food effect study, a high fat meal did not impact the plasma exposure of zanubrutinib AUC 
and Cmax are increased by 37% and 56% respectively after a low-fat meal. Since this increase is still 
within the variability of zanubrutinib exposure (approximately 50% CV), and given zanubrutinib 
has a larger therapeutic window, effect of food on zanubrutinib bioavailability is not considered to 
be clinically relevant. Therefore, there will be no food restriction in this study, patients can choose 
to be fasting or take zanubrutinib after a meal, and should try to take the capsules under similar 
conditions each day.  
1.8 
Zanubrutinib in non-GCB Diffuse Large B Cell Lymphoma 
Bruton’s tyrosine kinase (BTK), a member of the tyrosine kinase expressed in hepatocellular 
carcinoma (TEC) family kinases, is a critical component of the B-cell receptor (BCR) signaling 
cascade.  Inhibition of BTK has emerged as a promising strategy for targeting B-cell malignancies.  
Ibrutinib, the first-in-class Food and Drug Administration (FDA)-approved BTK inhibitor, has 
demonstrated promising anti-tumor activity in MCL, CLL, and Waldenstom macogloulinemia.  
Zanubrutinib is a potent, specific and irreversible BTK inhibitor. The data generated in preclinical 
studies using biochemical, cell based and animal studies suggest that zanubrutinib could offer 
significant patient benefit in inhibiting tumor growth in non-GCB DLBCL, and as zanubrutinib was 
shown to be more selective than ibrutinib for inhibition of BTK, may have a favorable side effect 
profile, allowing for higher and more prolonged exposure to drug, allowing for more sustained BTK 
inhibition, potentially enhancing clinical efficacy.   
For these reasons, we believe that a single-arm Phase 2 open-label study of the Bruton’s tyrosine 
kinase inhibitor zanubrutinib, in subjects with relapsed or refractory non-GCB DLBCL is 
warranted, especially with the aim to find molecular markers associated with efficacy endpoints. 


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The lack of treatment-related SAEs and preliminary efficacy results from the Phase 1 study supports 
further investigation of 160 mg PO BID in subsequent Phase 2 and Phase 3 studies to confirm the 
benefit/risk profiles of zanubrutinib in B-cell malignancies.  Refer to the Investigator’s Brochure 
(IB) for more detailed information on the background of zanubrutinib.  
2 
OBJECTIVES  
2.1 
Primary Objective 
To evaluate the efficacy of zanubrutinib at a dose of 160 mg orally (PO) twice daily (BID), in 
subjects with relapsed or refractory non-Germinal Center B cell type Diffuse Large B cell 
Lymphoma (non-GCB DLBCL) as assessed by the objective response rate according to the 2014 
International Working Group in Non-Hodgkin’s Lymphoma (NHL) criteria (Cheson et al 2014). 
2.2 
Secondary Objective 
To evaluate the efficacy of zanubrutinib as measured by progression free survival (PFS). 
To evaluate the efficacy of zanubrutinib as measured by duration of response (DOR). 
To evaluate the efficacy of zanubrutinib as measured by time to response (TTR). 
To evaluate the safety and tolerability of zanubrutinib at a dose of 160 mg PO BID in subjects with 
relapsed or refractory non-GCB type DLBCL. 
2.3 
Exploratory Objective  
 
.  
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint of the study is the rate of objective response, defined as the achievement of 
either a partial response (PR) or complete response (CR) by the 2014 modification of the 


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International Working Group on Non-Hodgkin’s lymphoma (NHL) Criteria (Cheson et al 2014) 
(Appendix 3) at any time on study drug. 
3.2 
Secondary Endpoints 
Efficacy: 
• Progression free survival (PFS): defined as time from first dose of zanubrutinib until first 
documentation of progression (by IWG on NHL criteria) or death, whichever comes first. 
• Duration of response (DOR) is defined as the time from the date that the response criteria are 
first met to the date that progressive disease (PD) is objectively documented or death, whichever 
occurs first. 
• Time to response (TTR) is defined as the time from first dose of zanubrutinib to documentation 
of a response. 
Safety: 
• To evaluate the safety and tolerability of zanubrutinib, as defined by: 
o The incidence and severity of treatment-emergent adverse events (TEAEs), SAEs and 
treatment-related AEs according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.03 (NCI CTCAE v4.03). 
o The incidence, severity, timing, and causation of adverse events leading to study drug 
discontinuation. 
3.3 
Exploratory Endpoints 
4 
STUDY DESIGN 
4.1 
Summary of Study Design 
This is a single-arm, open-label, multi-center Phase 2 study in subjects with histologically 
documented non –GCB DLBCL who have relapsed after ≥ 1 prior treatment regimen including 
rituximab(s), patients also have to be ineligible for intensive chemotherapy and bone marrow 
transplantation.  The study is composed of an initial screening phase (up to 28 days), a single-arm 
treatment phase of up to 2 years, and a follow-up phase (30 days), at the end of which if the patient 
is still benefiting from therapy, will be allowed to join the long term extension study.   
Up to approximately 40 subjects will be enrolled.  The primary efficacy analysis will be conducted 
no later than 12 months after the last subject received the first dose of study drug.  Tumor response 


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will be assessed by investigator review according to 2014 International Working Group in NHL 
(Appendix 3).  Patient will receive a PET and contrast CT at screening, after 12 and 24 weeks of 
therapy, and at suspected complete remission. Contrast CT alone will be performed at weeks 36, 48, 
and thereafter, once every 16 weeks. Response will be assessed on the basis of radiological 
evaluations. Complete responses should be confirmed by PET and contrast CT in all subjects, by 
endoscopy for any subjects with a documented history of gastrointestinal involvement, and by bone 
marrow biopsy in these subjects with bone marrow tumor involvement prior to study drug. Bone 
marrow biopsy has to be performed at screening. 
All subjects will be followed for AEs for 30 additional days after the last dose of study drug.  All 
treatment-related AEs and SAEs will be followed until resolution or stabilization. 
Screening phase:  Screening evaluations will be performed within 28 days prior to the first dose of 
study drug.  Subjects will sign the informed consent form prior to any screening evaluations.  Please 
refer to Table 2 for details on screening procedures.  Screening evaluations can be repeated within 
the screening period.  
Treatment phase:  All subjects will receive zanubrutinib 160 mg BID. All subjects in the study will 
be treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the 
study is terminated by the sponsor for final analysis.  At the time of final analysis, subjects who 
remain on treatment will be considered for participation in the extension study when eligible.  A 
treatment cycle consists of 28 days. 
Follow-up phase:  Subjects will return approximately 30 days after the last dose of study drug for 
safety follow-up visit.  Assessments to be performed are presented in Table 2.  Radiological 
assessments will continue until documented disease progression.  If a subject discontinues study 
drug due to reasons other than disease progression, radiological assessments will continue until 
subject exhibits first progression, starts new anti-cancer therapy, withdrawal of consent, death, lost 
to follow-up or study termination by sponsor, whichever occurs first.  
Survival phase: Subjects will be followed for survival via phone contact (with patient guardian, if 
applicable) every 3 months after the subject’s last visit until withdrawal of consent, lost to follow-
up, death, or the date of data cutoff for the final analysis.  


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Figure 1 
Schema for Study BGB-3111-207 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BGB-3111 
160 mg PO twice daily, 1 cycle=28 days 
until disease progression (PD) or intolerable toxicity 
Discontinue 
due to PD 
Safety Follow-up visit 
(30 ± 7 days after last dose) 
Survival Follow-up every 
3 months 
Histologically confirmed DLBCL,  
Hans algorithm defined non-GCB type DLBCL 
Safety Follow-up visit 
(30 ± 7 days after last dose) 
Continue efficacy evaluations 
(tumor assessments) until PD 
Discontinue 
due to reason other than PD 
End of Treatment (EOT) 


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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Histologically confirmed non-GCB DLBCL, by immunohistochemistry using the Hans 
algorithm,  
- 
CD10- and BCL6- 
- 
CD10- and BCL6+、but MUM1+ 
2. Men and women ≥18 years of age. 
3. ECOG performance status of 0-2.  
4. Measurable disease is defined as at least one lymph node >1.5 cm in longest diameter and 
measurable in 2 perpendicular dimensions.  
5. All subjects must provide fresh tumor biopsy or recent tumor tissue samples (within 2 years of 
study entry [informed consent form signed]).  
6. Received at least one prior therapy for DLBCL that includes anthracycline based chemotherapy. 
7. Patient not eligible for or refuses intensive chemotherapy and autologous bone marrow 
transplantation. 
8. Documented failure to achieve at least PR with, or documented disease progression after 
response to, the most recent treatment regimen. 
9. Neutrophils ≥ 1 x 109/L, independent of growth factor support within 7 days of first dose of 
study drug. 
10. Platelets ≥ 75 x 109/L, independent of growth factor support or transfusion within 7 days of first 
dose of study drug. 
11. Creatinine clearance of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or estimated 
glomerular filtration rate [eGFR] from the modification of diet in renal disease [MDRD]). 
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of 
normal (ULN).  
13. Bilirubin ≤ 2 x ULN (unless documented Gilbert’s syndrome, up to 5 x ULN). 


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14. Independent of erythropoietin (EPO) support or transfusion within 7 days of first dose of study 
drug 
15. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time 
(APTT) ≤ 1.5 x ULN. 
16. Subjects may be enrolled who relapse after autologous stem cell transplant, at least 6 months 
after transplant, subjects should have no active infections (ie, fungal or viral). 
17. Females of childbearing potential must agree to use highly effective forms of birth control 
throughout the course of the study and at least up to 90 days after last dose of study drug.  
Highly effective forms of birth control can be defined as abstinence, hysterectomy, bilateral 
oophorectomy with no menstrual bleeding for up to 6 months, intrauterine contraception, 
hormonal methods such as contraceptive injection, oral contraceptive, etc.  Males must have 
undergone sterilization–vasectomy, or utilize a barrier method where the female partner utilizes 
the effective forms of birth control noted above.  
18. Life expectancy of > 3 months. 
19. Able to provide written informed consent and can understand and comply with the requirements 
of the study. 
5.2 
Exclusion Criteria 
Subjects will not be entered in the study for any of the following reasons: 
1. Current or history of CNS lymphoma. 
2. Prior exposure to a BTK inhibitor. 
3. Prior corticosteroids (at dosages equivalent to prednisone > 20 mg/day) given with anti-
neoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 
3 weeks, or antibody-based therapies or Chinese anti-cancer herbal therapies within 4 weeks of 
the start of study drug. 
4. Major surgery within 4 weeks of screening. 
5. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, absolute neutrophils, 
and platelets. For neutrophils and platelets, please following inclusion criteria #9 [neutrophils] 
and #10 [platelets]). 
6. History of other active malignancies within 2 years of study entry, with exception of (1) 
adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell 


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carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
7. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, 
congestive heart failure, any Class 3 or Class 4 cardiac disease as defined by the New York 
Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 
6 months of screening. Left Ventricular Ejection Fraction (LVEF) is lower than 50% measured 
by echocardiography (ECHO). 
8. QTcF (Fredericia’s correction) > 450 msecs or other significant electrocardiogram (ECG) 
abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV 
block. 
9. Unable to swallow capsules or having a disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
10. Uncontrolled systemic infection or infection requiring parenteral antimicrobial therapy. 
11. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection 
(detected positive by polymerase chain reaction [PCR]). 
 
Inclusion 
Exclusion 
HIV 
Antibody (-) 
Antibody(+)         
HB
V 
HBsAg (-)  
HBsAg (+) 
HBsAg (-) 
HBcAb (+) 
HBV DNA<1000 IU/mL, 
After enrollment, check 
HBV DNA monthly or 
every 3 cycles for 
patients receiving anti-
HBV medication to 
prevent HBV reactivation 
HBsAg(-) 
HBcAb(+)  
HBV DNA ≥1000 
IU/mL 
HC
V 
Antibody (-) 
 
 
 
Antibody (+)  
HCV 
RNA<1(log10IU/mL), and 
monthly monitoring or 
treatment with anti-HCV 
medication.  
Antibody(+) 
HCV RNA 
≥1(log10IU/mL) 
HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B 
surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus. 
HBV evaluation includes HBsAg, HBcAb, HBsAb. If subject is HBsAg- but HBcAb+ (without 
considering HBsAb status), will evaluate HBV DNA using PCR, the acceptable upper limit is 
1000IU/ml, however, because different assays are used in different hospitals, the acceptable 
upper limit will be that of the upper limit at the hospital where the test is conducted. HCV 
evaluation involves the HCV Ab, if positive, to evaluate HCV RNA as above. 
12. Pregnant or lactating women. 


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13. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, or put the study at risk. 
14. On medications which are strong CYP3A inhibitors or CYP3A inducers.  See Section 6.6.2 for 
clarification on medications which are strong cytochrome P450, family 3, subfamily A (CYP3A) 
inhibitors or CYP3A inducers (Appendix 4). 
6 
STUDY TREATMENTS 
6.1 
Study Treatment  
Subjects will receive zanubrutinib 160 mg (two - 80 mg white opaque capsules) orally twice daily 
(BID) with a minimum 8 hours between two consecutive doses. 
6.2 
Study Treatment Preparation and Dispensation 
6.2.1 Packaging and Labeling 
The capsule supplies of zanubrutinib will be provided in a child-resistant high density polyethylene 
(HDPE) bottle with induction seal and bottle label.  The label will include at minimum, space to 
enter the subject number and name of investigator, content and quantity of zanubrutinib, protocol 
number, batch number, directions for usage, storage conditions, and cautions. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
6.2.2 Handling and Storage 
The study drug 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. 
Study drug must be dispensed or administered according to procedures described herein.  Only 
subjects 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.  All 
study drug must be stored in a secure area with access limited to the investigator and authorized 
study center personnel and under physical conditions that are consistent with study drug-specific 


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requirements.  The study drug must be kept at the condition as specified on the labels, or according 
to the latest version of the IB. 
6.2.3 Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel at each subject visit and 
information provided by the subject and/or caregiver will be captured in the Drug Accountability 
Form.  This information must be captured in the source document at each subject 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 subjects, if applicable. 
6.2.4 Disposal and Destruction 
After completion of the study, all unused zanubrutinib will be inventoried and packaged for return 
shipment by the hospital unit pharmacist or other designated study center personnel.  The 
inventoried supplies will be returned to the sponsor or destroyed on site or depot, after receiving 
written sponsor approval.  
6.3 
Subject Numbering and Treatment Assignment 
6.3.1 Subject Numbering 
Subjects will be identified by a subject number.  Each subject enrolled in this study will receive a 
unique subject number which will be assigned when the subject is screened or enrolled in the study.  
Subject will be assigned in chronological order starting with the lowest number.  Once a subject 
number has been assigned to a subject, it cannot be reassigned to any other subject. Subject can be 
re-screened if the subject did not previously meet the inclusion and exclusion criteria. Re-screening 
is defined as repeating the screening procedures or tests within the original screening window. A 
new informed consent is not required and subject shall maintain the same subject number as 
originally assigned. 
6.3.2 Treatment Assignment 
All subjects in the study will receive zanubrutinib. 
6.3.3 Treatment Blinding 
This is an open-label study. 
6.4 
Dosage and Administration 


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Zanubrutinib will be dispensed by the study center personnel on Day 1 of each cycle (every 
4 weeks) during the first year and Day 1 of every other cycle thereafter (every 8 weeks starting on 
cycle 13).  Subjects will be provided with an adequate supply of study drug for self-administration 
at home.  The investigator should instruct the subject to take the study drug exactly as prescribed.  
Subjects will be requested to bring their unused medication including empty packaging to the center 
at each visit.  All dosages prescribed and dispensed to the subject and all 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, with a minimum of 8 hours between consecutive doses.  Zanubrutinib will be taken 
daily from Cycle 1 Day 1 until disease progression, unacceptable toxicity or death, withdrawal of 
consent, or the study is terminated by the sponsor for final analysis. Zanubrutinib capsules should 
not be opened, broken, or chewed at any time. 
Subjects will be advised that if a dose of the study drug is not taken at the scheduled time, they 
should take the missed dose as soon as they remember and return to the normal schedule for the 
next dose.  Subjects should skip the missed dose if it is 4 hours or less to the next scheduled dose.  
An extra dose of the study drug should not be taken to make up for the missed dose. 
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) and non-hematologic toxicities (Section 6.5.2). 
Table 1  
Zanubrutinib Dose Reduction Steps 
Dose Level 
Zanubrutinib Dose 
0 = starting dose 
160 mg BID 
-1 dose level 
80 mg BID 
-2 dose level 
80 mg QD 
BID= twice a day QD=once a day 
Study drug may be held for a maximum of 28 consecutive days.  If, in the investigator’s opinion, it 
is in the subject’s best interest to restart treatment after more than 28 days, then written approval 
must be obtained from the sponsor medical monitor. 
6.5.1 Dose Reductions for Hematologic Toxicity 


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Dosing will be held for individual subjects under any of the following conditions:  
• Grade 4 neutropenia (lasting >7days, however, earlier interruption acceptable if medically 
indicated)  
• Grade 4 thrombocytopenia (lasting >7days, however, earlier interruption acceptable if 
medically indicated)  
• >Grade 3 febrile neutropenia 
• >Grade 3 thrombocytopenia associated with bleeding 
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, subjects will restart at one dose 
level lower upon recovery of the toxicity to ≤ Grade 1 or baseline. A maximum of 2 dose reductions 
will be allowed. Subjects 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. Subjects with 
treatment-related lymphocytosis should remain on study treatment and continue with all study-
related procedures. For fever associated with neutropenia, take medical history, perform physical 
examination, and the relevant imaging, and blood, body fluid cultures to ascertain cause of 
infection, and administer anti-infective therapy as per hospital guidelines. Growth factor use should 
be considered as per investigator judgement. 
6.5.2 Dose Reductions for Non-Hematologic Toxicity 
For non-hematological toxicities ≥ Grade 3, other than hypertension that is 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 
the original dose level. If the event recurs at ≥ Grade 3, drug will be held until recovery to ≤ Grade 1 
or baseline and restarted at Dose Level -1.  If the event recurs at ≥ Grade 3, drug will be held until 
recovery to ≤ Grade 1or baseline and restarted at Dose Level -2.  If the event recurs at ≥ Grade 3 at 
Dose Level -2, the subject will be discontinued from study treatment. For subjects experiencing 
atrial fibrillation that is symptomatic and/or incompletely controlled: after 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. 
6.6 
Concomitant Medications and Non-Drug Therapies 
6.6.1 Permitted Medications 
All concomitant medications taken during the study will be recorded in the eCRF with indication 
and dates of administration.  Tumor Lysis Syndrome (TLS) has not been reported with zanubrutinib 
treatment, but has been reported rarely with ibrutinib.  Subjects with high tumor burden should be 


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monitored closely and prophylactic measures, including allopurinol, may be instituted per 
institutional standards. 
6.6.2 Prohibited Medications 
Subjects should not receive other anti-cancer therapy (cytotoxic, biologic, Chinese herbal 
medications or hormones, other than for replacement) while on treatment in this study.  Other 
anti-cancer 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.   
Drugs known to prolong the QT/QTc interval are prohibited, in accordance with FDA Guidance for 
Industry:  E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs.  A link to a list of drugs with QTc prolongation potential is provided 
through the Arizona Center for Education and Research on Therapeutics (CERT; “Drugs That 
Prolong the QT interval and/or Induce Torsades de Pointes”):  http://www.azcert.org/medical-
pros/drug-lists/drug-lists.cfm and is provided in Appendix 2. 
The primary metabolic pathway for zanubrutinib involves the CYP3A isoform.  The 
compounds/substances presented in Appendix 4 are either strong CY3A4 inhibitors or inducers 
which are prohibited in the current study.  When treatment with a strong CYP3A4 inhibitor or 
inducer becomes medically necessary during the study, and an acceptable alternative medication is 
not available, consultation with the sponsor medical monitor is required.  Subjects are allowed to 
take moderate CY3A4 inhibitors but need to be closely monitored.   Please refer to the drug-drug 
interaction (DDI) database from Indiana University, the University of Washington, and FDA for 
more information. 
6.6.3 Medications to be used with Caution 
Zanubrutinib is a moderate inhibitor of human CYP isoenzyme CYP2C8 (IC50 = 4.03 M), 
CYP2C9 (IC50 = 5.69 M), and CYP2C19 (IC50 = 7.58 M).  Although unlikely to reach the drug 
concentration that could cause significant inhibition of these CYP enzymes in clinic, investigators 
should be aware that zanubrutinib has the potential to interfere with the appropriate metabolism of 
medications that rely on CYP2C8, CYP2C9, and CYP2C19.  Examples of these medications 
include, but are not limited to those listed in Appendix 5 and these should be used cautiously with 
the monitoring of drug concentrations where appropriate.  Please refer to the DDI database from 
Indiana University, the University of Washington, and FDA for updated information and Appendix 
5. 


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6.7 
Discontinuation of treatment and premature withdrawal 
When the study drug is permanently discontinued regardless of reason, the subject will have an End 
of Treatment (EOT) visit within 7 days of stopping study drug. A visit should be scheduled as soon 
as possible, at which time all of the assessments listed for the End of Treatment (EOT) visit will be 
performed (see Table 2). The reason for discontinuation from treatment will be recorded on eCRF. 
6.7.1 
Discontinuation of treatment  
Subjects may discontinue study drug for one of the following reasons: 
• Death  
• Disease progression 
• Adverse event(s) 
• Pregnancy 
• Drug interruption >28days  
• Subject withdrew consent 
All subjects who discontinue study drug will have a safety follow-up visit approximately 30 days after 
the last dose of study drug to collect AEs and SAEs that may have occurred after the subject 
discontinued from the treatment.  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 
will only be performed if the subject had an ongoing laboratory abnormality at the previous visit 
which the investigator considered to be related to study drug. If the subject is unable to return to the 
clinic and no laboratory assessment is necessary, the investigator or his/her designee will contact the 
subject or caregiver to collect this information.  
Subjects who are discontinued from study drug for any reason (i.e. AE or administrative reasons 
etc.) other than disease progression should not be considered withdrawn from the study. They will 
continue to be followed for efficacy evaluations per protocol schedule until subject exhibits first 
progression, starts new anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or study 
termination from sponsor, whichever occurs first. If subjects refuse to return for these visits or are 
unable to do so, every effort should be made to contact them or retrieve information by telephone to 
determine the subject’s disease status and survival.  
Subjects may voluntarily withdraw from the study (i.e. withdraw consent) or be dropped from it at 
the discretion of the investigator at any time. Subjects lost to follow up should be recorded as such 
on the CRF. For subjects who are lost to follow-up, the investigator should demonstrate "due 
diligence" by documenting in the source documents steps taken to contact the subject, e.g., dates of 
telephone calls, registered letters, etc. 
6.7.2 
Early Termination 
• Study termination by sponsor 
• Protocol violation 
• If zanubrutinib is on market, sponsor can transfer patient onto marketed drug 


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BGB-3111-207                                                     CONFIDENTIAL 
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• Lost to follow-up 
7 
STUDY ASSESSMENTS 
7.1 
Study Flow and Visit Schedule 
The study-specific assessments and procedures are shown in Table 2.   


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BGB-3111-207                                                                                       CONFIDENTIAL 
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Table 2  
Study Assessment and Procedure Schedule for Study BGB-3111-207 
 
Pre-
treatment 
Treatment 
All cycles are 28 days (4 weeks) in duration 
End of Study Assessments 
 
Screenin
g  
Cycle 1 
Cycle 2 
Cycle 3 to 
Cycle 13 (Every 
4 weeks)  
Cycle 15, Cycle 17, 
Cycle 19, etc… 
(Every 8 weeks) 
EOT 
Safety Follow-
up Visit 
Survival 
Follow-
up 
Day of cycle 
-28 
to -1 
Day 1 
Day 1 (+/-
3 days) 
Day 1 (+/- 3 
days)  
Day 1 (+/- 7 days) 
(Within 7 days 
after stopping 
treatment) 
30 ± 7 days 
after last dose 
of study drug 
Every 
3 months 
± 7 days 
Visit 
0 
1 
2 
3, 4, 5, etc.… 
 
 
 
 
Informed consent 
X 2 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 3 
 
 
 
 
 
 
 
Demography 
X 4 
 
 
 
 
 
 
 
Medical/surgical history/current medical 
conditions 
X 5 
 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 6 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
12-lead ECG 7 
X7  
X 7 
 
 
 
X 
 
 
Lipid panel 
X 8 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
Height (in cm) 
X 
 
 
 
 
 
 
 
Weight (in kg) 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs and physical examination 
(including assessment of B symptoms and 
liver and spleen enlargement) 
X 9 
X 
X 
X 
X 
X 
X 
 
Hematology 10 
X 
X 
X 
X 
X 
X 
 
 
Chemistry 10 
X 
X 
X 
X 
X 
X 
 
 
Coagulation 10 
X 
X 
 
 
 
 
 
 
Urinalysis (macroscopic; microscopic if 
required) 10 
X 
X 
X 
X 
X 
X 
 
 
Hepatitis B/C testing and HIV testing 10 
X 
 
 
 
 
 
 
 
Urine or serum pregnancy test (if applicable)   
X10 
X 
X 
X 
X 
X 
 
 


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BGB-3111-207                                                                                       CONFIDENTIAL 
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Pre-
treatment 
Treatment 
All cycles are 28 days (4 weeks) in duration 
End of Study Assessments 
 
Screenin
g  
Cycle 1 
Cycle 2 
Cycle 3 to 
Cycle 13 (Every 
4 weeks)  
Cycle 15, Cycle 17, 
Cycle 19, etc… 
(Every 8 weeks) 
EOT 
Safety Follow-
up Visit 
Survival 
Follow-
up 
Day of cycle 
-28 
to -1 
Day 1 
Day 1 (+/-
3 days) 
Day 1 (+/- 3 
days)  
Day 1 (+/- 7 days) 
(Within 7 days 
after stopping 
treatment) 
30 ± 7 days 
after last dose 
of study drug 
Every 
3 months 
± 7 days 
Study drug administration 11 
 
X 
X 
X 
X 
 
 
 
Bone marrow biopsy/aspiration 12 
X 
At time of CR 
 
 
 
Endoscopy 13 
 
At time of CR 
 
 
 
Echocardiogram14 
X 
 
 
 
 
Imaging 15 
 
 
 
 
PET+contrast CT scan 
X 
At week 12, week 24, and at time of CR 
 
 
 
CT scan with contrast of neck/chest/abdomen 
and pelvis (or MRI) 
X 
At week 36 and week 48, then every 16 weeks after week 48 
 
 
 
Brain CT/MRI scan with contrast 
As clinically indicated 
 
 
 
Concomitant medications 
Throughout 
 
AEs/SAEs 
Throughout 
 
Antineoplastic therapies since discontinuation 
of study drug 
 
 
 
 
 
 
X 16 
X 16 
Survival follow-up 17 
 
 
 
 
 
 
 
X 
Tumor tissue collection for biomarkers 18 
X 
 
 
 
 
 
 
 
Abbreviations:  AEs: adverse events; CR:  complete response; CT:  computed tomography; ECG:  electrocardiogram; ECOG:  Eastern Cooperative Oncology 
Group; EOT:  End of Treatment; MRI:  magnetic resonance imaging; PET: positron emission tomography; SAEs: serious adverse events; X:  to be performed  


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BGB-3111-207                                                                                       CONFIDENTIAL 
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Windows:  days allowed for reschedule of an entire visit due to logistical reasons (eg, Public Holidays).  These are:  ECOG, weight, vital signs, physical 
examination (including B symptoms), hematology, clinical chemistry, lipid panel, urinalysis, concomitant medications, AEs/SAEs, pregnancy test, and study 
drug administration.     
Assessments scheduled on Cycle 1 Day 1 should be performed prior to the administration of the first dose of zanubrutinib.  Screening blood and urine tests 
performed within 72 hours of the first administration of study drug do not need to be repeated on Cycle 1 Day 1. 
1. Screening evaluations will be performed and completed within 28 days prior to the first dose of zanubrutinib.  The results of all screening assessments 
and evaluations must be completed and reviewed by the investigator prior to the Cycle 1 Day 1.   
2. Written informed consent form(s) must be signed by the subject before any study-specific procedures are performed. 
3. The investigator will review and ensure that the subject meets all of the inclusion and none of the exclusion criteria.  
4. Demography includes gender and date of birth (or age). 
5. Relevant medical history (ie. previous diagnoses, diseases or surgeries) not pertaining to the study indication, started before signing the informed 
consent, and considered relevant for the subject’s study eligibility, and current medical conditions. 
6. Other background information including history of disease and current disease status, staging, bone marrow involvement, sites of disease, prior 
anticancer therapies, and prior medications/significant non-drug therapies will be collected.  
7. Perform a 12-lead ECG in triplicate at screening and EOT.  Subjects should be in the semi-recumbent or supine position.  
8. Lipid panel includes cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides performed at screening only. 
9. A complete or targeted physical examination, vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, temperature, and 
respiratory rate), weight, and B symptoms examination will be performed at the time points specified.  Complete physical exam includes assessments of 
cardiovascular, respiratory, abdominal and neurological systems as well as lymph nodes /spleen, skin, oropharynx, and extremities.   Targeted physical 
exams should be limited to systems of clinical relevance (ie, cardiovascular, respiratory, lymph nodes, liver, and spleen), and those systems associated 
with clinical signs/symptoms.  Clinical suspicion of disease progression at any time will require a physical examination to be performed promptly, rather 
than waiting for the next scheduled radiological assessment.  B symptoms includes unexplained weight loss > 10% over previous 6 months, fever 
(>38°C), and/or drenching night sweats. If the physical examination is not completed +/- 7 days of the radiological tumor assessment, a separate 
physical examination should be performed. 
10. Laboratory assessments include the following:  
a. 
Screening laboratory tests performed within 72 hours of the first administration of study drug do not need to be repeated on Cycle 1 Day 1. 
b. Hematology, including red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, absolute differential count 


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BGB-3111-207                                                                                       CONFIDENTIAL 
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(neutrophils, eosinophils, lymphocytes, monocytes, basophils, blasts) and platelet count.  In the event of neutropenia (absolute neutrophil count 
< 1000/mm3) or thrombocytopenia (platelets of less than 75,000/mm3), these assessments will be conducted as frequently as the investigator 
feels it necessary and until toxicity resolves to ≤ Grade 2 or baseline (ANC ≥ 1000/ mm3). 
c. 
Clinical chemistry includes sodium, potassium, chloride, bicarbonate, fasting glucose, blood urea nitrogen (BUN), creatinine, calcium, 
phosphate, magnesium, total bilirubin, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate 
dehydrogenase (LDH), alkaline phosphatase and uric acid.  In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be 
conducted as frequently as the investigator feels it necessary and until toxicity resolves to ≤ Grade 2.  
d. Coagulation profile will be performed at screening and Cycle 1 Day 1, and includes activated partial thromboplastin time (APTT) (screening 
only) and prothrombin time (PT), which will also be reported as international normalized ration (INR).  
e. 
Hepatitis B/C serologic markers and viral load will be tested.  The hepatitis B testing includes HBsAg, HBcAb, and HBsAb as well as hepatitis 
B virus (HBV) DNA by PCR if the subject is negative for HBsAg but HBcAb positive (regardless of HBsAb status). If HBV DNA is lower 
than 1000 IU/mL or normal value, subjects will be enrolled and screened for HBV DNA every month or every 3 cycles for patients receiving 
anti-viral therapy. The hepatitis C testing includes Hepatitis C virus (HCV) antibody as well as HCV RNA by PCR if the patient is HCV 
antibody positive. If HCV RNA is lower than normal value, subjects will be enrolled and screened for HCV DNA every month or take anti-
viral therapy. Subjects with positive HBsAg and/or detectable level of HBV DNA or detectable level of HCV RNA are not eligible. 
f. 
Urinalysis will be assessed using urine dipstick.  Urine microscopy will be performed if urine dipstick is abnormal.  Urinalysis includes pH, 
glucose, and protein.  If urine protein is ≥2+ by dipstick, a 24-hour urine for total protein and creatinine will be obtained and evaluated. 
g. All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
11. Subjects will receive zanubrutinib at a dosage of 160 mg (two - 80 mg white opaque capsules) orally twice daily.  Zanubrutinib will be administered on 
a 28-day cycle and will continue until disease progression, unacceptable toxicity, death, withdrawal of consent, or discontinuation from the study for any 
reason.  All subjects will have an end of treatment (EOT) visit within 7 days after stopping study drug.  All subjects will have a follow-up visit 
30 ± 7 days after the last dose of the study drug to collect AEs and SAEs that may have occurred after the subject discontinued from the study.  The 
investigator or his/her designee will also continue to collect information on new anticancer therapy given after the last dose of study drug. 
12. A bone marrow aspiration and biopsy must be performed at screening for all subjects if not performed within 60 days of first dose.  In those subjects 
who had evidence of bone marrow disease at the time of enrollment, upon achieving a possible CR (eg, physical exam or CT scan indicating a possible 


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BGB-3111-207                                                                                       CONFIDENTIAL 
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CR), a bone marrow aspirate and biopsy will be obtained to confirm the CR.  
13. Gastrointestinal endoscopy must be performed to confirm CR for any subject with a documented history of gastrointestinal involvement.  
14. An echocardiogram to be performed at screening; an echocardiogram performed within 30 days of first dose can be substituted. 
15. CT scans should encompass neck, chest, abdomen, and pelvis and include oral and intravenous contrast.  A brain scan is required if clinically indicated.  
In all cases, an MRI may be used in place of CT only for anatomic lesions which cannot be adequately visualized by CT, or for subjects who cannot 
undergo CT.  All efforts will be made to ensure that the imaging equipment, contrast agent, and person (investigator or radiologist) performing the 
evaluation is kept constant throughout a subject’s course on study.  Tumor response will be assessed according to 2014 International Working Group in 
NHL (Appendix 3).  Tumor assessment by PET and contrast CT scan at screening, 12 weeks, and 24 weeks will be performed. If subjects do not have 
PET-avid disease at screening, contrast CT will be performed after screening. Subjects will be performed contrast CT scan at week 36 and week 48; 
thereafter, contrast CT scan every 16 weeks until disease progression or end of study, whichever comes first. Complete response should be confirmed by 
PET and CT for subjects who had PET-avid disease during screening.  In subjects with bone marrow tumor involvement prior to study drug, CR should 
be confirmed by bone marrow biopsy.  Unscheduled response assessments may be performed based on physical examination or laboratory findings, at 
the discretion of the investigator.  Clinical suspicion of disease progression at any time will require radiological confirmation to be performed promptly, 
rather than waiting for the next scheduled radiological assessment. 
16. The investigator or his/her designee will also continue to collect information on new anticancer therapy given after the last dose of study drug. 
17. Survival information will be collected via telephone call every 3 months ± 7 days after the subject’s last visit until after the subject’s last visit until 
withdrawal of consent, lost to follow-up, death, or the date of data cutoff for the final analysis. The investigator or his/her designee will also continue to 
collect information on new anticancer therapy given after the last dose of study drug. 
18. For all subjects, fresh tumor biopsy or recent tumor tissue samples (within 2 years of study entry) will be collected. Either a formalin-fixed paraffin-
embedded block with tumor tissue or at least 10 unstained slides (5 µm) should be sent to the central laboratory for genetic biomarker analysis. For 
subjects without sufficient tumor samples for genetic biomarker analysis, tumor tissue biopsy can be used as replacement. For subjects with accessible 
tumor site and in agreement with tumor tissue biopsy, tumor tissue biopsy will be performed at screening. The detailed information of tumor tissue 
collection will be described in lab manual. 




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7.3 
Efficacy 
Response will be evaluated using the 2014 International Working Group in NHL criteria (Appendix 
3).  
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in Table 2, 
based on physical examination, radiological assessment and bone marrow biopsy (to confirm 
complete responses in subjects with bone marrow tumor involvement prior to study drug). Tumor 
assessment by PET and CT (with contrast) at screening, 12 weeks, and 24 weeks will be performed. 
CT (with contrast) will be performed at week 36 and week 48, and thereafter, every 16 weeks until 
disease progression or end of study, whichever comes first. 
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 case of an unscheduled or delayed tumor assessment for any reason, 
subsequent tumor assessments must be performed according to the originally planned schedule from 
baseline. 
Complete responses should be confirmed by positron emission tomography (PET) and contrast CT 
in subjects who had PET-avid disease at screening, by endoscopy for any subjects with a 
documented history of gastrointestinal involvement, and by bone marrow biopsy in these subjects 
with bone marrow tumor involvement prior to study drug.  
7.3.1 Physical Examination 
Evaluation of disease related B symptoms (unexplained fever of ≥ 38°C; unexplained, recurrent 
drenching night sweats; or unexplained loss of >10% body weight within the previous 6 months) 
and enlargement of liver and spleen is included in the physical examination at each visit.  If the 
physical examination is not completed ± 7 days of the radiological tumor assessment, a separate 
physical examination should be performed.  
7.3.2 Radiological Tumor Assessment 
Baseline radiological tumor assessment should be performed within 28 days of the first dose.  
Tumor assessment by PET and CT (with contrast) at screening, 12 weeks, and 24 weeks will be 
performed. CT (with contrast) will be performed at week 36 and week 48, and thereafter, every 
16 weeks until disease progression or end of study, whichever comes first. Complete responses 
should be confirmed by positron emission tomography (PET) and contrast CT in subjects who had 
PET-avid disease at screening, by endoscopy for any subjects with a documented history of 
gastrointestinal involvement. CT of the brain is only indicated if clinical findings or symptoms 


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suggest CNS involvement. Subjects will be treated by the investigator according to the local 
radiologist’s assessments. 
A CT scan of diagnostic quality performed as part of PET/CT is required, provided bi-dimensional 
nodal and liver/spleen measurements can be made.  An MRI may be used in place of CT only for 
anatomic lesions which cannot be adequately visualized by CT, or for subjects who cannot undergo 
CT.  All efforts will be made to ensure that the imaging equipment, contrast agent, and person 
(investigator or radiologist) performing the evaluation is kept constant throughout a subject’s course 
on study.   
All CT scans, MRIs, PET scans, and PET/CT scans obtained during the study will be collected and 
archived.  De-identified copies of all scans and radiology reports (including those from screening) 
must be provided to the sponsor or designee (eg, central imaging vendor). 
7.3.3 Bone Marrow Assessment 
A unilateral bone marrow aspirate and biopsy must be performed at screening if not performed 
within 60 days of the first dose for all subjects, provided there has been no intervening therapy 
between the time of the biopsy and start of study drug.  In those subjects who had evidence of bone 
marrow disease at screening, upon achieving a possible CR (eg, physical exam or CT scan 
indicating a possible CR), a bone marrow aspirate and biopsy should be obtained to confirm the CR.  
Testing will be performed at the study center’s local laboratory.  De-identified copies of all bone 
marrow biopsy/aspirate results must be provided to the sponsor or designee. 
7.3.4 Endoscopy 
Gastrointestinal endoscopy must be performed to confirm CR for any subject with a documented 
history of gastrointestinal involvement.  
7.4 
Safety 
Safety assessments should be performed at all visits to the study center and throughout the study.  
The list of events and the time when they will be performed are presented in Table 2. 
7.4.1 Adverse Events 
 All AEs and SAEs, regardless of the relationship to the study drug, will be collected from the time 
of subject informed consent. All subjects will be followed for safety 30 additional days after the last 
dose of study drug.  All treatment-related AEs and SAEs will be followed until resolution or 


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BGB-3111-207                                                     CONFIDENTIAL 
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stabilization. The accepted regulatory definition for an AE is provided in Section 9.1.  Important 
additional requirement for reporting SAEs are explained in Section 9.2.  
7.4.2 Physical Examination, Vital Signs, Height, and Weight 
A complete or targeted physical examination, vital signs (sitting blood pressure, pulse rate, body 
temperature, and respiratory rate), weight, and B symptoms examination will be performed at each 
study visit.  Height (cm) is determined at screening/baseline only.  B symptoms includes 
unexplained weight loss > 10% over previous 6 months, fever (>38°C), and/or drenching night 
sweats. 
A complete physical exam includes assessments of cardiovascular, respiratory, abdominal and 
neurological systems as well as lymph nodes/spleen, skin, oropharynx and extremities.  Targeted 
physical exams should be limited to systems of clinical relevance (ie, cardiovascular, respiratory, 
lymph nodes, liver, and spleen), and those systems associated with clinical signs/symptoms.  A 
targeted physical exam will be at all visits except where a complete physical exam is required for 
screening/baseline.  
If the physical examination is not completed ± 7 days of the radiological tumor assessment, a 
separate physical examination should be performed. 
7.4.3 ECOG Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed at the Screening Visit, 
each visit during study treatment, and at End of Treatment Visits.  Appendix 6 will be used to assess 
performance status.  
7.4.4 Echocardiogram 
An echocardiogram is to be performed at screening unless one has been performed within 30 days 
of first dose. 
7.4.5 Laboratory Evaluations 
Laboratory assessments should be performed at a local certified laboratory. Clinical chemistry, 
hematology, coagulation and urinalysis will be performed at the time points specified in Table 2, 
and may also be performed as medically necessary.  On Cycle 1 Day 1, laboratory assessments 
should be done before the study drug administration.  Screening blood and urine tests were 


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BGB-3111-207                                                     CONFIDENTIAL 
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performed within 72 hours of the first study drug administration do not need to be repeated on 
Cycle 1 Day 1.   
7.4.5.1 
Hematology 
Hematology includes hemoglobin, hematocrit, reticulocyte, platelet count, red blood cell (RBC) 
count, white blood cell (WBC) count with differential including neutrophils (including bands), 
lymphocytes, monocytes, eosinophils, and basophils. In the event of neutropenia (absolute 
neutrophil count < 1,000/mm3) or thrombocytopenia (platelets of less than 75,000/mm3), these 
assessments will be conducted as frequently as the investigator feels it necessary and until toxicity 
resolves to ≤ Grade 2 baseline (ANC sm 1,000/ mm3). 
7.4.5.2 
Clinical Chemistry 
Clinical chemistry includes albumin, alkaline phosphatase, AST, ALT, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, fasting glucose, LDH, magnesium, phosphate, 
potassium, sodium, total bilirubin, total protein, and uric acid.  In the event of ≥ Grade 3 clinical 
chemistry toxicity, these assessments will be conducted as frequently as the investigator feels it 
necessary and until toxicity resolves to ≤ Grade 2.  
7.4.5.3 
Serum Lipid Profile 
Lipid panel includes cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), 
and triglycerides will be performed at screening only. 
7.4.5.4 
Coagulation 
The coagulation profile includes APTT (screening only) and prothrombin time (PT), which will also 
be reported as international normalized ratio (INR).  The coagulation profile will be performed at 
screening and on Cycle 1 Day 1. 
7.4.5.5 
Urinalysis 
Urinalysis will be assessed using urine dipstick.  Urine microscopy will be performed if urine 
dipstick is abnormal. Urinalysis 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. 
7.4.5.6 
Pregnancy test 
A serum pregnancy test will be performed at screening and end of treatment in women of 
childbearing potential.  Any female subject who is pregnant will not be eligible for the study.  Urine 
pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.  A subject who has a positive pregnancy 


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test result at any time after the study drug administration will be immediately withdrawn from 
participation in the study.  
7.4.5.7 
Hepatitis B/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 hepatitis B virus (HBV) DNA by polymerase chain 
reaction (PCR) if the subject is negative for HBsAg but HBcAb positive (regardless of HBsAb 
status). The hepatitis C testing includes Hepatitis C virus (HCV) antibody as well as HCV RNA by 
PCR if the subject is HCV antibody positive. Subjects with positive HBsAg and/or detectable level 
of HBV DNA or detectable level of HCV RNA are not eligible. Subjects HBsAg negative, HBcAb 
positive and HBV DNA negative must undergo monthly HBV DNA screening PCR.  Subjects 
positive for HCV antibody but negative for HCV RNA must undergo monthly HCV RNA 
screening. Subjects with known HIV are excluded from the study. 
Table 4 shows how the results for HIV, HBV, and HBV testing at screening relate to inclusion and 
exclusion criteria 
Table 4  
HBV, HCV, and HIV Testing for Inclusion/Exclusion 
Inclusion 
Exclusion 
HIV 
Antibody (-) 
Antibody(+)         
HBV 
HBsAg (-)  
HBsAg (+) 
HBsAg (-) 
HBcAb (+) 
HBV DNA<1000 IU/mL, 
Monitor monthly, or initiate 
anti-HBV therapy。 
HBsAg(-) 
HBcAb(+)  
 HBV DNA≥1000 IU/mL 
HCV 
Antibody (-) 
 
 
 
Antibody (+) 
HCV RNA<1 (log10IU/mL), 
monitor monthly, or anti-
HCV therapy 
Antibody(+) 
HCV RNA≥1 (log10IU/mL) 
7.4.6 Electrocardiogram  
Perform a 12-lead ECG in triplicate at screening and EOT. Subjects should be in the semi-
recumbent or supine position. 
7.5 
Biomarkers 
7.5.1 
Predictive Biomarkers 
For all subjects, fresh tumor biopsy or recent tumor tissue samples (in 2 years) will be collected. 
Either a formalin-fixed paraffin-embedded block with tumor tissue or at least 10 unstained slides (5 
µm) should be sent to the central laboratory for genetic biomarker analysis. For subjects without 
sufficient tumor samples for genetic biomarker analysis, tumor tissue biopsy can be used as 
replacement. For subjects with accessible tumor site and in agreement with tumor tissue biopsy, 


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BGB-3111-207                                                     CONFIDENTIAL 
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tumor tissue biopsy will be performed at screening. The detailed information of tumor tissue 
collection will be described in lab manual. 
7.6 
Appropriateness of Measurements 
All safety assessments used in this study are standard, ie, are widely used and generally recognized 
as reliable, accurate, and relevant.  
 
 


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8 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.  Site audits will 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.   
8.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by International 
Conference on Harmonisation (ICH) guidelines, the CRF is a printed, optical, or electronic 
document designed to record all of the protocol-required information to be reported to the sponsor 
on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF. The investigator or designee as identified on Form FDA 1572 
must sign the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs 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 software applications used in the collection of data will be properly validated following standard 
computer system validation that is compliant with all regulatory requirements.  All data, both CRF 
and external data (eg, laboratory data), will be entered into a clinical system. 
The Data Management Plan defines and documents the procedures necessary to ensure data quality.  
These activities must be followed to ensure that data are properly entered, validated, coded, 
integrated, reconciled, and reviewed. 
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 
Organization Drug Dictionary (WHO-DD).  Concomitant diseases/medical history will be coded 
using the MedDRA Version 18.1 or higher. 


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BGB-3111-207                                                     CONFIDENTIAL 
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8.3 
Quality Assurance 
To ensure compliance with Good Clinical Practice (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. 
 
 


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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.  During the study, when there is a 
safety evaluation, the investigator or study center personnel will be responsible for detecting AEs 
and SAEs, as detailed in this section of the protocol.  All AEs and SAEs, regardless of the 
relationship to the study drug, will be collected from the time of subject informed consent, and until 
resolution or stabilization of all study drug related AEs.  
9.1 
Adverse Events 
9.1.1 Definitions and Reporting 
An AE is an untoward medical occurrence in a clinical investigational subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
An AE can therefore be 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. 
Examples of an AE include: 
• Significant or unexpected worsening or exacerbation of the condition/indication under study.   
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions 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.  
• Significant failure of expected pharmacological or biological action.   
Examples of an AE do not include: 
• Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to the 
procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 


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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
When an AE or 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 AE or SAE in the eCRF.  It is not 
acceptable for the investigator to send photocopies of the subject’s medical records to the sponsor in 
lieu of completion of the appropriate AE or SAE eCRF pages.  However, there may be instances 
when copies of medical records for certain cases are requested by the sponsor.  In this instance, all 
subject identifiers will be blinded on the copies of the medical records prior to submission to the 
sponsor. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  In such cases, the diagnosis should be documented as the AE or SAE 
and not the individual signs/symptoms. Adverse events are independent components of the study.   
9.1.1.1 
Period and Method of Detecting AEs and SAEs 
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 study drug.  
The Investigator or designee will ask 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.  All AEs and SAEs will be reported in 
the eCRF. 
9.1.1.2 
Assessment of Severity 
The investigator will make an assessment of severity for each AE and SAE reported during the 
study.  When applicable, AEs and SAEs should be assessed and graded based upon the NCI CTCAE 
v4.03.   


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9.1.1.3 
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 clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study drug will be considered and 
investigated.  The investigator will also consult the IB and/or Product Information, 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 an assessment of causality for every event prior to transmission of the SAE eCRF to 
the sponsor.  The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE eCRF accordingly.  The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
Investigators must also systematically assess the causal relationship of AEs to IMP(s)/study 
treatment (including any other non-IMPs, radiation therapy, etc.) using the following definitions.  
• 
Definitely 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 subject’s medical history, 
concurrent medical condition, or other the subject’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 (e.g., the event 
occurred within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). 
• 
Unlikely related: There is little evidence to suggest there is a causal relationship.  There is 
another reasonable explanation for the event. 
• 
Not related: An adverse event will be considered “not related” to the use of the product if any 
of the following tests are met:  


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o An unreasonable temporal relationship between administration of the product and the onset 
on the AE (e.g., the event 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 (e.g., death 
as a passenger in an automobile accident); 
o A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event). 
 
9.1.1.4 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each subject 
and provide further information to the sponsor on the subject’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, until the condition stabilizes, until the event is 
otherwise explained, or until the subject 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 health care professionals. 
The sponsor may request that the investigator perform or arrange 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 subject 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.  
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 resent to 
the sponsor within the time frames outlined in Section 9.2.2.1. 
9.1.2 Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, hematology, coagulation, urinalysis) or other 
abnormal assessments (eg, ECGs, X-rays, vital signs, etc.) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE (as 
defined in Section 9.1) or an SAE (as defined in Section 9.2).  Clinically significant abnormal 


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laboratory findings or other abnormal assessments that are detected during the study or are present 
at baseline and significantly worsen following the start of the study will be reported as AEs or 
SAEs.  However, clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with the disease being studied, unless judged by the investigator as more severe 
than expected for the subject’s condition, or that are present or detected at the start of the study and 
do not worsen, will not be reported as AEs or SAEs. 
The investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
9.1.2.1 
Post-study Adverse Events and Serious Adverse Events 
A post-study AE or SAE is defined as any event that occurs outside of the AE/SAE detection 
period, defined in Section 9.1.1.1 
Investigators are not obligated to actively seek AEs or SAEs in former subjects.  However, if the 
Investigator learns of any SAE, including a death, at any time after a subject has been discharged 
from the study, and he/she considers the event reasonably related to the investigational product, the 
Investigator will promptly notify the Sponsor or designee. 
9.1.3 AE due to disease progression 
Adverse events that are clearly consistent with the expected picture of progression of the underlying 
disease (e.g., new metastases or transformation to more aggressive histology) should NOT be 
recorded as adverse events. They should be recorded on CRF as efficacy data, not reported as 
adverse events.  
If there is any uncertainty regarding whether an adverse event is due to disease progression, it 
should be reported as an adverse event. 
9.1.4 Adverse Events Secondary to Prior Events 
A medically significant secondary adverse event that is a clinical sequelae of a prior event should be 
reported as an independent event. For example, if a patient has an initial adverse event of cough and 
a few days later the patient develops pneumonia, both events should be reported separately on the 
CRF. If a patient has neutropenia that is followed by a subsequent infection, both events should be 
reported separately. The start date of the former event should be the onset date for that event. The 
start date of the subsequent event should be the onset date for the subsequent event. 
If it is unclear as to whether the events are interrelated, all events should be reported separately on 
CRF. 
9.1.5 Recurrent Adverse Events 


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A recurrent adverse event is an event that resolves and subsequently recurs. All recurrent events 
should be reported separately on CRF. 
9.1.6 Death 
Death is an outcome of an adverse event and the adverse term “death due to {condition}” should 
NOT be reported as an adverse event.  Deaths that occur during the adverse event reporting period 
that are assessed by the investigator as solely to disease progression should be recorded on Study 
Completion or Early Discontinuation CRF. They should not be reported as adverse events. If deaths 
are attributed by the investigator not solely due to disease progression, whether they are assessed as 
related or not related to the study drug, they should be reported as serious adverse events as per the 
timeline stipulated in the 8.2.2.1 timeframes for Submitting Serious Adverse Event. If deaths occur 
outside of the adverse event reporting period, the investigator will promptly notify the sponsor 
according to descriptions provided in Section 9.1.2.1. 
9.2 
Serious Adverse Events 
9.2.1 Definitions 
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 
subject 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 were more severe. 
• Requires hospitalization or prolongation of existing hospitalization. 
NOTE:  In general, hospitalization signifies that the subject 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 out-patient 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. 


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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 (e.g., sprained ankle) which may interfere or prevent everyday life 
functions, but do not constitute a substantial disruption. 
• Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These should also be considered serious.  Examples of such events are invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
• Disease progression should not be reported as an AE/SAE, but symptoms meeting the definition 
of, and associated with, disease progression should be reported. 
9.2.2 Reporting 
9.2.2.1 
Timeframes for Submitting Serious Adverse Events 
Serious adverse events will be reported promptly to the sponsor as described in Table 5 once the 
investigator determines that the event meets the protocol definition of a SAE. 
Table 5  
Timeframe for Reporting Serious Adverse Events to the Sponsor 
Type of SAE 
Initial SAE Report 
Document 
Follow-up SAE Report 
Document 
All SAEs 
24 hours of 
investigator’s 
knowledge 
SAE report 
form/eCRF 
ASAP 
Updated SAE 
report form/eCRF 
SAE:  serious adverse event; eCRF:  electronic case report form 
 
9.2.2.2 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a subject, he/she will report the 
information to the sponsor within 24 hours as outlined in Section 9.2.2.1.  The SAE report form will 
always be completed as thoroughly as possible with all available details of the event, signed by the 
investigator, and forwarded to the sponsor within the designated timeframes.  If the investigator 
does not have all information regarding an SAE, he/she will not wait to receive additional 
information before notifying the sponsor of the event and completing the form.  The form will be 
updated when additional information is received. 


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The investigator will always provide an assessment of causality at the time of the initial report as 
described in Section 9.1.1.2. 
Facsimile transmission of the SAE report form is the preferred method to transmit this information 
to the project contact for SAE receipt.  In rare circumstances and in the absence of facsimile 
equipment, notification by telephone is acceptable, with a copy of the SAE report form sent by 
overnight mail.  Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE report form within the time frames outlined in Section 9.2.2.1. 
The sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, 
and mailing addresses. 
The following pages of the eCRF must accompany the SAE report forms that are forwarded to the 
sponsor: “demography”, “medical history”, “concomitant medications”, “study medication records”, 
and “death form” (if applicable). 
9.2.2.3 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 9.2.2.2.  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 subjects 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 filed to 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.  Such a report is prepared for an SAE that is both 
attributable to study drug and unexpected.  The purpose of the report is to fulfill specific regulatory 
and GCP requirements regarding the product under investigation. 


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When a study center receives an initial or follow-up report or other safety information (eg, revised 
IB) from the sponsor, the responsible person according to local requirements is required to promptly 
notify his/her IRB or IEC.  
9.2.2.4 
Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (eg, procedures, invasive tests), even if it occurs 
during the post-treatment period, will be reported promptly to the sponsor (Section 9.2.2.2). 
9.3 
Pregnancies 
A serum pregnancy test will be performed at Screening in women of childbearing potential.  Any 
female subject 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. 
9.3.1 
Time Point for Collecting Pregnancy Information. 
The time points for collecting information on whether a pregnancy occurs is from Screening until 30 
days after the last investigational product administration.  Information on pregnancies identified 
prior to the investigational product administration does not need to be reported to sponsor. 
9.3.2 
Action to be Taken and Reporting if a Pregnancy Occurs 
A subject 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 subject or a 
female partner of a male subject 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 within 24 hours of learning of a subject’s or male subject’s female partner’s 
pregnancy.  The subject or male subject’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.   
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. 
A spontaneous abortion is always considered to be an SAE.  Furthermore, any SAE occurring 
because of a post-study pregnancy and is considered reasonably related to the study drug by the 
Investigator, will be reported to the Sponsor.  While the Investigator is not obligated to actively seek 
this information in former subjects, he/she may learn of an SAE through spontaneous reporting. 


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9.4 
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). 
9.5 
Safety Monitoring Committee 
All enrolled subjects will be evaluated clinically and with standard laboratory tests during their 
participation in this study.  Safety evaluations will consist of medical interviews, recording of 
adverse events (AEs), physical examinations, and laboratory measurements (hematology, chemistry, 
and urinalysis).  
Subjects will be evaluated for AEs (all grades, according to NCI CTCAE v.4.03) and serious AEs. 
Subjects who, at time of progression, have an ongoing AE that leads to treatment discontinuation 
will be followed until the event resolves, the investigator assesses the event as stable; the subject is 
lost to follow-up, or the subject starts a different anti-tumor therapy. 
A Safety Monitoring Committee (SMC) will monitor safety data periodically throughout the study.  
As the efficacy endpoints require longer length of follow-up to be adequately evaluated, a formal 
interim review of data collected during the study by the SMC will focus on the safety aspects of the 
study.  This early safety review will occur about 3 months after enrollment of the 25th subject.  No 
recruitment stop is planned for this interim safety review.  At the safety review, special attention 
will be paid to significant safety events (SSE).  Subsequent safety data review is outlined in SMC 
charter.  
A SSE is defined as any of the following: 
• General toxicity (NCI CTCAE v.4.03):  Grade 3 and Grade 4 AEs and SAEs 
• Any adverse event that requires dose interruption, reduction or discontinuation of the study 
drug. 
• A subject’s death 
In the case of major toxicity concerns, the SMC can recommend to modify the trial conduct. 


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10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL 
PLAN 
All statistical analyses will be performed by the sponsor or designee after the study is completed and 
the database is locked and released.  Data will be listed and summarized using SAS® Version 9.3 or 
higher (SAS Institute, Inc., Cary, North Carolina) according to sponsor agreed reporting standards, 
where applicable.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP). 
10.1 Primary, Secondary and Exploratory Study Endpoints 
10.1.1 Primary Endpoint 
The primary endpoint of the study is the rate of objective response, defined as the achievement of 
either a partial response (PR) or complete response (CR) by the 2014 modification of the 
International Working Group on Non-Hodgkin’s lymphoma (NHL) Criteria (Cheson et al 2014) 
(Appendix 3) at any time on study drug. 
10.1.2 Secondary Endpoints 
Efficacy: 
• Progression free survival (PFS): defined as time from first dose of zanubrutinib until first 
documentation of progression (by IWG on NHL criteria) or death, whichever comes first. 
• Duration of response (DOR) is defined as the time from the date that the response criteria are 
first met to the date that progressive disease (PD) is objectively documented or death, 
whichever occurs first. 
• Time to response (TTR) is defined as the time from first dose of zanubrutinib to 
documentation of a response. 
Safety: To evaluate the safety and tolerability of zanubrutinib, as defined by: 
• The incidence and severity of treatment-emergent adverse events (TEAEs), SAEs and treatment-
related AEs according to NCI CTCAE v4.03 
• The incidence, severity, and causation of adverse events leading to study drug discontinuation. 
10.1.3 Exploratory Endpoints 


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10.2 Statistical Analysis 
10.2.1 Analysis Populations   
The Safety Population includes all subjects who received any dose of zanubrutinib.  It will be the 
population for the efficacy and safety analyses.   
The Per-Protocol Population (PP) includes subjects who received any dose zanubrutinib and had no 
major protocol deviations. Criteria for exclusion from the PP will be determined and documented 
before the database lock for the primary analysis. This will be the secondary analysis population for 
efficacy analyses.   
10.2.2 Subject Disposition 
The number of subjects enrolled, treated, prematurely discontinued from study drug (defined as 
those who discontinued study drug due to any reason except for progressive disease) and those with 
major protocol deviations will be counted.  The primary reason for study drug discontinued will be 
summarized according to the categories in the eCRF.  The end of study status (alive, death, 
withdrew consent or lost to follow-up) at the data cutoff date will be summarized using the data 
from the eCRF. 
Major protocol deviations will be summarized and listed by each category. 
10.2.3 Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in safety population using 
descriptive statistics.  Continuous variables include age, weight, vital signs, time since initial 
DLBCL diagnosis; categorical variables include sex, age group, disease stage, ECOG-PS, prior line 
of therapy for DLBCL, DLBCL IPI, and Ki67. 
10.2.4 Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes.  Concomitant medications will be further coded to the appropriate 
Anatomical Therapeutic Chemical (ATC) code indicating therapeutic classification.  Prior and 
concomitant medications will be summarized and listed by drug and drug class in the Clinical Study 
Report (CSR) for this protocol.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be 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 ± 7 days after the 


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subject’s last dose.  A listing of prior and concomitant medications will be included in the CSR of 
this protocol. 
10.2.5 Efficacy Analyses 
10.2.5.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is overall response rate (ORR) as determined by investigator review 
using the 2014 International Working Group in NHL criteria (Appendix 3).  ORR is defined as the 
proportion of subjects achieving a best overall response of CR or PR. 
The ORR in this study is estimated as 35%, which is deemed a clinical meaningful improvement.   
Two-sided Clopper-Pearson 95% confidence interval (CI) of ORR will be constructed to assess the 
precision of the rate estimate. No hypothesis testing will be done. 
Best overall response (BOR) is defined as the best response recorded from the start of zanubrutinib 
until data cut or start of new anti-neoplastic treatment.  Subjects with no post-baseline response 
assessment (due to any reason) will be considered non-responders for BOR.  The proportion and its 
corresponding Clopper-Pearson 95% CI for each of the response categories (CR, PR, stable disease 
[SD], and progressive disease [PD]) will be presented. 
The primary efficacy analysis will be conducted approximately 12 months after the first dose of the 
last subject, and will be based on the safety population. 
10.2.5.2 
Secondary Efficacy Analysis 
Progression-free survival (PFS) is defined as the time from the starting date of zanubrutinib to the 
date of first documentation of disease progression or death, whichever occurs first.  Subjects who do 
not have disease progression will be censored at their last valid tumor assessment. 
Kaplan-Meier (KM) method will be used to estimate progression event-free curves and 
corresponding quantiles (including the median).  A two-sided 95% CIs of median, if estimable, will 
be constructed with a generalized Brookmeyer and Crowley method.  The PFS at 6 and 12 months, 
defined as the percentages of subjects in the analysis population who remain alive and progression-
free at the specified time points, will be estimated using the KM method along with the 
corresponding 95% CI constructed using Greenwood’s formula. 
The PFS censoring rule will follow FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007). 
Duration of response (DOR) is defined as the time from the date that the response criteria are first 
met to the date that PD is objectively documented or death, whichever occurs first.  Subjects who do 
not have disease progression will be censored at their last valid assessment. Time to response (TTR) 


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is defined as time from the starting date of zanubrutinib to the date the response criteria are first 
met. 
Time to event variables (DOR and TTR) will be similarly analyzed using the KM method as 
described above.  The KM estimates of DOR and TTR will be plotted over time. 
Sensitivity analysis will be performed for primary and secondary endpoints in the PP population. 
10.2.5.3 
Exploratory Efficacy Analysis 
10.2.5.4 
Subgroup Analysis 
Primary and selected secondary endpoints will be summarized descriptively in the specified 
subgroups: sex, age group (≥60), disease stage, ECOG-PS (0 vs. ≥1), number of prior lines of 
therapy, IPI (<3 vs. ≥3), bulky disease (> 7.5 cm).  Within group values (rates or means/medians) 
will be presented in forest plots.   
10.3 Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by NCI CTCAE v4.03. 
Laboratory values (hematology, clinical chemistry, coagulation, and urinalysis), vital, physically 
examine and ECGs findings will also be used in determining the safety. Descriptive statistics will be 
used to analyze all safety data in the safety population. 
10.3.1 
Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the number of cycles received 
(number and percentage of subjects), duration of exposure (days), cumulative total dose received 
per subject (mg), dose intensity (mg/day) and relative dose intensity. 
The number (percentage) of subjects requiring dose reductions, dose interruption, and drug 
discontinuation due to AEs will be summarized.  The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics.  Frequency of 
reductions and dose interruptions will be summarized.  


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10.3.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into standardized 
medical terminology using Medical Dictionary for Regulatory Activities (MedDRA®).  Adverse 
events will be coded to MedDRA (Version 18.1 or higher) lower level term closest to the verbatim 
term.  The linked MedDRA preferred term (PT) and primary system organ class (SOC) are also 
captured in the database. 
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset date on or after 
the first dose of study drug up to 30 ± 7 days following study drug discontinuation or was worsening 
in severity from baseline (pretreatment).  Only those AEs that were treatment emergent will be 
included in summary tables.  All AEs, treatment emergent or otherwise, will be presented in subject 
data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once by the highest severity grade according to NCI 
CTCAE v4.03 within an SOC and PT, even if the subject experienced more than 1 TEAE within a 
specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized 
by relationship to the study drug.  Treatment-related AEs include those events considered by the 
investigator to be possibly or probably related to study drug or with missing assessment of the 
causal relationship.  Serious adverse events, deaths, TEAE with grade 3 or above, and TEAEs that 
led to treatment discontinuation, dose reduction or dose interruption will be summarized. 
10.3.3 Laboratory Analyses 
Clinical laboratory (ie, hematology, serum chemistry, and qualitative urinalysis) values will be 
evaluated for each laboratory parameter by subject.  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 CSR for this protocol.  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 v4.03 will be summarized by CTCAE grade.  
In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE grading in 


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both high and low directions (eg, calcium, glucose, magnesium, potassium, sodium) will be 
summarized separately. 
10.3.4 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], heart rate, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit for all 
visits.  Vital signs will be listed by subject and visit. 
10.3.5 Electrocardiogram 
Electrocardiogram assessments will be performed at the Screening visit.  Descriptive statistics for 
baseline ECG parameters will be presented.  
10.4 Sample Size Consideration 
Approximately 40 subjects will be enrolled. 
The sample size calculation was based on the level of precision of the estimated ORR. Assuming an 
ORR of 35%, the 95% exact confidence interval will be 20.6% to 51.7%.  
10.5 Interim Analysis 
No interim analysis is planned in this study. 
10.6 Other Statistical Issues 
Not applicable. 
 
 


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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 
appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2 Investigator Responsibilities 
11.2.1 Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” ICH guidelines, and that the basic principles of “Good Clinical Practice,” 
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 participation of the investigator and any sub-investigator. The investigator 
and sub-investigator agree to notify BeiGene of any change reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date that the last 
subject 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 
subjects (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, 


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the approved informed consent form, and any other information that the IEC/IRB has approved for 
presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IEC/IRB has approved 
for presentation to potential subjects is amended during the study, the investigator is responsible for 
ensuring the IEC/IRB reviews and approves, where applicable, these amended documents.  The 
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 new 
subjects consent 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 to the sponsor promptly. 
11.2.3 Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and before undertaking any study-related procedures. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent. 
Informed consent will be obtained before the subject 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 
As indicated in Section 9.1, 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 the conduct of the study at 
his/her 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 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only subject initials, date of birth, 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 subjects screened and for all subjects enrolled in the trial. 


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The investigator agrees that all information received from BeiGene, including but not limited to the 
IB, this protocol, 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 subject enrolled, a CRF 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 subjects who fail to complete the study (even during a pre-randomization screening period if a 
CRF was initiated).  If a subject withdraws from the study, the reason must be noted on the CRF.  If 
a subject is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome. 
11.2.7 Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused study drug.  This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition), subject dispensing records and returned or destroyed study 
product.  Dispensing records will document quantities received from BeiGene and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, subject 
initials, 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 and BeiGene or its representative for destruction 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. 


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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, except those intended to reduce immediate risk to study subjects, may be 
made only by BeiGene. All protocol modifications must be submitted to the IRB/IEC in accordance 
with local requirements. Approval must be obtained before changes can be implemented. 
11.3.2 Study Report and Publications 
A clinical study report 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. 
For multi-center studies, the first publication or disclosure of study results shall be a complete, joint 
multi-center publication or disclosure coordinated by the sponsor.  Thereafter, any secondary 
publications will reference the original publication(s). 
After conclusion of the study and without prior written approval from BeiGene, investigators in this 
study may communicate, orally present, or publish in scientific journals or other scholarly media 
only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the consent of 
BeiGene in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 2 years. 
No such communication, presentation, or publication will include BeiGene’s confidential 
information.  
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation.  The investigator will comply with BeiGene’s request to delete references to its 
confidential information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary. 


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If a written contract for the conduct of the study, which includes publication provisions inconsistent 
with this statement is executed, that contract’s publication provisions shall apply rather than this 
statement.  
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: 
• 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. 
In addition, the sponsor reserves the right to temporarily 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. 


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11.5 Records Retention and Study Files 
11.5.1 Study Files and Retention of Records 
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) subject 
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. 
Subject 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: subject 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 (e.g., 
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 back up 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 of 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 subject, 
appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the sponsor for a 
period up to 1 year for purposes of this study. 
11.6 Provision of Study Results and Information to Investigators 
When the clinical study report 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 subject(s). 
The sponsor will not routinely inform the investigator or subject 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 subject’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 subject’s medical records) will be kept by the investigator and 
other 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: 


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• 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 
subject. 
• 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 subject records needed to verify the 
entries on the CRFs.  The investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of 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 
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 
Agarwa R, Lade S, Liew D, et al. Role of immunohistochemistry in the era of genetic testing in 
MYC-positive aggressive B-cell lymphomas: a study of 209 cases. J Clin Pathol 2016;69:266–270. 
Alizadeh AA, Eisen MB, Davis E, et al. Distinct types of diffuse large B-cell lymphoma identified 
by gene expression profiling. Nature 2000;403:503. 
Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC Is Associated With Poor Prognosis in 
Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab. J Clin Oncol 
2010;28:3360. 
BeiGene Investigator’s Brochure, BGB-3111. Edition 3, document number BGB-3111-012016, 
January 2016. 
Brookmeyer B, Crowley J. A confidence interval for the median survival time, Biometrics 38(1), 
p29-41, 1982. 
Camicia R, Winkler HC, Hassa PO. Novel drug targets for personalized precision medicine in 
relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review. Molecular Cancer 
2015;14:207. 
Cheson BD, et al. Novel targeted agents and the need to refine clinical end points in chronic 
lymphocytic leukemia. J Clin Oncol. 2012 30(23):2820-2. 
Cheson, BD et al. Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014;32:3059–
3068. 
de Jonge AV, Roosma TJ, Houtenbos I, et al. Diffuse large B-cell lymphoma with MYC gene 
rearrangements: Current perspective on treatment of diffuse large B-cell lymphoma with MYC gene 
rearrangements; case series and review of the literature. Eur J Cancer. 2016;55:140-6. 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine. http://medicine.iupui.edu/flockhart/table.htm 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research (2007). 
https://www.fda.gov/downloads/Drugs/NewsEvents/UCM601619.pdf  
Food and Drug Administration Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007). 
https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf  
Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabel
ing/ucm093664.htm 


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Food and Drug Administration Guidance for Industry:  E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073
153.pdf 
Gifford GK, Till AJ, Stevenson WS. Molecular subtyping of diffuse large B-cell lymphoma: update 
on biology, diagnosis and emerging platforms for practicing pathologists. Pathology 2016; 48(1):5–
16. 
Greenwood, M. The natural duration of cancer. Reports on Public Health and Medical Subjects, 
HMSO, London,1926;33:1-26. 
GLOBOCAN 2012: Estimated Cancer Incidence Mortality and Prevalence Worldwide in 2012. 
International Agency for Research on Cancer, World Health Organization. 
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx 
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;103:275-282. 
Metabolism and Transport Drug Interaction Database, University of Washington, Department of 
Pharmaceutics www.druginteractioninfo.org 
Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the 
United States, 1992-2001. Blood 2006;107(1):265-76. 
National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.03. Cancer 
Therapy Evaluation Program. 14 June 2010. 
Xie Y, Pittaluga S, Jaffe ES. The histological classification of diffuse large B-cell lymphomas. 
Semin Hematol. 2015;52(2):57-66. 
Zelenetz AD, Gordon LI, Wierda WG, et al. J Natl Comprehensive Cancer Network. Diffuse Large 
B-Cell Lymphoma Version 1.2016. 2016;14(2):196-231. 
 
 


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13 
APPENDICES 
 
 


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Appendix 1 Signature of Investigator 
PROTOCOL TITLE: 
A Phase 2, Single arm, Multicenter, Open-label Study of Bruton’s 
Tyrosine Kinase (BTK) inhibitor BGB-3111 in subjects with 
relapsed/refractory non-GCB type Diffuse Large B cell lymphoma 
  
PROTOCOL NO: 
 
BGB-3111-207 
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 according to 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 PAREXEL International 
(IRL), Limited. 
 
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 Medications which are known to prolong the QT interval and/or 
induce Torsades de pointes to be avoided 
 
Antiarrhythmics 
amiodarone 
disopyramide 
dofetilide 
flecainide 
ibutilide 
procainamide 
quinidine 
sotalol 
Anticancer 
arsenic trioxide 
vavdetanib 
Antihistamines 
astemizole 
terfenadine 
Antibiotics 
azithromycin 
clarithromycin 
erythromycin 
moxifloxacin 
sparfloxacin 
Antianginal 
bepridil 
Antimalarial 
chloroquine 
halofantrine 
Antipsychotics 
chlorpromazine 
haloperidol 
mesoridazine 
pimozide 
thioridazine 
Antinausea 
domperidone 
droperidol 
dolasetron (intravenous and oral) 
Anti-infective 
pentamidine 


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Antilipemic 
probucol 
Antidpressants 
citalopram 
Opiate agonists 
levomethadyl 
methadone 
GI stimulant 
cisapride 
 
 
 








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b 
PET 5-point scale: 
1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum; 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. 
c 
Splenomegaly = vertical spleen length > 13 cm (reference: Cheson, BD et al. Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 2014;32:3059–3068). 
 


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Appendix 4 Prohibited Medications (CYP3A Inhibitors and CYP3A 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 
 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin 
(rifampicin), St. John’s wort (hypericum perforatum) 
 
Moderate CYP3A Inhibitors 
CYP3A4, CYP3A5, CYP3A7 
Antibiotics:  ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers:  diltiazem, verapamil 
Tyrosine kinase inhibitors (anti-cancer):  imatinib 
Food products:  grapefruit juice (citrus paradisi fruit juice) 
Herbal medications:  Schisandra sphenanthera  
Others:  aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam  
 
 
 
 


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Version 2.0, 16 April 2018 
Appendix 5 Medications to be Used with Caution  
Medications are sensitive CYP2C8, CYP2C9, and CYP2C19 substrates or CYP2C8, CYP2C9, and 
CYP2C19 substrates with a narrow therapeutic index. 
 
CYP2C8 Substrates 
CYP2C9 Substrates 
CYPC19 Substrates 
repaglinide1 
celecoxib 
Anti-epileptics: 
paclitaxel 
phenytoin2 
S-mephenytoin1,2  
warafarin2 
 
  
Proton Pump Inhibitors  
 
 
lansoprazole1 
 
omeprazole1 
 1  Sensitive substrates:  Drugs that exhibit an area under the plasma concentration-time curve (AUC) ratio 
(AUCi/AUC) of 5-fold or more when co-administered with a known potent inhibitor. 
2  Substrates with narrow therapeutic index (NTI):  Drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (eg, 
Torsades de Pointes). 
 
 


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Version 2.0, 16 April 2018 
Appendix 6 ECOG Performance Status 
Grade 
Description 
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, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
As published by Oken MM, et al. Toxicity and Response Criteria of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982; 5:649-655. 
 
 

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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111-207 
Study Protocol 
Title: 
A Phase 2, Single arm, Multicenter, Open-label Study of Bruton’s 
Tyrosine Kinase (BTK) inhibitor BGB-3111 in subjects with 
relapsed/refractory non-GCB type Diffuse Large B cell lymphoma 
 
Date: 
June 11, 2019 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
8 
2 
STUDY OVERVIEW 
8 
3 
STUDY OBJECTIVES 
10 
3.1 
Primary Objectives 
10 
3.2 
Secondary Objectives 
10 
3.3 
Exploratory Objectives 
10 
4 
STUDY ENDPOINTS 
10 
4.1 
Primary Endpoints 
10 
4.2 
Secondary Endpoints 
10 
4.3 
Exploratory Endpoints 
11 
5 
SAMPLE SIZE CONSIDERATIONS 
11 
6 
STATISTICAL METHODS 
11 
6.1 
Analysis Populations 
11 
6.2 
Data Analysis General Considerations 
11 
6.2.1 
Definitions and Computations 
11 
6.2.2 
Conventions 
12 
6.2.3 
Handling of Missing Data 
12 
6.2.4 
Handling of Treatment Cycles 
13 
6.2.5 
Adjustment for Covariates 
13 
6.2.6 
Multiplicity Adjustment 
13 
6.2.7 
Data Integrity 
13 
6.3 
Subject Characteristics 
13 
6.3.1 
Subject Disposition 
13 
6.3.2 
Protocol Deviations 
14 
6.3.3 
Demographic and Other Baseline Characteristics 
14 
6.3.4 
Disease History 
14 
6.3.5 
Prior Anti-Cancer Drug Therapies and Surgeries 
14 
6.3.6 
Prior and Concomitant Medications 
14 
6.3.7 
Medical History 
15 
6.4 
Efficacy Analysis 
15 
6.4.1 
Primary Efficacy Endpoints 
15 
6.4.2 
Secondary Efficacy Endpoints 
15 
6.4.3 
Subgroup Analyses 
17 
6.4.4 
Exploratory Efficacy Endpoints 
17 
6.5 
Safety Analyses 
17 
6.5.1 
Extent of Exposure 
17 
6.5.2 
Adverse Events 
18 
6.5.3 
Laboratory Values 
20 
6.5.4 
Vital Signs 
21 
6.5.5 
Electrocardiograms (ECG) 
21 
6.5.6 
Eastern Cooperative Oncology Group (ECOG) 
21 


 
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6.6 
Other Analyses 
21 
7 
INTERIM ANALYSIS 
22 
8 
CHANGES IN THE PLANNED ANALYSIS 
22 
9 
REFRENCES 
23 
10 
APPENDIX 
24 
10.1 
Appendix 1: Missing Data Imputation Rule 
24 
10.1.1 
Adverse Events 
24 
10.1.2 
Prior/Concomitant Medications/Procedures 
24 
10.1.3 
Initial Diagnosis and Most Recent Progression Relapse 
25 
10.2 
Appendix 2 Revised criteria for response assessment of lymphoma 
(Cheson et al) 
26 
10.3 
Appendix 3 Safety Monitoring Committee Charter 
30 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AEs 
Adverse events 
AESIs 
Treatment-emergent adverse events of special interest 
ADI 
Actual dose intensity 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice daily 
BOR 
Best overall response 
BP 
Blood pressure 
BTK 
Bruton’s Tyrosine Kinase 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DLBCL 
Diffuse Large B cell Lymphoma 
DOR 
Duration of response 
EAIR 
Exposure-Adjusted Incidence Rate 
ECG 
Electrocardiograms 
ECOG-PS 
Eastern Cooperative Oncology Group performance status 


 
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eCRF 
Electronic case report form 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
IWG 
International Working Group 
LDH 
Lactate dehydrogenase 
LDi 
Longest diameter 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI  
National Cancer Institute  
NHL 
Non-Hodgkin’s Lymphoma 
non-GCB 
non-Germinal Center B cell type 
NR 
No response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease/disease progression 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PO 
Per os (orally) 
PR 
Partial response 
PT 
Preferred term 
RDI 
Relative dose intensity 
SAEs 
Serious adverse events 
SAP 
Statistical analysis plan 


 
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SAS 
Safety Analysis Set 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SOC 
System organ class 
TBL 
Total bilirubin 
TEAEs 
Treatment-emergent adverse events 
TTR 
Time to response 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
zanubrutinib 
BGB-3111 
 
 
 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for study BGB-3111-207.The focus of this 
SAP is for the planned analysis specified in the study protocol. The plan is written in accordance 
with the protocol version 2.0 dated 16 April 2018. 
The analysis details for Biomarker analyses are not described within this SAP.  
2 
STUDY OVERVIEW 
This is a single-arm, open-label, multi-center Phase 2 study in subjects with histologically 
documented non-Germinal Center B cell type Diffuse Large B cell Lymphoma (non-GCB 
DLBCL) who have relapsed after ≥ 1 prior treatment regimen including rituximab(s), patients 
also have to be ineligible for intensive chemotherapy and bone marrow transplantation.  The 
study is composed of an initial screening phase (up to 28 days), a single-arm treatment phase of 
up to 2 years, and a follow-up phase (30 days), at the end of which if the patient is still benefiting 
from therapy, will be allowed to join the long-term extension study.   
Up to approximately 40 subjects will be enrolled.  The primary efficacy analysis will be 
conducted no later than 12 months after the last subject received the first dose of study drug.  
Tumor response will be assessed by investigator review according to 2014 International Working 
Group (IWG) in Non-Hodgkin’s Lymphoma (NHL) (Cheson et al 2014) (Appendix 2).  Patient 
will receive a positron emission tomography (PET) and contrast computed tomography (CT) at 
screening, after 12 and 24 weeks of therapy, and at suspected complete remission. Contrast CT 
alone will be performed at weeks 36, 48, and thereafter, once every 16 weeks. Response will be 
assessed based on radiological evaluations. Complete responses should be confirmed by PET and 
contrast CT in all subjects, by endoscopy for any subjects with a documented history of 
gastrointestinal involvement, and by bone marrow biopsy in these subjects with bone marrow 
tumor involvement prior to study drug. Bone marrow biopsy has to be performed at screening. 
All subjects will be followed for adverse events (AEs) for 30 additional days after the last dose 
of study drug.  All treatment-related AEs and serious adverse events (SAEs) will be followed 
until resolution or stabilization. 
Screening phase:  Screening evaluations will be performed within 28 days prior to the first dose 
of study drug.  Subjects will sign the informed consent form prior to any screening evaluations.  
Screening evaluations can be repeated within the screening period.  
Treatment phase:  Subjects will receive the first dose of zanubrutinib at Cycle 1 Day 1. All 
subjects in the study will be treated with 160 mg, administered orally (PO) twice daily (BID), 
and will continue to be treated until disease progression, unacceptable toxicity, death, withdrawal 


 
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of consent, or the study is terminated by the sponsor for final analysis.  At the time of final 
analysis, subjects who remain on treatment will be considered for participation in the extension 
study when eligible.  A treatment cycle consists of 28 days. 
Follow-up phase:  Subjects will return approximately 30 days after the last dose of study drug 
for safety follow-up visit.  Radiological assessments will continue until documented disease 
progression.  If a subject discontinues study drug due to reasons other than disease progression, 
radiological assessments will continue until subject exhibits first progression, starts new anti-
cancer therapy, withdrawal of consent, death, lost to follow-up or study termination by sponsor, 
whichever occurs first.  
Survival phase: Subjects will be followed for survival via phone contact (with patient guardian, 
if applicable) every 3 months after the subject’s last visit until withdrawal of consent, lost to 
follow-up, death, or the date of data cutoff for the final analysis.  
Figure 1 
Schema for Study BGB-3111-207 
 
BGB-3111 
160 mg PO twice daily, 1 cycle=28 days 
until disease progression (PD) or intolerable toxicity 
Discontinue 
due to PD 
Safety Follow-up visit (30 ± 7 days 
after last dose) 
Survival Follow-up every 3 months 
Histologically confirmed DLBCL,  
Hans algorithm defined non-GCB type DLBCL 
Safety Follow-up visit (30 ± 7 days 
after last dose) 
Continue efficacy evaluations 
(tumor assessments) until PD 
Survival Follow-up every 3 months 
Discontinue 
due to reason other than PD 
End of Treatment (EOT) 


 
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3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
• To evaluate the efficacy of zanubrutinib at a dose of 160 mg orally (PO) twice daily 
(BID), in subjects with relapsed or refractory non-GCB DLBCL as assessed by 
investigator review using the overall response rate according to the 2014 International 
Working Group in NHL criteria (Cheson et al 2014). 
3.2 
SECONDARY OBJECTIVES  
• To evaluate the efficacy of zanubrutinib by investigator as measured by progression free 
survival (PFS). 
• To evaluate the efficacy of zanubrutinib by investigator as measured by duration of 
response (DOR). 
• To evaluate the efficacy of zanubrutinib by investigator as measured by time to response 
(TTR). 
• To evaluate the safety and tolerability of zanubrutinib at a dose of 160 mg PO BID in 
subjects with relapsed or refractory non-GCB type DLBCL. 
3.3 
EXPLORATORY OBJECTIVES 
•
•
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• The primary endpoint of the study is the rate of overall response, defined as the 
achievement of either a partial response (PR) or complete response (CR) by investigator 
review according to the 2014 modification of the International Working Group on NHL 
Criteria (Cheson et al 2014) (Appendix 2) at any time on study drug. 
4.2 
SECONDARY ENDPOINTS 
Efficacy (using response assessment as determined by investigator): 
• Progression free survival (PFS): defined as time from first dose of zanubrutinib until first 
documentation of progression (by IWG on NHL criteria) or death, whichever comes first. 
• Duration of response (DOR) is defined as the time from the date that the response (PR or 
CR) criteria are first met to the date that progressive disease (PD) is objectively 
documented or death, whichever occurs first. 


 
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• Time to response (TTR) is defined as the time from first dose of zanubrutinib to 
documentation of a response. 
Safety: 
• 
To evaluate the safety and tolerability of zanubrutinib, as defined by: 
o The incidence and severity of treatment-emergent adverse events (TEAEs), SAEs and 
treatment-related AEs according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.03 (NCI CTCAE v4.03). 
o The incidence, severity, timing, and causation of adverse events leading to study drug 
discontinuation. 
4.3 
EXPLORATORY ENDPOINTS 
• 
• 
5 
SAMPLE SIZE CONSIDERATIONS 
Approximately 40 subjects will be enrolled.  
The sample size calculation was based on the level of precision of the estimated ORR. Assuming 
an ORR of 35%, the 95% exact confidence interval will be 20.6% to 51.7%.  
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
The Safety Analysis Set (SAS) includes all subjects who received any dose of zanubrutinib.  It 
will be the population for the efficacy and safety analyses.   
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first dose of 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, study day and any corresponding 
durations will be presented based on the imputations specified in Appendix 1. 
Treatment duration: The treatment duration will be calculated as (end date of the latest exposure 
of study drug – date of first dose of study drug + 1). 


 
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Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the administration of the first dose of study drug. 
All calculations and analyses will be conducted using SAS version 9.4 or higher. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
• 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
• 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 significant digit. 
• Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
• P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
• Time-to-event or duration of event endpoints will be based on the actual date the 
radiograph was obtained rather than the associated visit date. 
• Missing efficacy or safety data will not be imputed unless otherwise specified. 
• For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator, unless otherwise specified. 
• For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, 25 percentile (Q1), 75 percentile (Q3), and range (minimum and maximum). 
• For categorical endpoints, summary statistics will include frequencies and percentages. 
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events, prior/concomitant 
medications/procedures, initial diagnosis date or most recent progression relapse date as provided 
in Appendix 1. 
When summarizing categorical variables, subjects 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, subjects with missing data are not included in 
calculations. No imputations are made. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For observed 
data analyses, missing data will not be imputed and only the observed records will be included.  
If the start day of a subsequent anti-cancer therapy is missing, it will be assumed to be the first day 
of the month if the end of treatment date is earlier. If the end of treatment date is later than the first 
day of the month, then the start date of subsequent anti-cancer therapy will be assumed to be the 
end of treatment date plus 1 day. 


 
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If only the day of death date is missing, the death will be assumed to be on the first day of the 
month if the last known alive date is earlier. If the last known alive date is later than the first day 
of the month, then the death date will be assumed to be the last known alive date plus 1 day. 
If both day and month of death date are missing, the death will be assumed to be on the first day 
of January if the last known alive date is earlier. If the last know alive date is later than the first 
day of January, then the death date will be assumed to be the last known alive date plus 1 day. 
No imputation of AE grades will be performed. TEAEs with missing CTCAE grade will only be 
summarized in the all-grades column. 
If the assessment of the relationship of an AE to study treatments is missing, then the AE is 
assumed to be related to the study treatments in the safety analysis, but no imputation should be 
done at the data level. 
6.2.4 Handling of Treatment Cycles 
A treatment cycle consists of 28 days. The following cycles will not be reset if the planned visit 
did not occur due to certain reason or there is dose held in current treatment cycle. 
6.2.5 Adjustment for Covariates 
No adjustments for covariates are planned for primary and secondary analyses in the study.  
6.2.6 Multiplicity Adjustment 
Not applicable. 
6.2.7 Data Integrity 
Before 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 each patient’s 
relevant outcomes from the clinical database. All essential data should be complete and reviewed 
up to a pre-specified cutoff date. Critical consistency checks and appropriate source data 
verification should be completed according to the final data extraction plan. 
 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The number (percentage) of subjects enrolled, treated, discontinued from study drugs and 
discontinued from the study will be summarized in the safety analysis set.  The primary reason for 
end of treatment (study drug discontinuation) and end of study will be summarized by categories 
in the electronic case report form (eCRF).  
Study follow-up time, defined as the time from the first dose date to the death date or end of study 
date (whichever occurs earlier) for patients discontinued from the study, or the database cutoff 
date for ongoing patients, will be summarized descriptively.  


 
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Survival status (alive, death, or lost to follow-up) at the data cutoff date will be summarized using 
the data from the survival follow-ups. 
6.3.2 Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol deviations 
will be identified and documented. Major protocol deviations will be summarized for all patients 
in the safety analysis set. They will also be listed by each category. 
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the safety analysis set. Continuous variables include age, height and weight; categorical variables 
include sex, race, age group (< 65 vs. ≥ 65 years), Eastern Cooperative Oncology Group 
performance status (ECOG-PS), HBcAb, HBV DNA and HCV antibody. A listing of demographic 
and other baseline characteristics will be provided. 
6.3.4 Disease History 
The number (percentage) of subjects reporting a history of disease and characteristic, as recorded 
on the CRF, will be summarized in the safety analysis set. Disease characteristics include time 
since initial diagnosis of non-GCB DLBCL, disease status at study entry (Relapsed vs. Refractory), 
time from most recent progression relapse, disease stage at study entry, extra-nodal disease, 
international prognostic index (IPI) at study entry, bulky disease (defined as the longest diameter 
(LDi) of any target lesion > 7.5 cm), confirmed GI involvement and baseline bone marrow 
involvement, elevated lactate dehydrogenase (LDH) at baseline, spleen enlargement, liver 
enlargement and B-symptoms (defined as unexplained weight loss > 10% over previous 6 months 
or fever (> 38 ℃) or drenching night sweats). A listing of disease history will be provided. 
6.3.5 Prior Anti-Cancer Drug Therapies and Surgeries 
The number of prior lines of therapy, duration of last prior therapy, best response for last prior 
therapy, time (months) from the end of last prior therapy to first dose of study drug, number (%) 
of patients with prior anti-cancer radiotherapy will be summarized in the safety analysis set. The 
therapies and surgeries with the same sequence/regimen number are counted as one prior 
therapy/surgery.     
6.3.6 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO DD) drug codes version September 2018 (B3 format) and will be further 
classified to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of subjects reporting prior and concomitant medications will be 
summarized by ATC medication class level 2 and WHO DD preferred name in the safety analysis 
set. Prior medications are defined as medications that started before the first dose date. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study treatment and were continuing at the time of the first dose of study treatment, or (2) started 
on or after the date of the first dose of study treatment up to 30 days after the patient’s last dose or 


 
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initiation of a new anti-cancer therapy. 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 22.0. The number (percentage) of subjects reporting a history of any medical condition, as 
recorded on the CRF, will be summarized by system organ class and preferred term in the safety 
analysis set. A listing of medical history will be provided. 
 
6.4 
EFFICACY ANALYSIS 
Analysis of efficacy endpoints will be conducted in the safety analysis set with the exception of 
DOR which will be summarized for responders only. 
6.4.1 Primary Efficacy Endpoints 
Overall Response Rate (ORR)  
The primary efficacy endpoint of the study is ORR, defined as the proportion of subjects achieving 
a best overall response of CR or PR determined by investigator review using the 2014 International 
Working Group in NHL criteria (Appendix 2).   
The ORR in this study is estimated as 35%. Two-sided Clopper-Pearson 95% confidence interval 
(CI) of ORR will be constructed to assess the precision of the rate estimate. No hypothesis testing 
will be done. 
Best overall response (BOR) is defined as the best response recorded from the start of zanubrutinib 
until data cut or start of new anti-neoplastic treatment.  Patients with no post-baseline response 
assessment (due to any reason) will be considered as non-responders.  The number and proportion 
of patients who achieved each of the response categories (CR, PR, stable disease/no response 
[SD/NR], and PD) will be summarized. The corresponding Clopper-Pearson 95% CI for CR rate 
and PR rate will also be presented. 
The primary efficacy analysis will be conducted no later than 12 months after the first dose of the 
last patient and will be based on the safety analysis set. 
6.4.2 Secondary Efficacy Endpoints 
Progression Free Survival (PFS) 
PFS is defined as the time (in months) from the first dose date of zanubrutinib to the earlier date 
of disease progression or death due to any cause.  
PFS = (The earlier of disease progression or death date –first dose date +1) / 30.4375 
PFS will be based on investigator’s assessment. The distribution of PFS, including median PFS 
and PFS rates at selected timepoints such as 3, 6 and 12 months will be summarized descriptively 
using the Kaplan-Meier method. Kaplan-Meier curves will be constructed to provide a visual 
description of the PFS change with time. Two-sided 95% CIs of median and other quantiles, if 


 
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estimable, will be constructed with a generalized Brookmeyer and Crowley method (Brookmeyer 
and Crowley, 1982). The corresponding 95% CIs for PFS rates at selected timepoints will also be 
generated by using Greenwood’s formula (Kalbfleisch and Prentice, 1980). Median of the follow-
up time for PFS will be estimated by reverse Kaplan-Meier method (Schemper and Smith, 1996). 
The PFS censoring rule will follow Food and Drug Administration (FDA) “Guidance for 
Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007)” and 
be provided in Table 1. 
Note that the frequency of disease assessments is every 12 weeks in the first 48 weeks and every 
16 weeks thereafter. Therefore, missing more than one disease assessment will be interpreted as 
gaps longer than 24 weeks in the first 48 weeks or gaps longer than 32 weeks thereafter for 
censoring purposes of PFS. 
Table 1  Censoring Rules for Analysis of Progression-Free Survival 
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline and/or post-baseline disease 
assessments 
Date of the first dose  
Censored 
2 
Death or PD between planned disease 
assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Progressed 
3 
Alive without documented disease 
progression at the time of data cut-off or 
withdrawal from study (including lost-to-
follow-up without disease progression) 
Date of last disease assessment  
Censored 
4 
New anticancer treatment started before  
documented disease progression or death 
Date of last disease assessment prior 
to date of new anticancer treatment 
Censored 
5 
Death before first disease assessment 
Date of death 
Progressed 
6 
Death or progression after more than one 
missed scheduled disease assessment 
Date of last disease assessment 
without documented disease 
progression before missed tumor 
assessments 
Censored 
 
Duration of Response (DOR) 
DOR for responders (CR or PR) is defined as the time from the date that the response criteria are 
first met to the date that PD is objectively documented or death for any cause (whichever occurs 
earlier). Censoring rule for DOR will follow PFS censoring rule. Kaplan-Meier curve will be used 
to estimate median time and 95% confidence interval for duration of response.  
DOR will be based on investigator’s assessment. 
Time to response (TTR) 
TTR for responders (CR or PR) is defined as the time interval between the first dose date of 
zanubrutinib to the date the response criteria are first met. TTR will be summarized by sample 


 
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statistics such as mean, median and standard deviation for responders only. TTR will be based on 
investigator’s assessments. 
6.4.3 Subgroup Analyses 
Primary and selected secondary endpoints will be summarized descriptively in the specified 
subgroups: Sex (male vs female), age group (< 65 vs. ≥65 years), disease stage at study entry 
(Stage I/II vs. Stage III/ IV), ECOG-PS (0 vs. ≥1), IPI (low, low-intermediate, high-intermediate, 
high), bulky disease (LDi ≤ 7.5 vs. LDi > 7.5 cm), baseline bone marrow involvement (yes vs. no), 
baseline extra-nodal disease (yes vs. no), elevated LDH at baseline (yes vs. no), number of prior 
lines of therapy (1 vs. ≥2), prior rituximab containing therapy (yes vs. no), prior autologous stem 
cell transplantation (yes vs. no), prior Hyper CVAD use (yes vs. no) and MYD88/CD79B mutation 
(MYD88L265P&CD79BMut vs. others). Within group values (rates for ORR or medians for PFS) 
will be presented in forest plots. 
The subgroup variables and the cutoff values are subject to change if warranted to better represent 
the data.   
6.4.4 Exploratory Efficacy Endpoints 
6.5 
SAFETY ANALYSES 
All safety analyses will be based on the safety analysis set. The study will set up a Safety 
Monitoring Committee (SMC). The SMC will monitor safety data according to the SMC charter 
(Appendix 3) periodically throughout the study. 
Safety and tolerability will be assessed, where applicable, by summarizing the incidence, severity, 
and causation of all TEAEs graded by NCI CTCAE v4.03.  
Laboratory values (hematology, clinical chemistry and urinalysis), vital signs and ECGs findings, 
and the change from baseline values will be summarized using descriptive statistics (e.g., n, mean, 
standard deviation, median, Q1, Q3, minimum, maximum for continuous variables; n [%] for 
categorical variables. Abnormal values will be flagged. 
6.5.1 Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively with respect to the following: 


 
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• 
Duration of exposure (months): defined as the duration (months) from the date of the 
first dose to the last dose of the study drug. 
• 
Number of treatment cycles received: defined as the total number of treatment cycles in 
which at least one dose of the study drug is administered. 
• 
Total dose received per subject (mg): defined as the cumulative dose of the study drug 
during the treatment period of the study 
• 
Actual dose intensity (ADI, mg/day): defined as the total dose (mg) received by a 
subject divided by the treatment duration (days) 
• 
Relative dose intensity (RDI, %): defined as the ratio of the actual dose intensity 
(mg/day) and the planned starting dose intensity (mg/day).  
The number (percentage) of patients requiring dose reduction and dose interruption due to AEs, 
and patients with dose missing will be summarized. The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics. Frequency of 
reductions and dose interruptions will be summarized.  
6.5.2 Adverse Events  
AEs will be graded by the investigators using CTCAE v4.03. The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology using 
the MedDRA. Adverse events will be coded to the MedDRA (Version 20.0 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary system 
organ class (SOC) are also captured in the database. 
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug 
up to 30 days following study drug discontinuation (Safety Follow-up visit) or initiation of new 
anticancer therapy, whichever comes first. Only those AEs that were treatment emergent will be 
included in summary tables.  All AEs, treatment emergent or otherwise, will be presented in 
subject data listings. 
An overview table, including the incidence of and the number of subjects with TEAEs, serious 
TEAEs, TEAEs with grade 3 or above, TEAEs that led to death, TEAEs that led to treatment 
discontinuation, TEAEs that led to dose modification (including dose reduction and dose 
interruption) and all above TEAEs that were treatment-related will be provided. Treatment-related 
AEs include those events considered by the investigator to be related, probably related, possibly 
related and unlikely related to study treatment or with missing assessment of the causal 
relationship.   
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once by the highest severity grade according to 
CTCAE v.4.03 within an SOC and PT, even if the subject experienced more than 1 TEAE within 
a specific SOC and PT.  
The number (percentage) of subjects with all TEAEs, treatment-related TEAEs, serious TEAEs, 
treatment-related serious TEAEs, TEAEs with grade 3 or above, treatment-related TEAEs with 


 
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grade 3 or above, and TEAEs that led to treatment discontinuation, dose modification (reduction 
or interruption) will be summarized by SOC, PT and maximum severity. TEAEs and treatment-
related TEAEs that led to death will be summarized by SOC and PT. All TEAEs, serious TEAE, 
TEAEs with grade 3 or above and treatment-related TEAEs will also be summarized by PT in 
descending order.  
TEAEs of special interest (AESIs) are TEAEs known to be associated with ibrutinib and other 
BTK inhibitors and thought to be a class effect. The events and search terms for AESIs are shown 
in Table 2. The categories of AESIs are subject to change if warranted to better represent the safety 
of zanubrutinib before database lock.  
Table 2: 
Adverse Events of Special Interest 
AESI  
Search Criteria 
Hemorrhage 
Hemorrhage terms (excluding laboratory terms) (SMQ) Narrow 
Major hemorrhage 
Major hemorrhage is defined as Subdural haematoma PT, Subdural 
haemorrhage PT and all Hemorrhage PT if AE SOC is 'Nervous system 
disorders' or serious or grade 3 and above Hemorrhage PT if AE SOC 
is not 'Nervous system disorders' 
Atrial fibrillation and flutter 
Atrial fibrillation PT, Atrial flutter PT 
Hypertension 
Hypertension (SMQ) Narrow 
Second primary malignancies 
    Skin cancers 
Malignant Tumours (SMQ) Narrow 
 Subcategory-Skin malignant tumours (SMQ) Narrow 
Tumor lysis syndrome 
Tumor lysis syndrome (SMQ) Narrow 
Infections 
Infections and Infestations SOC 
    Opportunistic infections 
 Subcategory- Opportunistic infections (CMQ) 
Anemia 
Anaemia PT, Hemoglobin decreased PT 
Neutropenia 
Neutropenia PT, Neutrophil count decreased PT, Febrile neutropenia 
PT, Agranulocytosis PT, Neutropenic infection PT, Neutropenic sepsis 
PT 
Thrombocytopenia 
Thrombocytopenia PT, Platelet count decreased PT 
Anemia 
Anaemia PT, Hemoglobin decreased PT 
Abbreviations: AESI, adverse event of special interest; CMQ, Customized MedDRA Query; PT, Preferred Term; 
SMQ, Standardized MedDRA Query; SOC, System Organ Class. 
 
Incidence of all AESIs, AESIs with grade 3 or above, serious AESIs, AESIs leading to treatment 
discontinuation, AESIs leading to dose modification (dose interruption or dose reduction), AESIs 
leading to death, and treatment-related AESIs will be summarized by AESI category and PT. AESI 
will also be summarized by category, PT, and maximum severity.  
Exposure-Adjusted Incidence Rates (EAIR) 
An exposure adjusted analysis is also planned to analyze AESIs by category. 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 from the first dose date to the first 


 
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event date (or exposure time if the first event has occurred after last dose date) (non-censored data), 
or 2) by the total duration of exposure in case the patient does not experience the event (censored 
data). 
The EAIR per event considers the first event per patient only, and the corresponding exposure time 
in the denominator: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= ∑
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,𝑖𝑖
𝑛𝑛
𝑖𝑖=1
∑
𝑡𝑡𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,𝑖𝑖
𝑛𝑛
𝑖𝑖=1
 
Whereby 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,𝑖𝑖 represents if patient i experienced the event (1) or not (0),  and 𝑡𝑡𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒,𝑖𝑖 as 
the time from the first dose date to the first event date (or exposure time if the first event has 
occurred after last dose date) (non-censored data) or total duration of treatment exposure if no 
event occurs (censored data).   
The EAIR analysis will also be provided for serious TEAEs or TEAEs with grade 3 or above if 
needed. 
The overall summary for TEAEs may be repeated in the first 6 month after first dose to provide 
temporal incidence trend. Summaries will also be provided for patients experiencing the first AESI 
within each exposure interval (≤ 3 months, 3 to 6 months, 6 to 9 months, 9 to 12 months, and >12 
months). 
Subject data listings of all AEs, SAEs, treatment-related AEs, grade 3 or above AEs, AEs that led 
to death, AEs that led to dose modification (reduction/interruption) and AEs that led to treatment 
discontinuation will be provided. 
All deaths and causes of death will be summarized, including those occurred during the study 
treatment period and those reported during the survival follow-up period after treatment 
completion/discontinuation.    
6.5.3 Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters described in Table 3. 
Descriptive summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, 
maximum for continuous variables; n [%] for categorical variables) for laboratory parameters and 
their changes from baseline will be summarized by visit and by worst post-baseline visit. 
Laboratory parameters that are graded in NCI CTCAE (v.4.03) will be summarized by shifts 
from baseline CTCAE grades to maximum post-baseline grades. In the summary of laboratory 
parameters by CTCAE grade, parameters with CTCAE grading in both high and low directions 
(e.g. calcium, glucose, potassium, sodium) will be summarized separately. Number (percentage) 
of subjects with abnormal postbaseline laboratory values will be summarized by visit and by any 
post-baseline visit. 
 


 
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Table 3  Selected Laboratory Tests 
Serum Chemistry 
Haematology 
Urinalysis 
Albumin 
Hemoglobin 
Urine pH 
Alkaline phosphatase (ALP) 
Platelet counts 
Urine Specific Gravity 
Alanine aminotransferase (ALT) 
White blood cell (WBC) count Urine Glucose 
Aspartate aminotransferase (AST) Neutrophil (Absolute) 
Urine Protein 
Calcium 
Lymphocyte(Absolute) 
Urine Occult Blood 
Creatinine 
 
 
Glucose (Fasting) 
 
 
Lactate dehydrogenase (LDH) 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin (TBL) 
 
 
Uric acid 
 
 
A summary of the liver function test abnormalities will also be presented based on Hy’s law 
laboratory criteria defined as ALT or AST > 3xULN and TBL > 2xULN and ALP < 2xULN at 
any post-baseline visit, where TBL and ALP were both within 28 days after ALT or AST elevation. 
Subject data listings of selected hematology, serum chemistry parameters including Hy’s Law 
index, and urinalysis will be provided. 
6.5.4 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], pulse 
rate, temperature, respiratory rate, and weight) and changes from baseline will be presented by 
visit for all visits.  Blood pressures will be summarized by shifts from baseline CTCAE grades to 
maximum post-baseline grades. Vital signs will be listed by subjects and visits. 
6.5.5 Electrocardiograms (ECG) 
ECG assessments will be performed at Screening and EOT visit.  Descriptive statistics for ECG 
parameters (heart rate, PR, QRS, QT and QTcF interval) and change from baseline will be 
presented. 
6.5.6 Eastern Cooperative Oncology Group (ECOG) 
A shift table from baseline to worst post-baseline in ECOG performance score will be summarized. 
ECOG scores will be summarized by visit. 
6.6 
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. 


 
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7 
INTERIM ANALYSIS 
Not applicable.  
8 
CHANGES IN THE PLANNED ANALYSIS 
Not applicable.  
 
 


 
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9 
REFRENCES 
1. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time[J]. 
Biometrics, 1982, 38(1):29-41.  
2. 
Cheson B D, Fisher R I, Barrington S F, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification[J]. Journal of Clinical Oncology, 2014, 32(27):3059-3068. 
3. 
Food and Drug Administration. Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007, 
https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf 
4. 
Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time 
Data, New York: John Wiley & Sons. 
5. 
National Cancer Institute. Common Toxicity Criteria for Adverse Events, Version 4.03. 
Cancer Therapy Evaluation Program. 14 June 2010. 
6. 
Schemper M, Smith T L. A note on quantifying follow-up in studies of failure time.[J]. 
Controlled Clinical Trials, 1996, 17(4):343-346. 
 
 


 
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10 APPENDIX 
10.1 APPENDIX 1: MISSING DATA IMPUTATION RULE  
In general, missing or partial dates will not be imputed as data level. The following rules will apply 
for the specific analysis and summary purposes mentioned below only.   
10.1.1 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 set to January 01 or treatment start date if they 
have the same year, whichever is later. 
• If only day is missing, then set to the first day of the month or treatment start date if they 
have the same month and year, whichever is later. 
• If start date is completely missing, set to treatment start date as long as adverse event end 
date is not before treatment start date 
If end date of an adverse event 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 end date is completely missing, do not impute. 
If the imputed adverse event end date > death date or end of study date, then set to the death date 
or end of study date, whichever occurs first. 
 
10.1.2 Prior/Concomitant Medications/Procedures 
When the start date or end date of a medication/procedure is partially missing, the date will be 
imputed to determine whether the medication/procedure is prior or concomitant. The following 
rules will be applied to impute partial dates for medications/therapies: 
If start date of a medication/procedure 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 of the month 


 
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If end date of a medication/procedure 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/procedure is completely missing, do not impute.   
If the imputed end date > death date or end of study date, then set to the death date or end of study 
date, whichever occurs first. 
 
10.1.3 Initial Diagnosis and Most Recent Progression Relapse 
If the initial 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 most recent progression relapse 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 the initial diagnosis date or most recent progression relapse date is completely missing, do not 
impute. If the imputed initial diagnosis date or most recent progression relapse date is on or after 
the treatment start date, then set to treatment start date-1. 
 
 
 








 
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the mediastinum with complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
b 
PET 5-point scale: 
1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum; 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. 
c 
Splenomegaly = vertical spleen length > 13 cm (reference: Cheson, BD et al. Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 2014; 32:3059–3068). 
 
 
 


 
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10.3 APPENDIX 3 
SAFETY MONITORING COMMITTEE CHARTER