Conditions: Lymphoma Leukemia
Keywords: Relapsed Refractory
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 75
Healthy volunteers: no

Brief summary:
This study is evaluating the safety and preliminary efficacy of BGB-3111 in combination with BGB-A317 in participants with B-cell lymphoid malignancies.

Detailed description:

Arms:
arm 1: Based on results of the dose escalation cohorts and the identified recommended Phase 2 dose, all patients will receive zanubrutinib at 160 mg orally twice daily in combination with intravenous infusion of tislelizumab 200mg given every 21 days, to be continued until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination

Interventions: intervention 1: Zanubrutinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 1 of 132
 
Version 5.0: 02 May 2019 
 
Clinical Study Protocol 
Protocol Title:  
A Phase 1b, Open Label, Multiple Dose, Dose Escalation, and 
Expansion Study to Assess Safety, Tolerability, and 
Antitumor Activities of the Combination of BGB-3111 with 
BGB-A317 in Subjects with B-Cell Lymphoid Malignancies 
Protocol Number: 
BGB-3111_BGB-A317_Study_001 
Date of Protocol: 
 
 
Original: Version 1.0, 25 January 2016 
Amendment: Version 2.0, 7 November 2016 
Amendment: Version 3.0, 28 June 2017 
Amendment: Version 4.0, 15 March 2018 
Amendment: Version 5.0, 02 May 2019 
Study Phase: 
1b 
Sponsor: 
BeiGene Aus Pty Ltd 
c/o Becis Pty Ltd, 1C/528 Compton Road,  
Stretton, Queensland 4116, Australia 
Sponsor Medical Monitor: 
 
Coordinating Investigator: 
 
 
 
 
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. 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                 CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:2 of 132
 
Version 5.0: 02 May 2019 
SIGNATURE 
 
PROTOCOL TITLE: 
A Phase 1b, Open-Label, Multiple-Dose, Dose Escalation, and 
Expansion Study to Assess Safety, Tolerability, and Antitumor 
Activities of the Combination of BGB-3111 with BGB-A317 in 
Subjects with B-Cell Lymphoid Malignancies 
PROTOCOL NO: 
 
BGB-3111_BGB-A317_Study_001 
 
____________________________________ 
 
 
___________________ 
  
 
 
 
 
 
Date 
Sponsor Medical Monitor 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 3 of 132
 
Version 5.0: 02 May 2019 
PROTOCOL AMENDMENT 5.0 - AMENDMENT RATIONALE 
Rationale:  
This protocol is being amended to include the following major changes: 
 Changed all references to “Safety Population” to “Safety Analysis Set.” Text revised as 
correction and for consistency with other BeiGene protocols. 
 Deleted text regarding which version of Statistical Analysis Program is used. Text is more 
appropriately documented in the SAP. 
 Removal of QT interval prolongation medications.  The BGB-3111-106 study was 
recently completed in healthy volunteers and has shown that both therapeutic and 
supratherapeutic doses of zanubrutinib had no clinically relevant effect on ECG 
parameters, including QTc intervals. 
 Added results of drug-drug interaction study. 
 Closed Cohort 4A to enrolment due to the dosing schedule not being ideal for decreasing 
tumor burden rapidly as BTK-inhibition is not initiated until the 5th cycle, according to 
investigator feedback, and opened Cohort 4B immediately. 
 
 
In addition, administrative updates (eg, adding abbreviations, correcting numbering in numbered 
lists), corrections of minor typographical and formatting errors, editorial changes, and/or style and 
formatting revisions have been made to improve clarity and consistency throughout the document. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 4 of 132
 
Version 5.0: 02 May 2019 
SYNOPSIS 
Name of Sponsor/Company: 
BeiGene Aus Pty Ltd 
Name of Finished Product: 
Zanubrutinib (BGB-3111) and Tislelizumab (BGB-A317) 
Name of Active Ingredient: 
Zanubrutinib (a Bruton’s tyrosine kinase [BTK] inhibitor) and tislelizumab (a 
humanized anti-programmed death-1[PD-1] monoclonal antibody) 
Title of Study:  
A Phase 1b, Open Label, Multiple Dose, Dose Escalation, and Expansion Study to Assess 
Safety, Tolerability, and Antitumor Activities of the Combination of BGB-3111 with BGB-
A317 in Subjects with B-Cell Lymphoid Malignancies  
Protocol No: 
BGB-3111_BGB-A317_Study_001 
Study Centers: 
10-15 study centers globally 
Study duration: Screening (up to 28 days), treatment (until 
progression), safety follow-up (30 days), and survival follow-up (every 3 
months by telephone to assess survival until death or conclusion of the 
study) 
Phase: 1b 
Objectives: 
Primary: 
 
To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of 
tislelizumab when given in combination with zanubrutinib. 
 
To assess the safety and tolerability of zanubrutinib in combination with tislelizumab (Cohorts 1 to 3 
and 4B) or single-agent tislelizumab followed by the combination of tislelizumab and zanubrutinib 
(Cohort 4A) in previously treated subjects with B-cell malignancies. 
Secondary: 
 
To assess the preliminary antitumor activity of zanubrutinib in combination with tislelizumab (Cohorts 1 
to 3 and 4B) or a single-agent tislelizumab followed by the combination of zanubrutinib and tislelizumab 
(Cohort 4A) in previously treated subjects with B-cell malignancies. 
 
To characterize the pharmacokinetics (PK) of zanubrutinib and tislelizumab when administered in 
combination. 
 
To assess host immunogenicity to tislelizumab when administered in combination with zanubrutinib. 
Exploratory: 
 
Methodology: 
This is a Phase 1b study to evaluate safety, tolerability, and preliminary efficacy of zanbrutinib in combination 
with tislelizumab in subjects with B-cell malignancies, including relapsed/refractory chronic lymphocytic 
leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), non-germinal center B-cell 
(non-GCB) diffuse large B-cell lymphoma (DLBCL), GCB DLBCL, follicular lymphoma (FL), marginal zone 
lymphoma (MZL), hairy cell leukemia (HCL), transformed FL, Richter’s transformation, primary central nervous 
system lymphoma (PCNSL), and secondary CNS lymphoma (SCNSL) of breast or testicular origin (Note: WM 
subjects are excluded from enrollment as of Amendment 3). The study is divided into dose escalation and a dose 
expansion. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 5 of 132
 
Version 5.0: 02 May 2019 
Study Treatment: 
Zanubrutinib will be administered orally every day with or without food. Tislelizumab will be administered 
intravenously (2.0 mg/kg, 5.0 mg/kg, or 200 mg flat dose, depending on assigned dose level cohort) every 21 
days (Q3W). When the 2 study drugs are administered on the same day (except on the days both PK samples are 
collected), zanubrutinib should be taken at least 30 minutes before tislelizumab infusion.  
For dose escalation, Cycle 1 will be 28 days and all subsequent cycles will be 21 days. Zanubrutinib will be 
administered on Cycle 1 Day 1 and then continuously every day. Tislelizumab will be administered on Cycle 1 
Day 8 and then on Day 1 of all subsequent cycles. The period for DLT assessment is 21 days from Cycle 1 Day 8 
to Cycle 1 Day 28. 
For dose expansion, all cycles will be 21 days. On Day 1 of each cycle, zanubrutinib and tislelizumab will be 
administered on the same day, except for 10 subjects of the CNS lymphoma cohort (Cohort 4A) as described 
below.  
For PCNSL and SCNSL (Cohorts 4A and 4B), 10 subjects (Cohort 4A) will initially receive single-agent 
tislelizumab for 4 cycles at 200 mg intravenously Q3W. On Day 1 of Cycle 5 and thereafter, these 10 subjects 
will receive combination zanubrutinib and tislelizumab at the RP2D defined by dose escalation. For Amendment 
5.0, Cohort 4A is being discontinued.  There were no safety or tolerability signals that led to the discontinuation 
of Cohort 4A. Cohort 4B will be immediately activated with Amendment 5.0. As of March 2019, 3 subjects with 
CNSL have been enrolled in Cohort 4A; however, no subjects remain on study treatment in this cohort, which is 
now closed to treatment and further enrollment. For Cohort 4B, 10 subjects with PCNSL and SCNSL will receive 
combination zanubrutinib and tislelizumab at the RP2D defined by the dose escalation starting at Day 1 of Cycle 
1 and all cycles thereafter. When the 2 study drugs are administered on the same day (except on the days both PK 
samples are collected), zanubrutinib should be taken at least 30 minutes before tislelizumab infusion. All cycles 
will be 21 days.  
Subjects will continue to take zanubrutinib and tislelizumab as scheduled until one of the events listed in Section 
4.2.4.3 occurs.   
Dose Escalation 
The purpose of dose escalation is to determine the MTD for this study. During dose escalation, three dose levels 
will be explored in the following order: 
 
Dose level 1: zanubrutinib 320 mg QD in combination with tislelizumab 2.0 mg/kg Q3W. If 
Dose Level 3 has cleared, subjects will be converted to dose level 3 dosing. 
o 
Dose level -1 (applicable only if dose level 1 exceeds MTD): zanubrutinib 160 mg QD 
in combination with tislelizumab 2.0 mg/kg Q3W. Further reductions of zanubrutinib 
or tislelizumab dose levels may be allowed until a safe dose combination is identified.  
 
Dose level 2: zanubrutinib 320 mg QD with tislelizumab 5.0 mg/kg Q3W. If dose level 3 has 
cleared, subjects will be converted to dose level 3 dosing. 
 
Dose level 3: zanubrutinib 160 mg BID with tislelizumab 200 mg flat dose Q3W 
Dose escalation will follow the same principles as stipulated for a standard 3+3 dose escalation design, with each 
cohort evaluated for safety based on the number of dose-limiting toxicities (DLTs) observed. DLTs are defined in 
Section 4.1.1. Evaluation of a cohort of at least 3 subjects completing the DLT assessment at any given dose level 
is required prior to determining the next dose level and dose regimen for the subsequent cohort. Three subjects in 
the cohort are sufficient if no DLTs are observed within the DLT window for all 3 subjects. More than 3 subjects 
are required per cohort depending on the number of observed DLTs as follows: 
 
< 6 subjects enrolled in the cohort:  
o 
1 subject experiences a DLT during the DLT assessment period: the cohort must enroll a 
minimum of 6 subjects evaluable for DLT.   
o 
≥ 2 subjects experience a DLT during the DLT assessment period: the MTD is considered to 
have been exceeded, and no additional subjects will be treated at the current or higher doses.   
 
≥ 6 subjects enrolled in the cohort: 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 6 of 132
 
Version 5.0: 02 May 2019 
o 
1 subject experiences a DLT during the DLT assessment period: the cohort is considered 
tolerable and to not exceed the MTD. 
o 
 ≥ 33% of subjects (i.e., 2 out of 6) experience a DLT during the DLT assessment period: the 
MTD is considered to have been exceeded, and no additional subjects will be treated at the 
current or higher doses.  
Additional subject(s), may be enrolled to each dose escalation cohort beyond the minimum necessary (3 for 0 
DLT, 6 for 1 DLT).  
The MTD is considered the dose level below that at which ≥ 2 (or ≥ 33%) subjects experience a DLT. If that does 
not occur at any dose level, the MTD is considered not to be reached. The RP2D will be selected by taking into 
account, the MTD, safety, tolerability, and PK profile, under the guidance of the Safety Monitoring Committee 
([SMC] Section 7.3.1). 
Dose Escalation Safety Expansion (additional subject enrollment for Dose Levels 1, 2, and 3) 
Once a dose level has been determined to have not exceeded the MTD, up to 9 additional subjects may be 
enrolled to that dose level cohort (eg, a total of 15 subjects for a dose level found tolerable in a dose escalation 
cohort of 6 subjects) to provide additional safety information on that dose level prior to proceeding to the dose 
expansion part of the study. More than 9 additional subjects may be enrolled if requested by the Safety 
Monitoring Committee for additional safety information (see Section 7.3.1). 
Dose Expansion 
In the dose expansion, there will be 4 dose expansion cohorts at the RP2D for the combination of tislelizumab 
and zanubrutinib (see Section 4.2.1 for the specific inclusion requirements of each cohort): 
 
Cohort 1 (n = 10): GCB DLBCL 
 
Cohort 2 (n = 10): Non-GCB DLBCL 
 
Cohort 3 (n = 20): Transformed lymphoid malignancy 
 
Cohort 4: PCNSL or SCNSL of breast or testicular origin 
- 
Cohort 4A (n = 10): begin with 4 cycles of single-agent tislelizumab at 200 mg Q3W, combination 
of zanubrutinib and tislelizumab starting Cycle 5 
- 
Cohort 4B (n = 10): combination of zanubrutinib and tislelizumab starting Cycle 1 
The dose and schedule of combination zanubrutinib and tislelizumab will be the RP2D as determined by the 
SMC for the non-CNS disease types (Cohorts 1 to 3). The dose and schedule of single-agent tislelizumab will be 
200 mg IV Q3W for Cohort 4 followed by the RP2D for the combination. Approximately 10 to 20 subjects each 
per classification of non-Hodgkin lymphoma will be enrolled in dose expansion. Cohorts 1, 2, 3, and 4A will 
open simultaneously once the RP2D has been determined. 
Planned Number of Subjects: 
Approximately 85 subjects 
Study Population 
Inclusion Criteria:  
1. Dose escalation for Dose Levels 1, 2, and 3: Subjects with relapsed 
or refractory World Health Organization (WHO) classification-
defined B-lymphoid malignancy following at least 1 line of therapy, 
with no therapy of higher priority available, including CLL/SLL, 
MCL, FL, HCL, MZL, non-GCB DLBCL, GCB DLBCL, 
transformed FL, and Richter’s transformation (NOTE: subjects with 
WM are excluded from enrollment as of Amendment 3).  
2. Dose expansion for Cohorts 1 to 4: Subjects with either of the 
following relapsed or refractory WHO-classified lymphoid 
malignancies who have received at least 1 prior line of standard 
therapy:   
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 7 of 132
 
Version 5.0: 02 May 2019 
a. 
Cohort 1: GCB DLBCL, with cell-of-origin defined by 
either immunohistochemistry or gene expression profiling.  
b. Cohort 2: non-GCB DLBCL, with cell-of-origin defined by 
either immunohistochemistry or gene expression profiling. 
Subjects who have transformed to DLBCL from another 
histology will be allowed to enroll in Cohort 3. 
c. 
Cohort 3: Transformed lymphoid malignancy, including but 
not limited to: 
i. Large cell transformation of chronic lymphocytic 
leukemia (Richter’s transformation). 
ii. Large cell transformation of other WHO-classified 
indolent non-Hodgkin lymphoma, including FL 
and MZL. 
d. Cohort 4: Histologically confirmed PCNSL or SCNSL of 
breast or testicular origin: 
i. Must be able to tolerate lumbar puncture and/or 
Ommaya taps 
ii. Must have received at least 1 prior CNS directed 
therapy. 
iii. Presence of brain parenchymal and/or 
leptomeningeal disease. 
3. Aged ≥ 18 years, able and willing to provide written informed 
consent and to comply with the study protocol. 
4. Measurable disease for non-Hodgkin lymphoma defined as ≥ 1 
nodal lesion that is > 15 mm in the longest diameter and can be 
accurately measured in at least 2 dimensions with computed 
tomography (CT) scan, or ≥ 1 extra-nodal lesion that is > 10 mm in 
the longest diameter and can be accurately measured in at least 2 
dimensions with CT scan, except for PCNSL or SCNSL. 
5. Subjects with an accessible tumor lesion must agree to a tumor 
biopsy at Screening and before the drug administration on Cycle 1 
Day 8, ideally taken from the same tumor lesion, for the biomarker 
analysis (up to first 12 qualified subjects), except for PCNSL. 
Additionally, subjects with DLBCL must have archival tumor tissue 
or agree to have a biopsy for confirmation of the DLBCL subtype.  
6. Laboratory parameters as specified below: 
a. 
Hematologic: platelet count ≥ 50 × 109/L; absolute 
neutrophil count ≥1.0 × 109/L; subjects with neutrophils 
< 1.0 × 109/L unless cytopenias are a direct result of active 
leukemia or lymphoma, in which case platelet count ≥ 35 
× 109/L, absolute neutrophil count ≥ 0.75 × 109/L are 
allowed. (Note: Platelet transfusion administered ≤ 7 days 
of screening to raise pre-treatment platelet count to ≥ 35 x 
109/L is prohibited) 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 8 of 132
 
Version 5.0: 02 May 2019 
b. Hepatic: total bilirubin ≤ 1.5 ×the upper limit of normal 
(ULN) or ≤ 2.0 × ULN for subjects with Gilbert syndrome, 
aspartate aminotransaminase (AST), and alanine 
aminotransaminase (ALT) ≤ 3× ULN 
c. 
Renal: creatinine clearance ≥ 30 mL/min (as estimated by 
the Cockcroft-Gault equation or as measured by nuclear 
medicine scan or 24-hour urine collection). Subjects 
requiring hemodialysis will be excluded. 
7. Anticipated survival of at least 4 months 
8. Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 to 2. 
9. Female subjects of childbearing potential and non-sterile males must 
practice at least 1 of the following methods of birth control with 
partner(s) throughout the study and for ≥ 3 months after 
discontinuing study drugs: total abstinence from sexual intercourse, 
double-barrier contraception, intrauterine device or hormonal 
contraceptive initiated at least 3 months prior to first dose of study 
drug. 
10. Male subjects must not donate sperm from initial study drug 
administration, until 180 days after drug discontinuation. 
Exclusion Criteria: 
1. Known, active, central nervous system lymphoma or leukemia, 
except for Cohort 4 
2. Diagnosis with Waldenstrom’s macroglobulinemia (WM). 
3. For PCNSL and SCNSL (Cohort 4): 
a. 
Requires corticosteroid therapy > 16 mg dexamethasone 
daily or equivalent  
b. Corticosteroid therapy ≤ 16 mg dexamethasone daily or 
equivalent at study entry from which, in the Investigator’s 
opinion, it is expected that the subject cannot be tapered off 
after the first 4 weeks of study treatment 
c. 
Intraocular PCNSL without evidence of brain disease 
d. SCNSL actively receiving treatment for extra-CNS disease 
e. 
PCNSL actively receiving concomitant local or systemic 
therapy for CNS disease. 
4. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura 
5. History of stroke or cerebral hemorrhage within 6 months of 
enrollment 
6. History of significant cardiovascular disease, defined as: 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 9 of 132
 
Version 5.0: 02 May 2019 
a. 
Congestive heart failure greater than New York Heart 
Association (NYHA) class II according to the NYHA 
functional classification 
b. Unstable angina or myocardial infarction with 6 months of 
enrollment 
c. 
Serious cardiac arrhythmia or clinical significant 
electrocardiogram (ECG) abnormality: corrected QT wave 
(QTcF) > 480 msec based on the Fridericia’s formula or 
other ECG abnormalities including second-degree 
atrioventricular block type II, third-degree atrioventricular 
block. Subjects who have a pacemaker, will be allowed on 
study despite ECG abnormalities or the inability to 
calculate the QTc. 
7. Severe or debilitating pulmonary disease (dyspnea at rest, significant 
shortness of breath, congestive obstructive pulmonary disease).  
8. History of severe allergic or anaphylactic reactions to monoclonal 
antibody therapy. 
9. Prior BTK inhibitor or anti- PD-1/ PD-L1 treatment 
10. Any illness or condition that in the opinion of the investigator may 
affect safety of treatment or evaluation of any study endpoint.  
11. Active autoimmune diseases or history of severe autoimmune 
diseases; these include but are not limited to a history of immune 
related neurologic disease, multiple sclerosis, autoimmune 
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia 
gravis, systemic lupus erythematosus, rheumatoid arthritis, 
connective tissue diseases, scleroderma, inflammatory bowel 
disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, 
toxic epidermal necrolysis, Stevens-Johnson syndrome, or clinically 
manifest antiphospholipid syndrome. Note: Subjects are permitted to 
enroll if they have vitiligo, eczema, type I diabetes mellitus, or 
endocrine deficiencies, including thyroiditis managed with 
replacement hormones including physiologic doses of 
corticosteroids. Subjects with Sjögren's syndrome and psoriasis 
controlled with topical medication and subjects with positive 
serology, such as antinuclear antibodies, or antithyroid antibodies 
should be evaluated for the presence of target organ involvement 
and potential need for systemic treatment but should otherwise be 
eligible. 
12. A condition requiring systemic treatment with either corticosteroids 
(> 20 mg daily prednisone or equivalent) or other 
immunosuppressive medications within 14 days of study drug 
administration, except for PCNSL and SCNSL. Note: adrenal 
replacement doses ≤ 20 mg daily prednisone or equivalent are 
permitted in the absence of active autoimmune disease; subjects are 
permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  
13. History of interstitial lung disease or noninfectious pneumonitis 
except for that induced by radiation therapy. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 10 of 132
 
Version 5.0: 02 May 2019 
14. Requirement for medications which are strong cytochrome P450 
(CYP)3A inhibitors or inducers. 
15. Vaccination with a live vaccine within 28 days of the initiation of 
treatment. 
16. A candidate for hematopoietic stem cell transplantation or have 
received prior autologous hematopoietic stem cell transplant within 
the past 6 months. Subjects are excluded if they had received prior 
allogeneic stem cell transplantation.  
17. Participated in any investigational drug study within 28 days or not 
recovered from toxicity of any prior chemotherapy to Grade ≤ 1. 
18. History of other active malignancies within 2 years of study entry, 
with the exception of adequately treated in-situ carcinoma of cervix; 
localized basal cell or squamous cell carcinoma of skin; or previous 
malignancy confined and treated locally (surgery or other modality) 
with curative intent.  
19. Major surgery in the past 4 weeks prior to the first day of screening. 
20. Active and symptomatic fungal, bacterial, and/or viral infection, 
human T-cell lymphotropic virus type 1 seropositive status. 
21. HIV infection, or active hepatitis B (eg, hepatitis B surface antigen 
[HBsAg] reactive) or hepatitis C (eg, hepatitis C virus [HCV] 
ribonucleic acid [RNA] detected.   
 
Hepatitis B/C serologic markers and 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 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 (≥ 15 IU/mL) are not eligible.  Subjects 
negative for HBsAg, HBcAb positive, and HBV DNA 
negative must undergo monthly HBV DNA screening by 
PCR.  Subjects positive for HCV antibody but negative 
for HCV RNA (defined as <15 IU) must undergo monthly 
HCV RNA screening.  
22. Inability to comply with study procedures. 
23. Pregnant or nursing women. 
24. Men or women of childbearing potential who refuse to use an 
adequate measure of contraception unless they have past medical 
history of surgical sterilization.  
25. Currently taking or plan to take CNS penetrant therapy such as 
thiotepa, cytarabine, or partially CNS penetrant agents known to be 
active in lymphoid tumors such as rituximab. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 11 of 132
 
Version 5.0: 02 May 2019 
26. Has taken or plans to take any chemotherapy, immunotherapy (eg, 
interleukin, interferon, thymoxin) or any investigational therapies to 
treat leukemia or lymphoma within 28 days or 5 half-lives 
(whichever is shorter) of the first study drug administration, 
including CNS penetrating agents. Has received radiotherapy to treat 
leukemia or lymphoma within 21 days of the first study drug 
administration. 
Test product, dose, and mode 
of administration: 
Zanubrutinib: oral 80 mg capsules 
Tislelizumab: 10 mL/vial, 10 mg/mL 
Tislelizumab will be administered by intravenous (IV) infusion 
Reference therapy, dose, and 
mode of administration: 
Not applicable 
Criteria for Evaluation: 
Primary endpoint: 
 
Dose escalation: The MTD and/or RP2D of tislelizumab in combination with zanubrutinib, as determined 
based on the incidence of protocol-defined dose-limiting toxicities, safety, tolerability, and PK profile. 
 
Dose expansion: The safety and tolerability of combination zanubrutinib and tislelizumab (Cohorts 1 to 3, 
and 4B) or single agent tislelizumab followed by combination zanubrutinib and tislelizumab (Cohort 4A) in 
previously treated subjects with B-cell malignancies, as assessed by the occurrence and severity of AEs 
(Common Terminology Criteria for Adverse Events [CTCAE], version 4.03). 
Secondary endpoints: 
 
The antitumor activity of the combination of zanubrutinib and tislelizumab (Cohorts 1 to 3, and 4B), or 
single-agent tislelizumab, followed by combination zanubrutinib and tislelizumab (Cohort 4A) in previously 
treated subjects with specified B-cell malignancies, as determined by overall response rate (ORR, defined as 
the proportion of subjects who had complete response [CR] or partial response [PR] by standard disease-
specific response criteria), duration of response ([DOR]; defined as the time from the date that a confirmed 
objective response is first documented to the date of progressive disease [PD] or death due to any cause for 
those subjects with a confirmed PR or CR), and progression-free survival ([PFS]; defined as the time from 
the first dose of study medication to objective disease progression or death). 
 
The PK profiles of tislelizumab and zanubrutinib. 
 
The incidence of development of anti-drug antibody to tislelizumab when given in combination with 
zanubrutinib. 
Exploratory endpoints: 
 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 12 of 132
 
Version 5.0: 02 May 2019 
Statistical Methods: 
The number of dose levels in the dose escalation and the emerging zanubrutinib and/or tislelizumab toxicities will 
determine the sample size. It is anticipated that approximately 15 subjects per dose level will be required to 
complete the dose escalation of the study, and approximately 60 subjects (anticipated that approximately 10 
subjects per cohort for Cohorts 1 and 2 and 20 subjects per cohort for Cohorts 3 and 4) will be required to 
complete the dose expansion part of the study. Subjects dropping out before completion will be replaced by 
enrolling a new subject. 
Data will be listed and summarized using SAS® Version 9.2 or higher (SAS Institute, Inc., Cary, NC) according 
to the sponsor-agreed reporting standards, where applicable. Details of analysis methods will be documented in 
the statistical analysis plan. 
All subjects who are exposed to zanubrutinib and/or tislelizumab will be included in the safety analysis set. All 
subjects for whom valid zanubrutinib and/or tislelizumab PK parameters can be estimated will be included in the 
PK analysis set on an as treated basis. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 13 of 132
 
Version 5.0: 02 May 2019 
TABLE OF CONTENTS 
SIGNATURE ............................................................................................................................ 2 
PROTOCOL AMENDMENT 5.0 - AMENDMENT RATIONALE ........................................ 3 
SYNOPSIS ................................................................................................................................ 4 
TABLE OF CONTENTS ........................................................................................................ 13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 18 
1.0 
INTRODUCTION ....................................................................................................... 21 
1.1 
Background and Pharmacology ....................................................................... 21 
1.1.1 
Zanubrutinib (BGB-3111) ................................................................. 21 
1.1.2 
Tislelizumab (BGB-A317) ................................................................ 22 
1.2 
Overview of Clinical Pharmacology ............................................................... 23 
1.2.1 
Zanubrutinib ...................................................................................... 23 
1.2.2 
Tislelizumab ...................................................................................... 24 
1.3 
Overview of Safety and Efficacy .................................................................... 24 
1.3.1 
Zanubrutinib ...................................................................................... 24 
1.3.2 
Tislelizumab ...................................................................................... 25 
1.4 
Benefits and Risks ........................................................................................... 26 
1.4.1 
Zanubrutinib ...................................................................................... 26 
1.4.2 
Tislelizumab ...................................................................................... 26 
1.5 
Rationale for the Combination of Zanubrutinib and Tislelizumab.................. 27 
1.6 
Rationale for Zanubrutinib Dose and Schedule ............................................... 27 
1.7 
Rationale for Tislelizumab Flat Dose and Schedule ....................................... 28 
2.0 
STUDY OBJECTIVES ............................................................................................... 29 
2.1 
Primary Objectives .......................................................................................... 29 
2.2 
Secondary Objectives ...................................................................................... 30 
2.3 
Exploratory Objectives .................................................................................... 30 
3.0 
STUDY ENDPOINTS ................................................................................................. 30 
3.1 
Primary Endpoints ........................................................................................... 30 
3.2 
Secondary Endpoints ....................................................................................... 30 
3.3 
Exploratory Endpoints ..................................................................................... 31 
4.0 
INVESTIGATIONAL PLAN ..................................................................................... 31 
4.1 
Summary of Study Design ............................................................................... 31 
4.1.1 
Dose-Limiting Toxicity ..................................................................... 31 
4.1.2 
Drug Hold and Dose Modification .................................................... 32 
4.1.3 
Schedule of Assessments .................................................................. 34 
4.2 
Selection of Study Population ......................................................................... 47 
4.2.1 
Inclusion Criteria ............................................................................... 47 
4.2.2 
Exclusion Criteria .............................................................................. 48 
4.2.3 
Other Eligibility Criteria Considerations .......................................... 51 
4.2.4 
Subject Completion and Withdrawal ................................................ 52 
4.2.4.1 
Subject Completion ......................................................... 52 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 14 of 132
 
Version 5.0: 02 May 2019 
4.2.4.2 
Subject Withdrawal/Discontinuation .............................. 52 
4.2.4.3 
Subject Withdrawal from the Investigational 
Product ............................................................................ 52 
5.0 
STUDY TREATMENTS ............................................................................................ 54 
5.1 
Description of Investigational Product ............................................................ 54 
5.2 
Dosage and Administration ............................................................................. 54 
5.2.1 
Zanubrutinib ...................................................................................... 55 
5.2.2 
Tislelizumab ...................................................................................... 55 
5.2.3 
Dose Escalation ................................................................................. 56 
5.2.4 
Dose Escalation for Safety Expansion (Additional Subject 
Enrollment for Dose Levels 1, 2, and 3) ........................................... 57 
5.2.5 
Dose Expansion ................................................................................. 57 
5.3 
Treatment Assignment ..................................................................................... 58 
5.4 
Packaging and Labeling................................................................................... 58 
5.5 
Handling and Storage ...................................................................................... 58 
5.6 
Product Accountability .................................................................................... 59 
5.7 
Assessment of Compliance .............................................................................. 59 
5.8 
Treatment of Investigational Product Overdose .............................................. 59 
5.9 
Occupational Safety ......................................................................................... 59 
6.0 
CONCOMITANT MEDICATIONS AND NONDRUG THERAPIES ...................... 60 
6.1 
Permitted Medications ..................................................................................... 60 
6.2 
Prohibited Medications .................................................................................... 60 
6.3 
Medications to Be Used with Caution ............................................................. 61 
6.3.1 
Zanubrutinib ...................................................................................... 61 
6.3.2 
Tislelizumab ...................................................................................... 61 
7.0 
SAFETY, PHARMACOKINETIC, EFFICACY, AND OTHER 
ASSESSMENTS ......................................................................................................... 62 
7.1 
Screening: Demographic and Baseline Assessments ...................................... 62 
7.1.1 
Hepatitis B/C Testing ........................................................................ 63 
7.1.2 
Pulmonary Function Tests................................................................. 64 
7.2 
Assessments During Treatment ....................................................................... 65 
7.2.1 
Local Laboratory Evaluation............................................................. 65 
7.2.2 
Physical Examination, Vital Signs, and B Symptoms ...................... 66 
7.2.3 
Electrocardiogram and Cardiac Function .......................................... 66 
7.2.4 
Positron Emission Tomography (PET)-Computed 
Tomography (CT) and CT with Contrast Computed 
Tomography ...................................................................................... 67 
7.2.5 
Magnetic Resonance Imaging with Gadolinium of Brain ................. 67 
7.2.6 
Bone Marrow Evaluation .................................................................. 68 
7.2.7 
Ophthalmologic Examination ........................................................... 68 
7.2.8 
Ultrasound of Testicles ..................................................................... 68 
7.2.9 
Bilateral Breast Mammogram ........................................................... 69 
7.2.10 
Adverse Events .................................................................................. 69 
7.2.11 
Overall Disease Response Assessments............................................ 69 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 15 of 132
 
Version 5.0: 02 May 2019 
7.3 
Safety ............................................................................................................... 69 
7.3.1 
Safety Monitoring ............................................................................. 69 
7.3.1.1 
SMC during Dose Escalation .......................................... 70 
7.3.1.2 
SMC during Dose Expansion .......................................... 70 
7.3.2 
Pregnancy .......................................................................................... 71 
7.3.2.1 
Pregnancy Testing ........................................................... 71 
7.3.2.2 
Time Period for Collecting Pregnancy Information ........ 71 
7.3.2.3 
Action to Be Taken If a Pregnancy Occurs ..................... 71 
7.4 
Safety Follow-up ............................................................................................. 72 
7.5 
Efficacy Follow-up .......................................................................................... 72 
7.6 
Survival Follow-up .......................................................................................... 72 
7.7 
Treatment Beyond Disease Progression .......................................................... 72 
7.8 
Efficacy ............................................................................................................ 73 
7.9 
Pharmacokinetics ............................................................................................. 74 
7.10 
Other Assessments ........................................................................................... 74 
7.10.1 
Archival/Fresh Tumor Tissue ........................................................... 74 
7.10.2 
Anti-Tislelizumab Antibodies ........................................................... 75 
7.10.3 
Biomarkers in the Blood ................................................................... 75 
7.11 
Appropriateness of Measurements .................................................................. 75 
8.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 75 
8.1 
Monitoring ....................................................................................................... 76 
8.2 
Data Management/Coding ............................................................................... 77 
8.3 
Quality Assurance Audit ................................................................................. 78 
9.0 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................... 79 
9.1 
Definition of an Adverse Event ....................................................................... 79 
9.2 
Definition of a Serious Adverse Event ............................................................ 80 
9.3 
Lack of Efficacy .............................................................................................. 81 
9.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ................................................ 81 
9.5 
Time Period, Frequency, and Method of Detecting Adverse Events 
and Serious Adverse Events ............................................................................ 81 
9.5.1 
Adverse Event Reporting Period ....................................................... 81 
9.5.2 
Eliciting Adverse Events ................................................................... 81 
9.6 
Specific Instructions for Recording Adverse Events and Serious 
Adverse Events ................................................................................................ 82 
9.6.1 
Disease Progression .......................................................................... 82 
9.6.2 
Death ................................................................................................. 82 
9.7 
Recording of Adverse Events and Serious Adverse Events ............................ 82 
9.8 
Evaluating Adverse Events and Serious Adverse Events ................................ 83 
9.8.1 
Assessment of Severity ..................................................................... 83 
9.8.2 
Assessment of Causality ................................................................... 83 
9.9 
Follow-up of Adverse Events and Serious Adverse Events ............................ 84 
9.10 
Prompt Reporting of Serious Adverse Events ................................................. 85 
9.10.1 
Timeframes for Submitting Serious Adverse Events ........................ 85 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 16 of 132
 
Version 5.0: 02 May 2019 
9.10.2 
Completion and Transmission of the Serious Adverse Event 
Report ................................................................................................ 85 
9.11 
Regulatory Reporting Requirements for Serious Adverse Events .................. 86 
9.12 
Post-study Adverse Events and Serious Adverse Events ................................ 87 
9.13 
Serious Adverse Events Related to Study Participation .................................. 87 
9.14 
Management of AE of Special Interest ........................................................... 87 
9.14.1 
Zanubrutinib ...................................................................................... 87 
9.14.1.1 
Tumor Lysis Syndrome ................................................... 87 
9.14.1.2 
Immune-related Adverse Events ..................................... 87 
9.14.2 
Tislelizumab ...................................................................................... 88 
9.14.2.1 
Tumor Lysis Syndrome ................................................... 88 
9.14.2.2 
Infusion-related Reactions .............................................. 88 
9.14.2.3 
Severe Hypersensitivity Reactions and Flu-like 
Symptoms ........................................................................ 90 
9.14.2.4 
Immune-related Adverse Events ..................................... 90 
9.15 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees ......................................................... 92 
10.0 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................. 92 
10.1 
Sample Size Considerations ............................................................................ 92 
10.2 
General Considerations for Data Analysis ...................................................... 92 
10.2.1 
Analysis Set ....................................................................................... 92 
10.2.2 
Interim Analysis ................................................................................ 93 
10.2.3 
Withdrawal ........................................................................................ 93 
10.3 
Efficacy Analyses ............................................................................................ 93 
10.3.1 
Primary Analysis ............................................................................... 93 
10.3.2 
Efficacy Analysis .............................................................................. 94 
10.3.3 
Exploratory Analysis ......................................................................... 94 
10.4 
Safety Analyses ............................................................................................... 94 
10.4.1 
Extent of Exposure ............................................................................ 95 
10.4.2 
Electrocardiogram ............................................................................. 95 
10.5 
Pharmacokinetics Analyses ............................................................................. 95 
10.6 
Immunogenicity Analyses ............................................................................... 97 
10.7 
Biomarker Analyses ........................................................................................ 97 
11.0 
ETHICS ....................................................................................................................... 98 
11.1 
Regulatory Authority Approval ....................................................................... 98 
11.2 
Ethical Conduct of the Study and Ethics Approval ......................................... 98 
11.3 
Informed Consent ............................................................................................ 99 
11.4 
Investigator Reporting Requirements .............................................................. 99 
12.0 
STUDY ADMINISTRATION .................................................................................... 99 
12.1 
Study and Study Center Closure ...................................................................... 99 
12.2 
Records Retention ......................................................................................... 100 
12.3 
Provision of Study Results and Information to Investigators ........................ 100 
12.4 
Information Disclosure and Inventions ......................................................... 101 
12.4.1 
Study Report and Publication Policy .............................................. 102 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 17 of 132
 
Version 5.0: 02 May 2019 
13.0 
REFERENCES .......................................................................................................... 103 
14.0 
APPENDICES ........................................................................................................... 105 
APPENDIX 1: 
SIGNATURE OF INVESTIGATOR .............................................. 105 
APPENDIX 2: 
CLINICAL LABORATORY ASSESSMENTS ............................. 106 
APPENDIX 3: 
BLOOD REQUIREMENTS ........................................................... 107 
APPENDIX 4: 
RESPONSE CRITERIA ................................................................. 111 
APPENDIX 5: 
DRUG DILUTION CALCULATION ............................................ 120 
APPENDIX 6: 
IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT ............................................................................................. 122 
 
LIST OF TABLES 
Table 4-1 
Schedule of Assessments (Dose Escalation for Dose Levels 1, 2, and 
3) ...................................................................................................................... 35 
Table 4-2 
Schedule of Assessments (Dose Expansion) ................................................... 40 
Table 4-3 
Pharmacokinetic/ADA Sampling and Safety Measurements From the 
First 30 Subjects (Dose Escalation) ................................................................. 45 
Table 4-4 
Pharmacokinetic/ADA Sampling and Safety Measurements (Dose 
Expansion) ....................................................................................................... 46 
Table 6-1 
Dose Modification for Zanubrutinib when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers ............................................. 61 
Table 7-1:  
Active Hepatitis B or Hepatitis C Infection (Detected Positive by 
Polymerase Chain Reaction) ........................................................................... 64 
Table 9-1 
Timeframe for Reporting Serious Adverse Events to the Sponsor ................. 85 
Table 9-2 
Treatment Modification for Symptoms of Infusion-Related Reactions 
Due to Study Drug(s) ....................................................................................... 89 
Table 9-3 
Immune-Related Adverse Events .................................................................... 91 
 
LIST OF FIGURES 
Figure 1-1. 
Bruton’s Tyrosine Kinase Occupancy in Lymph Node Tissue from 
Patients with Different Types of Lymphoma and Doses of 
Zanubrutinib .................................................................................................... 28 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 18 of 132
 
Version 5.0: 02 May 2019 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AEs 
adverse events 
ALT 
alanine aminotransaminase 
anti-HBc 
hepatitis B core antibody 
AST 
aspartate aminotransaminase 
AUC 
area under the plasma concentration-time curve 
BCR 
B-cell receptor 
BID 
twice a day 
BTK 
Bruton’s tyrosine kinase 
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
electrocardiogram 
EGFR 
epithelial growth factor receptor 
EPG 
electrophoresis 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FL 
follicular lymphoma 
GCB 
germinal center B-cell 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCL 
hairy cell leukemia 
HCV 
hepatitis C virus 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
50% maximal inhibiting concentration 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 19 of 132
 
Version 5.0: 02 May 2019 
IgVH 
immunoglobin variable region heavy chain 
IHC 
immunohistochemistry 
IND 
investigational new drug 
IRB 
Institutional Review Board  
IV 
intravenous 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minor response 
MRI 
magnetic resonance imaging 
MTD 
maximal tolerated dose 
MUGA 
multigated acquisition scan 
MZL 
marginal zone lymphoma 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria 
OS 
overall survival 
ORR 
overall response rate 
PCR 
polymerase chain reaction 
PCNSL 
primary central nervous system (CNS) lymphoma 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed death ligand-1 
PD-L2 
programmed death ligand-2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response/remission 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
QD 
once a day  
QTc 
corrected QT wave 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SCNSL  
secondary CNS lymphoma 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
SOPs 
standard operating procedures 
t1/2 
terminal half-life 
TEC 
tyrosine kinase expressed in hepatocellular carcinoma 
TIL 
tumor-infiltrating lymphocyte 
tislelizumab 
BGB-A317 
tmax 
time to maximum observed plasma concentration 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 20 of 132
 
Version 5.0: 02 May 2019 
 
 
WBC 
white blood cell 
WHO 
World Health Organization 
WM 
Waldenstrom macroglobulinemia  
zanubrutinib 
BGB-3111 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 21 of 132
 
Version 5.0: 02 May 2019 
1.0 INTRODUCTION 
1.1 
Background and Pharmacology 
1.1.1 
Zanubrutinib (BGB-3111) 
Bruton’s tyrosine kinase (BTK), a member of the tyrosine kinase expressed in hepatocellular 
carcinoma (TEC) family of 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 has demonstrated promising anti-tumor activity in several B-cell 
malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), 
follicular lymphoma (FL), multiple myeloma, and activated B-cell-like subtype of diffuse large 
B-cell lymphoma (DLBCL).1,2 
Ibrutinib was approved by the US Food and Drug Administration (FDA) for treatment of MCL 
(November 2013) and CLL (February 2014) in subjects who had received at least 1 prior 
therapy.3,4   More recently it was also approved for the treatment of subjects with CLL with 17p 
deletion (July 2014) and Waldenstrom macroglobulinemia ([WM]; January 2015). 
While ibrutinib treatment frequently generates objective responses in these diseases, few of them 
are complete responses (CRs); thus management requires continuous treatment.5,6  In addition, 
though ibrutinib is well-tolerated in comparison to traditional chemotherapies, it is associated 
with adverse reactions that in some cases can be life threatening or treatment limiting. These 
adverse reactions, including but not limited to skin rash, nausea, vomiting, thrombocytopenia, 
bleeding, and atrial fibrillation, are believed to be due to ibrutinib’s off-target activities against 
epithelial growth factor receptor (EGFR)/Janus kinase 3/TEC. 
Zanubrutinib (also known as BGB-3111) is a potent, specific, and irreversible BTK inhibitor with 
a favorable pharmacology/ toxicology profile. Preclinical data suggests that zanubrutinib is 
differentiated from ibrutinib in the following aspects: 
1. Zanubrutinib is more selective than ibrutinib in the inhibition of BTK versus EGFR, Gardner-
Rasheed feline sarcoma viral oncogene homolog, Fyn-related kinase, human epidermal 
growth factor receptor (HER)2, HER4, interleukin-2-inducible T-cell kinase, Janus kinase 3, 
lymphocyte-specific protein tyrosine kinase, and TEC, and therefore may have fewer off-
target toxicities (eg, diarrhea). 
2. Zanubrutinib has high bioavailability when administered orally and has rapid clearance in 
rodents and dogs. The predicted efficacious dose of zanubrutinib in subjects is much lower 
than ibrutinib, which also could contribute to better tolerability. 
3. Due to its weaker interleukin-2-inducible T-cell kinase inhibitory activity, zanubrutinib 
displayed significantly less inhibitory effect on rituximab-induced antibody dependent cell-
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 22 of 132
 
Version 5.0: 02 May 2019 
mediated cytotoxicity than ibrutinib in preclinical studies and this could likely result in better 
efficacy in subjects when combined with rituximab or other antibody therapies that are 
dependent on antibody-dependent cell-mediated cytotoxicity.  
Refer to the Investigator’s Brochure (IB) for more detailed information on the background of 
zanubrutinib (BGB-3111). 
1.1.2 
Tislelizumab (BGB-A317) 
The immune checkpoint-inhibitory receptor, programmed cell death-1 (PD-1), is mainly 
expressed in activated T-cells including CD8+ cytotoxic T-lymphocytes and CD4+ T-helper 
lymphocytes.7 It is believed that PD-1 plays an important role in immune modulation of tumor 
progression by regulating the key inhibitory signaling in the T-cells when engaged by its ligands. 
The PD-1 signaling cascade negatively regulates T-cell receptor and attenuates T-cell 
proliferation and functional activities, leading to T-cell exhaustion. In general, PD-1 is rarely 
expressed on malignant B-cell-originated lymphoma cells and is frequently expressed on the 
T-cell lineage of tumor-infiltrating lymphocytes (TILs) in various subtypes of lymphoma, 
particularly those with follicular lymphoma and certain types of T-cell lymphoma. Chronic 
lymphocytic leukemia or small lymphocytic lymphoma is an exception because PD-1 expression 
is seen both on circulating malignant cells and in the tumor microenvironment. Programmed 
death ligand (PD-L)-1 overexpression is not usually seen in B-cell non-Hodgkin lymphoma. 
However, it is seen in the several disorders, including primary mediastinal B-cell lymphoma 
harboring a genetic mutation (9p24.1) that causes upregulation of PD-L1 and PD-L2, Epstein-
Barr virus-positive lymphomas in which the virus induces PD-L1 expression, T-cell histocyte-
rich diffuse large B-cell lymphoma, some cases of activated DLBCL, and lymphoplasmacytoid 
lymphoma.8  Such evidence provides the basis for cancer immunotherapeutic intervention via 
antagonist to PD-1. 
Three PD-1 inhibitors have been assessed in patients with lymphoid malignancies: pidilizumab, 
nivolumab, and pembrolizumab. Among them, pembrolizumab and nivolumab have been 
approved by FDA for treatment of advanced or unresectable melanoma. Nivolumab was 
approved to treat patients with advanced/metastatic squamous non–small cell lung cancer with 
progression on or after platinum-based chemotherapy, renal cell carcinoma as second line 
treatment after failure from anti-angiogenic agents, and classical Hodgkin lymphoma after 
autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation treatment 
with brentuximab vedotin. Toxic effects that are life threatening are rare, and few studies report 
treatment-related deaths. Moreover, the anti-tumor effects of anti-PD-1 antibodies have been 
observed in patients with other B-cell malignancies, including DLBCL and FL. Pidilizumab was 
evaluated in combination with rituximab in a single-arm Phase 2 study in relapsed or refractory 
FL. Among 32 total patients (29 eligible), 66% of patients achieved an overall response rate, 52% 
showed CR, and 14% showed partial response.9  The Phase 1 clinical study of nivolumab treated 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 23 of 132
 
Version 5.0: 02 May 2019 
82 patients with relapsed or refractory lymphoid malignancies. Responses were seen in 4 of 11 
patients with DLBCL, 4 of 10 patients with FL, and 2 of 5 patients with peripheral T-cell 
lymphoma.10  In another study, pembrolizumab was administered to 29 patients with classic 
Hodgkin lymphoma as a phase 1b study. These patients were extensively pretreated: 52% of them 
had undergone 5 or more previous lines of treatment, and all of them had received previous 
brentuximab therapy. Response to treatment was recorded in 20 (66%) patients, including 6 
patients who showed a CR. The disease was controlled in 25 of 29 patients (86%), and the 
median time to drug response was 12 weeks. Toxic effects were negligible.11 
Tislelizumab (also known as BGB-A317) is a humanized IgG4 variant monoclonal antibody 
against PD-1 being developed for treatment of human malignancies. Tislelizumab has 
demonstrated a favorable toxicology and safety pharmacology profile in nonclinical experiments. 
Moreover, tislelizumab binds to the extracellular domain of human PD-1 with high affinity and 
specificity; it potently blocks PD-1-mediated signal transduction and activates human T-cells and 
primary peripheral blood mononuclear cells in the in vitro cell-based assays, and it mobilizes 
immune cells inhibiting tumor growth in mouse cancer models. 
1.2 
Overview of Clinical Pharmacology 
1.2.1 
Zanubrutinib 
In the Phase 1, first-in-human study of zanubrutinib as monotherapy (A Phase 1, Open-Label, 
Multiple-Dose, Dose Escalation, and Expansion Study to Investigate the Safety and 
Pharmacokinetics (PK) of the BTK Inhibitor BGB-3111 in Subjects with B-Cell Lymphoid 
Malignancies; protocol number BGB-3111-AU-003), interim PK data in a limited number of 
subjects showed that zanubrutinib is rapidly absorbed and eliminated after oral administration. 
The maximum serum concentration and the drug exposure (area under the concentration-time 
curve [AUC]) increased in a nearly dose-proportional manner from 40 mg to 320 mg, both after 
the single dose and at steady state. The terminal half-life (t1/2) ranged from 1.8 hours to 3.7 hours. 
At 320 mg once daily (QD) and 160 mg twice daily (BID), the means for maximum observed 
plasma concentration (Cmax) and the area under the concentration-time curve from 0 to 24 hours 
(AUC0-24h) are around 646 ng/mL and 2,704 ng/mL*h, and 282 ng/mL and 3,006 ng/mL*h, 
respectively, at the steady state.  
In the same Phase 1 study, the pharmacodynamics of zanubrutinib as measured by BTK 
occupancy in peripheral blood mononuclear cells was determined in a limited number of subjects. 
The data indicate that even at the starting dose (40 mg), zanubrutinib achieved rapid, durable, and 
near complete inhibition of BTK. These data suggest that zanubrutinib is a very potent BTK 
inhibitor. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 24 of 132
 
Version 5.0: 02 May 2019 
Study BGB-3111-103 evaluated food effect on zanubrutinib after oral administration in human 
subjects. Dosing zanubrutinib with a high-fat or low-fat meal did not significantly affect the AUC 
of zanubrutinib. Zanubrutinib may be taken with or without food.  
Results from a dedicated drug-drug interaction study (BGB-3111-104) indicated that co-
administration of zanubrutinib with the strong CYP3A inducer rifampin (600 mg every day for 8 
days) decreased exposure of zanubrutinib by 13.5-fold for AUC0-∞, and 12.6-fold for Cmax, in 
healthy subjects.  Co-administration of zanubrutinib with the strong CYP3A inhibitor 
itraconazole (200 mg every day for 4 days) increased exposure of zanubrutinib by 3.8-fold for 
AUC0-∞, and 2.6-fold for Cmax.  These results are consistent with the role for CYP3A isoenzymes 
as the principal metabolic pathway for zanubrutinib. 
Based on the in vitro study, a clinical drug-drug interaction study (BGB-3111-108) was 
conducted to assess the effect of zanubrutinib on the PK of substrates of CYP3A (midazolam), 
CYP2C9 (warfarin), CYP2C19 (omeprazole), P-gp (digoxin), BCRP (rosuvastatin) using a 
cocktail approach.  The results show that zanubrutinib does not significantly affect drugs 
metabolized by CYP2C9 (warfarin) or transported by P-gp (digoxin) and BCRP (statins).  
Zanubrutinib has a mild induction effect on CYP3A and CYP2C19 enzymes.  AUC0-t and Cmax 
values were approximately 47% and 30% lower, respectively, when midazolam was 
coadministered with zanubrutinib.  AUC0-t and Cmax values were approximately 36% and 20% 
lower, respectively, when omeprazole was coadministered with zanubrutinib. 
1.2.2 
Tislelizumab 
There are 18 ongoing studies with tislelizumab, 7 with available preliminary data. For the most 
recent information on the clinical pharmacology experience with tislelizumab, please refer to the 
Investigator’s Brochure. Preliminary PK analysis set showed that a 2-compartment model with 
first order elimination best described the PK data.  Systemic clearance of tislelizumab was 0.173 
L/day, volume of distribution in the central and peripheral compartment were 2.89 and 1.76 L, 
respectively, and terminal elimination half-life was approximately 19 days. Race, gender, and 
body weight are not significant covariates on the clearance of tislelizumab, which supports fixed-
dosing across different ethnic groups. 
1.3 
Overview of Safety and Efficacy 
1.3.1 
Zanubrutinib  
Preliminary results have demonstrated that zanubrutinib has promising anti-tumor activity in 
patients with B-cell malignancies, including CLL, WM, MCL, hairy cell leukemia (HCL), 
DLBCL, marginal zone lymphoma (MZL), and FL. As of 19 October 2015, there are 25 patients 
enrolled in Part 1 (dose escalation) and30 patients enrolled in Part 2 (safety, schedule, and 
efficacy expansion) of the study (BGB-3111-AU-003). Four doses of zanubrutinib (40 mg, 
80 mg, 160 mg, and 320 mg, QD) and 2 dose regimens of zanubrutinib (320 mg QD versus 160 
mg BID) had been evaluated. Twenty-five patients in Part 1 and 14 patients in Part 2 have at least 
1 disease response assessment. Patients were evaluated per histology-specific standard criteria, 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 25 of 132
 
Version 5.0: 02 May 2019 
and the best responses were: 3 patients achieved complete CR, including 1 DLBCL patient and 2 
MCL patients; 26 patients achieved partial responses/remission (PR), including 13 with CLL, 6 
with WM, 6 with MCL, and 1 with HCL; 4 patients achieved stable disease (SD), including 1 
patient with CLL, 1 patient with MCL, 1 patient with MZL, and 1 patient with FL. Six patients, 3 
with DLBCL, 1 with WM, 1 with MCL, and 1 with Burkitt-like lymphoma, presented with 
progressive disease (PD).  
 Complete response/remission (n = 3): 1 DLBCL patients and 2 MCL patients. 
 Partial response/remission (PR; n = 26): 13 CLL patients, 6 WM patients, 6 MCL 
patients, 1 HCL patient. 
 Stable disease (SD; n= 4): 1 CLL patients, 1 MCL patient, 1 MZL patient, 1 FL patient. 
 Progressive disease (n = 6): 3 DLBCL patients; 1 WM patient, 1 MCL patient, 1 Burkitt-
like lymphoma patient. 
As of 19 October 2015, except for the 6 patients who had PD, all the remaining 33 patients who 
have had at least 1 disease assessment have received the treatment of zanubrutinib  for more than 
2 months. No dose limiting toxicities (DLT) were encountered, and the maximum tolerated dose 
(MTD) was not reached. There were no drug-related serious adverse events (SAEs). The only 4 
drug-related Grade 3/4 adverse events (AEs) were neutropenia events, which were transient and 
did not lead to drug discontinuation. Six patients had a baseline history of atrial 
fibrillation/flutter, but no exacerbation or new events of atrial fibrillation/flutter were reported. 
For the most recent information on the clinical experience with zanubrutinib, please refer to the 
Investigator’s Brochure. 
The QT interval prolongation potential of zanubrutinib was evaluated in healthy subjects in a 
thorough QT study (BGB-3111-106).  Results from this study demonstrated that single oral doses 
of zanubrutinib at a therapeutic dose of 160 mg and a supratherapeutic dose of 480 mg did not 
have a clinically relevant effect on ECG parameters, including QTc intervals and other ECG 
intervals. Because of the short half-life and no accumulation seen upon multiple-dosing, these 
results are also applicable for steady-state conditions. 
1.3.2 
Tislelizumab 
As of 8 October 2015, in the ongoing Phase 1 study, 32 subjects have been enrolled in 3 
escalating cohorts and 1 expansion cohort receiving tislelizumab at 0.5 mg/kg Q2W (n = 3), 2 
mg/kg Q2W (n = 23), and 5 mg/kg (n = 6). Tislelizumab has been well tolerated. There were no 
DLTs at 0.5 mg/kg and 2 mg/kg Q2W cohorts. One DLT (Grade 3 colitis) was observed among 6 
subjects treated at 5 mg/kg Q2W cohort. The dose escalation is ongoing at 10 mg/kg Q2W, and 
the MTD has not been reached to date. Efficacy data are too preliminary to draw conclusions. For 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 26 of 132
 
Version 5.0: 02 May 2019 
the most recent information on the clinical experience with tislelizumab, please refer to the 
Investigator’s Brochure 
1.4 
Benefits and Risks 
1.4.1 
Zanubrutinib 
Zanubrutinib has demonstrated a very favorable toxicology and safety pharmacology profile, as 
determined by pharmacologic characteristics in the ongoing clinical studies. Preliminary data 
show that zanubrutinib is well tolerated and has promising anti-tumor activity in advanced B-cell 
malignancies, including CLL, MCL, WM, HCL, DLBCL, FL, and MZL.  Approximately 400 
patients have been enrolled worldwide in completed and ongoing clinical trials evaluating 
zanubrutinib and received at least 1 dose of zanubrutinib.  Available data for zanubrutinib support 
a positive benefit-risk profile for the use of zanubrutinib as an investigational agent for treatment 
of previously untreated B cell lymphoid malignancies.  
Zanubrutinib is an investigational drug with only limited safety data in humans. Subjects enrolled 
in clinical studies with zanubrutinib must be closely monitored by means of AEs, vital signs, 
electrocardiograms (ECGs), and clinical laboratory safety tests of blood and urine.  For further 
discussion on safety profile of zanubrutinib, please refer to the most recent version of the 
Investigator’s Brochure. 
1.4.2 
Tislelizumab  
The subjects enrolled in clinical studies with tislelizumab must be closely monitored by recording 
AEs, recording vital signs and ECGs, and conducting clinical laboratory safety tests of blood and 
urine. 
Clinical experience with existing drugs of the same therapeutic class (anti-PD-1 monoclonal 
antibodies) suggests the most common AEs were Grade 1/2, including arthralgia, cough, 
diarrhea, fatigue, fever, nausea, pruritus, and rash. However, Grade 3/4 treatment-related AEs 
occurred in 15% of patients in the nivolumab study, and there were 3 deaths, all attributed to 
pulmonary toxicity.12,13  Grade 3/4 AEs were also reported in the pembrolizumab studies, 
including 1 subject who died of myocardial infarction while being treated for 
pneumonitis/pneumonia.14,15  Drug-related AEs of special interest (AEs with potentially immune-
related etiology) included, vitiligo, pneumonitis, hepatitis, colitis, thyroiditis, and hypophysitis, 
which may be observed during multiple dose escalation in subjects with cancer.16,17,18 
More than 400 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) and in combination. The safety profile is consistent with known class effects of 
anti-PD-1 antibodies, and included mostly mild/moderate AEs. Very few Grade 3/4 infusion-
related AEs have been observed, which are generally reversible and manageable with study drug 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 27 of 132
 
Version 5.0: 02 May 2019 
interruption and/or steroid treatment.  For further discussion on safety profile of tislelizumab, 
please refer to the most recent version of the Investigator’s Brochure. 
1.5 
Rationale for the Combination of Zanubrutinib and Tislelizumab 
As noted above, signaling via the aberrantly activated BCR pathway has a critical role in the 
pathogenesis of B-cell tumors by promoting survival and clonal expansion of malignant B-cells. 
Ibrutinib, a FDA-approved BTK inhibitor, has demonstrated objective responses among different 
B-cell malignancies in clinical studies, including CLL/small lymphocytic lymphoma (SLL), 
MCL, DLBCL, FL, and WM. Zanubrutinib is a more potent, more specific second-generation 
BTK inhibitor than ibrutinib. In the ongoing Phase 1 study (BGB-3111-AU-003), zanubrutinib 
has been shown to be well tolerated, safe, and active in various histopathological subtypes of B-
cell malignancies.  
Early clinical studies using PD-1 inhibitors have also shown significant clinical activity in 
various subtypes of relapsed lymphoma and a superior safety profile. PD-1 inhibitors are moving 
into later phases of clinical studies in hematologic malignancies and are being evaluated in the 
treatment of refractory/relapsed lymphomas (non-Hodgkin lymphoma and Hodgkin lymphoma) 
and will likely be used for earlier-line treatment of B-cell malignancies. The combination of 
PD-1/PD-L1 inhibitors (i.e., nivolumab, pembrolizumab, and MEDI-4736) with BCR pathway 
inhibitors (i.e., ibrutinib and ACP-196), are being evaluated in different B-cell malignancies with 
the expectation of greater benefit for patients.  
This study is designed to evaluate the safety, tolerability, and PK profile, as well as preliminary 
anti-tumor activity of zanubrutinib, in combination with tislelizumab in subjects with B-cell 
malignancies. The doses and regimens of zanubrutinib and tislelizumab are selected based on the 
PK, safety and tolerability, pharmacodynamics, and preliminary efficacy in the ongoing 
zanubrutinib study (BGB-3111-AU-003) and tislelizumab study (BGB-A317_Study_001).  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, the Declaration of Helsinki, and any applicable regulatory requirements. 
1.6 
Rationale for Zanubrutinib Dose and Schedule  
In the ongoing Phase 1 study of zanubrutinib monotherapy in patients with B-cell malignancies, 
30 subjects from the study receiving either zanubrutinib 320 mg orally QD (n = 12) or 160 mg 
orally BID (n = 18) were evaluated for BTK occupancy in lymph node tissue using a fluorescent 
probe assay on paired lymph node biopsies. Median occupancy was 100% in patients receiving 
zanubrutinib 160 mg BID (n = 18) versus 94% in patients receiving zanubrutinib 320 mg QD 
(n = 12; p = 0.002, Wilcoxon test). The proportion of subjects with ≥ 90% BTK occupancy was 
94% (160 mg BID) versus 58% (320 mg QD; p = 0.027, Fisher’s Exact test). Occupancy did not 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 28 of 132
 
Version 5.0: 02 May 2019 
appear to differ among histologic subtypes. The BTK occupancy in lymph node tissue by 
dose/schedule is shown in Figure 1-1. 
Figure 1-1. 
Bruton’s Tyrosine Kinase Occupancy in Lymph Node Tissue from Patients 
with Different Types of Lymphoma and Doses of Zanubrutinib  
 
BTK = Bruton’s tyrosine kinase; CLL = chronic lymphocytic leukemia; FL = follicular lymphoma; MZL = marginal 
zone lymphoma; MCL = mantle cell lymphoma; DLBCL = diffuse large B-cell lymphoma; WM = Waldenstrom 
macroglobulinemia; QD = once a day; BID = twice a day. 
The effect of food on zanubrutinib exposure has also been evaluated in a dedicated food-effect 
study in healthy volunteers (Study BGB-3111-103). Co-administration of zanubrutinib with 
low-fat or high-fat food did not result in any clinically meaningful changes in Cmax or AUC.  
Subjects will be allowed to take zanubrutinib with or without food. 
1.7 
Rationale for Tislelizumab Flat Dose and Schedule 
The fixed dose of tislelizumab at 200 mg for dose escalation level 3 and Cohort 4A of the dose 
expansion was selected on the basis of both nonclinical studies and available clinical data as 
described below.  
No tissue cross-reactivity was found in either human or monkey tissues, nor was any effect on 
cytokine release observed in human whole-blood assays. No apparent toxicity was noted in either 
mice or monkeys following a single dose up to 100 mg/kg or in monkeys following a repeat dose 
up to 30 mg/kg biweekly for 13 weeks. The toxicokinetics profile was characterized in monkey 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 29 of 132
 
Version 5.0: 02 May 2019 
studies, and the systemic exposure appeared to be dose proportional without sex differences or 
accumulation over the dosing period. No apparent immunotoxicity was observed, as no apparent 
changes in clinical pathology or histopathology were noted in these studies.  
The tislelizumab dose is also informed by available clinical activity, safety, and PK data. The 
safety of tislelizumab has been tested across a range of doses in Study BGB-A317-001 
(0.5 mg/kg to 10 mg/kg Q2W [n = 62]; 2 mg/kg to 5 mg/kg Q3W [n = 41]) with no MTD defined 
at the highest dose examined. MTD is the highest dose at which < 33% of the subjects experience 
a DLT, which may not be reached in the 4 planned doses. The recommended Phase 2 dose 
(RP2D) will be the dose at or below MTD identified in the dose escalation part of the study. It 
will be determined by taking safety, efficacy, and PK into consideration.) Based on 
recommendation of the Safety Monitoring Committee, tislelizumab at 5 mg/kg Q3W was selected 
as the dose for the indication expansion part of Study BGB-A317-001 (Phase 1B). Efficacy was 
demonstrated in 15 of 99 evaluable subjects to date who had been diagnosed with a variety of 
tumor types and were treated with single agent tislelizumab at doses that ranged from 2 mg/kg to 
5 mg/kg administered either Q2W or Q3W. According to the Phase 1A PK data from Australia, 
plasma concentrations of tislelizumab showed linear relationships for doses ranging from 0.5 
mg/kg Q2W to 10 mg/kg Q2W. Furthermore, according to the results of analysis of covariance, 
there was no significant correspondence between the weight of subjects and the in vivo clearance 
rate of tislelizumab. This conclusion supports fixed-dose administration. Simulations also do not 
suggest any clinically meaningful differences in exposure following fixed dose or dose adjusted 
for weight. 19 On the basis of these analyses, a fixed dose of 200 mg was selected (equivalent to a 
weight-based dose of 3.3 mg/kg, calculated with 60 kg) for Dose Level 3 and Cohort 4A. 
Selection of a Q3W dosing interval is supported by this preliminary PK evaluation, which will 
also allow convenient potential integration with common chemotherapeutic regimens.  
All available PK, safety, and efficacy data for tislelizumab will continue to be evaluated as 
described above to support the proposed 200-mg fixed dose. 
2.0 STUDY OBJECTIVES  
2.1 
Primary Objectives 
 To determine the MTD and/or RP2D of tislelizumab when given in combination with 
zanubrutinib. 
 To assess the safety and tolerability of zanubrutinib in combination with tislelizumab 
(Cohorts 1 to 3 and 4B) or single-agent tislelizumab followed by the combination of 
zanubrutinib and tislelizumab (Cohort 4A) in previously treated subjects with B-cell 
malignancies. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 30 of 132
 
Version 5.0: 02 May 2019 
2.2 
Secondary Objectives 
 
To assess the preliminary antitumor activity of zanubrutinib in combination with 
tislelizumab (Cohorts 1 to 3 and 4B) or a single-agent tislelizumab followed by the 
combination of zanubrutinib and tislelizumab (Cohort 4A) in previously treated subjects 
with B-cell malignancies. 
 
To characterize the PK of zanubrutinib and tislelizumab when administered in 
combination. 
 
To assess host immunogenicity to tislelizumab when administered in combination with 
zanubrutinib. 
2.3 
Exploratory Objectives 
 
 
 
3.0 STUDY ENDPOINTS 
3.1 
Primary Endpoints 
 Dose escalation: The MTD and RP2D of tislelizumab in combination with zanubrutinib, as 
determined based on the incidence of protocol-defined dose-limiting toxicities, safety, 
tolerability, and PK profile. 
 Dose expansion: The safety and tolerability of combination zanubrutinib and tislelizumab 
(Cohorts 1 to 3 and 4B) or single-agent tislelizumab followed by combination zanubrutinib 
and tislelizumab (Cohort 4A) in previously treated subjects with B-cell malignancies, as 
assessed by the occurrence and severity of AEs (Common Terminology Criteria for Adverse 
Events [CTCAE], version 4.03). 
3.2 
Secondary Endpoints 
 The antitumor activity of the combination of zanubrutinib and tislelizumab (Cohorts 1 to 
3 and 4B), or single-agent tislelizumab, followed by combination zanubrutinib and 
tislelizumab (Cohort 4A) in previously treated subjects with specified B-cell 
malignancies, as determined by overall response rate (ORR, defined as the proportion of 
subjects who had CR or PR by standard disease-specific response criteria), duration of 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 31 of 132
 
Version 5.0: 02 May 2019 
response ([DOR]; defined as the time from the date that a confirmed objective response is 
first documented to the date of PD or death due to any cause for those subjects with a 
confirmed PR or CR), and progression-free survival ([PFS]; defined as the time from the 
first dose of study medication to objective disease progression or death). -drug antibody to 
tislelizumab when given in combination with zanubrutinib. 
3.3 
Exploratory Endpoints 
 
 
 
4.0 INVESTIGATIONAL PLAN 
4.1 
Summary of Study Design 
This is a Phase 1b study to evaluate safety, tolerability, and preliminary efficacy of zanubrutinib 
in combination with tislelizumab in subjects with B-cell malignancies, including 
relapsed/refractory CLL/SLL, MCL, non-GCB, DLBCL, GCB DLBCL, FL, MZL, HCL, 
transformed FL, Richter’s transformation, primary central nervous system lymphoma (PCNSL), 
and secondary central nervous system lymphoma (SCNSL) of breast or testicular origin (Note: 
WM subjects are excluded from enrollment as of Amendment 3). The study is divided into a dose 
escalation and dose expansion. Refer to Section 5.2 for further dosage and administration details.  
For Amendment 5.0, Cohort 4A is being discontinued. There were no safety or tolerability 
signals that led to the discontinuation of Cohort 4A. As of March 2019, 3 subjects with CNSL 
have been enrolled in Cohort 4A; however, no subjects remain on treatment in this cohort, which 
is closed to treatment and further enrollment. Cohort 4B will be immediately activated with 
Amendment 5.0. 
4.1.1 
Dose-Limiting Toxicity 
A DLT is a toxicity or adverse event (AE) occurring during the DLT assessment period (21 days 
from Cycle 1 Day 8 to Cycle 1 Day 28), which cannot be primarily attributed to a cause other 
than zanubrutinib and/or tislelizumab (such as disease progression, underlying illness, concurrent 
illness, or concomitant medication) and meets 1 of the following criteria: 
1) Nonhematologic Grade 4 (or Grade 3 lasting > 3 days) toxicity excluding:  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 32 of 132
 
Version 5.0: 02 May 2019 
a. Laboratory abnormalities deemed by investigators as being not clinically 
important 
b. Grade 3 tumor flare  
c. Grade 3 infusion-related event that resolves to Grade 1 within 21 days  
d. Grade 3 nausea or vomiting  
e. Grade 3 hypertension  
2) Grade 4 neutropenia lasting > 7 days, not attributable to active leukemia or lymphoma 
3) Grade 4 thrombocytopenia lasting > 7 days, not attributable to active leukemia or 
lymphoma 
4) Any toxicity that requires drug hold of 1 or both investigational agents for more than 
2 weeks   
Subjects who received < 80% of the tislelizumab infusion in Cycle 1 (eg, the infusion had to be 
discontinued due to an infusion reaction) and did not experience a DLT will not be taken into 
account in the assessment of the overall DLT rate for the particular dose level cohort and will 
need to be replaced in the dose-escalation cohort. 
Subjects who did not complete the first cycle of zanubrutinib (28 days) and did not experience a 
DLT will not be taken into account in the assessment of the overall DLT rate for the particular 
dose level cohort and will need to be replaced in the dose-escalation cohort. 
Resumption of zanubrutinib and tislelizumab administration for subjects experiencing DLTs may 
be permitted, according to the criteria described in Section 4.1.2, if clinically appropriate, 
contingent on the return of the DLT to baseline or ≤ Grade 1 severity and interruption or delay of 
treatment for no more than 6 weeks from scheduled dose.  
4.1.2 
Drug Hold and Dose Modification 
The continuous safety evaluation will be performed by the sponsor, the coordinating investigator, 
and investigators. The Safety Monitoring Committee ([SMC]; refer to Section 7.3.1 for 
composition and responsibility) will be established for the determination of dose levels to be 
administered during the study.  
Where possible, the investigator should determine which of the 2 investigational agents is 
responsible for the toxicity; in the case where the investigator is unable to assign causality to 1 
specific agent, both drugs must be held. Dosing will be held for individual subjects under any of 
the following conditions (assuming that the condition is assessed as related to study drug and not 
the underlying disease): 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 33 of 132
 
Version 5.0: 02 May 2019 
 
Grade 4 neutropenia (lasting > 7 days) not attributable to active leukemia or lymphoma 
 
Grade ≥ 3 febrile neutropenia 
 
Grade 4 thrombocytopenia (lasting > 7 days) not attributable to active leukemia or lymphoma 
 
Grade 3 thromobocytopenia associated with bleeding 
 
For patients with baseline platelet count ≥ 35 x 109/L but < 50 x 109/L, platelet count < 35 x 
109/L associated with bleeding 
 
Grade 2 or higher immune-related events (See Section 9.14.1.2 and Section 9.14.2.4 for more 
specific instructions) 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 and up to 5 times 
upper limit of normal (ULN) or total bilirubin > 1.5 and up to 3 times ULN. For subjects with 
liver infiltration by disease who entered the study with Grade 2 elevation of AST/ALT, 
tislelizumab will be withheld if AST/ALT increase is ≥ 50% relative to baseline 
 
Any Grade ≥ 3 nonhematologic toxicities suspected to be related to study drug treatment and 
not covered above, with the following exceptions: 
 
laboratory abnormalities deemed nonserious by the investigator 
 
Grade 3 tumor flare 
 
infusion reaction that has resolved to ≤ Grade 1 within 28 days 
 
atrial fibrillation or hypertension adequately controlled with oral medication 
After complete resolution or improvement of the toxicity to Grade 1 or to baseline values within 
21 days, the investigator may elect to have the subject restart the treatment. If the subject’s 
toxicity improves to Grade 1 or baseline within 22 to 42 days of study drug discontinuation, and 
if, in the investigator’s opinion, it is in the subject’s best interest to restart treatment, then a 
written approval must be obtained from the sponsor medical monitor. 
If zanubrutinib is held, and in the investigator’s opinion, the toxicity is unrelated to zanubrutinib, 
the subject may be restarted at the dose preceding the event. However, if the toxicity recurs, the 
dose must be reduced to 50% of preceding dose. If, in the investigator’s opinion, the toxicity is 
related to zanubrutinib, the subject may restart therapy at 50% of preceding dose. For example, if 
a subject started with 160 mg BID, 50% dose reduction would be 80 mg BID. A second dose 
reduction to 80 mg QD, based on the criteria outlined above, may be considered upon 
consultation with the sponsor medical monitor. Any subjects who do not tolerate 80 mg QD must 
be removed from the study. Following dose reduction and resolution of the event, rechallenge to 
the dose prior to reduction may be possible with approval from the medical monitor. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                      CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001
IND number:  Not applicable
Protocol 
Page: 34 of 132
 
Version 5.0: 02 May 2019 
The administration of tislelizumab will be resumed at the same dose according to the original 
schedule. See Section 9.14.2.4 for more specific instructions related to tislelizumab.  
If, in the investigator’s opinion, the toxicity is related to 1 of the study drugs and the drug is 
discontinued, the subject may be continuously treated with the other study drug if the subject is 
benefiting from the treatment in the judgment of the investigator. 
Detailed guidelines for specific AEs related to tislelizumab are given in Section 9.14.2.4. 
Permanent discontinuation criteria for both zanubrutinib and tislelizumab are outlined in Section 
4.2.4.3. 
4.1.3 
Schedule of Assessments 
The Schedules of Assessments are presented in Table 4-1 and Table 4-2. PK and anti-drug 
antibody (ADA) sampling are presented in Table 4-3 and Table 4-4.  
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                        CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001 
IND number:  Not applicable
Protocol 
Page:35 of 132
 
Version 5.0: 02 May 2019 
Table 4-1 
Schedule of Assessments (Dose Escalation for Dose Levels 1, 2, and 3) 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic/medical 
history 
X 
 
 
 
 
 
 
 
 
 
Vital signs/weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
B symptoms6  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete physical 
examination7  
X 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination7  
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
X 
 
X 
 
 
X 
X 
 
 
Echocardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG8  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review AEs9 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Review concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Hematology10  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry11  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
parameters 
X 
X 
 
 
 
 
X 
X 
 
 
Urinalysis12  
X 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy test13  
X 
X 
 
 
 
 
X 
X 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:36 of 132
 
Version 5.0: 02 May 2019 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
Thyroid function14  
X 
 
 
 
 
 
X 
X 
 
 
IgA, IgG, and IgM 
level 15  
X 
 
 
 
 
 
X 
X 
X 
 
Viral serologies16  
X 
 
 
 
 
 
 
 
 
 
tislelizumab 
administration (30 to 
120 minutes infusion) 
 
 
 
X 
 
 
X 
 
 
 
Zanubrutinib 
administration in 
clinic17  
 
Orally every day 
 
 
 
Tumor assessment by 
CT scan18 
X 
Every 4 cycles 
X 
X19 
 
Bone marrow 
evaluation20  
X 
 
End of Cycle 4 
 
To confirm CR (at any time, Cycle 4 or later) 
 
 
 
Overall disease 
response 21 
 
Every 4 cycles 
 
X22 
 
CLL prognostic 
factors23  
X 
 
 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
CENTRAL LABORATORY STUDIES 
Anti-tislelizumab 
antibodies24  
 
 
 
X 
 
 
 
X 
X 
 
 
Archival tumor 
tissues25  
X 
 
 
 
 
 
 
 
 
 
 
Fresh tumor tissues25  
X 
 
 
X 
 
 
 
 
X 
 
 
PK blood sampling26  
 
X 
X 
 
 
 
 
X 
 
 
 
Pulmonary function 
tests27  
X 
 
 
 
 
 
 
 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:37 of 132
 
Version 5.0: 02 May 2019 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual acuity 
tests28 
X 
 
 
 
 
 
X29 
X29 
 
 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CLL = chronic lymphocytic leukemia; CR = complete 
response; CT = computed tomography; D = day; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EPG = electrophoresis; FISH = fluorescence in situ hybridization; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgVH – immunoglobin variable region heavy chain; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PCR = polymerase 
chain reaction; PD-1 = programmed cell death-1; PD-L1 = programmed death ligand-1; PD-L2 = programmed death ligand-2; PET = positron emission tomography; PK = 
pharmacokinetic; QTc = corrected QT wave; TSH = thyroid stimulating hormone; WBC = white blood cell. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified. 
1 Performed within 28 days prior to Day 1. Assessments that are performed as standard of care assessments may be used for screening.  
2 The maximum duration of treatment will be until disease progression.  
3 Safety follow-up performed within 30 days after the last dose of zanubrutinib (± 3 days). If the patient continues on single-agent tislelizumab, a second safety follow-up should be 
performed 30 days after last dose of tislelizumab. Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, 
associated with an AE or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of tislelizumab (see Section 7.4). Efficacy follow-up will apply only to 
subjects who discontinue study drug due to reasons other than disease progression. They will remain on study and should follow the guidance provided in Section 7.5. 
4 Once subjects progress or start the use of alternative anti-cancer therapy, subjects only need to establish survival status and are not required to come in for a visit. (see 
Section 7.6.) 
5 Vital sign time points for PK sampling will be obtained per Table 4-3. 
6 Unexplained weight loss > 10% over previous 6 months, fever (>38°C), and/or drenching night sweats. 
7 Complete physical exam includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical relevance (i.e., 
cardiovascular, respiratory, lymph nodes, liver, and spleen) and those systems associated with clinical signs/symptoms. 
8 Perform a 12-lead ECG in triplicate at screening and at the treatment completion/early termination visit. ECG time points for PK sampling will be obtained as per Table 4-3. 
Additional ECGs may be required if there is a prolongation of QT or QTc, see Section 7.2.3.  
9   AEs will be recorded from the time of the first dose and all SAEs will be collected after informed consent has been signed. Telephone contacts with patients should be conducted 
to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of 
tislelizumab. All AEs and SAEs, regardless of relationship to study drug, will be recorded until up to 90 days after the last dose of study drug.  Beyond the safety follow up 
period, all drug-related SAEs will be recorded by investigator until patient death, or lost to follow up, whichever occurs first. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:38 of 132
 
Version 5.0: 02 May 2019 
10 Hematology, including hemoglobin, reticulocyte count, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes) and platelet count. In the event of 
neutropenia (absolute neutrophil count < 1.0 × 109/L) or thrombocytopenia (platelets count < 50 ×109/L), assessments will be performed as frequent as the physician feels 
needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed with dosing; in 
these cases, a separate pre-treatment sample must still be taken. 
11 Clinical chemistry includes sodium, potassium, chloride, bicarbonate (total CO2), glucose, urea, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequent as 
the physician feels needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed 
with dosing; in these cases, a separate pre-treatment sample must still be taken. 
12Collect urine dipstick, as well as urine microscopy, if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24-hour urine test for total protein and a random urine test for 
total protein and creatinine will be obtained and evaluated on the first occasion; subsequent need for 24-hour collection will be determined by the investigator. Refer to 
Section 7.2.1. 
13 All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Laboratory-based highly sensitive pregnancy 
tests (urine or serum) will be performed at specified subsequent visits and continued (local laboratory is acceptable) every 4 weeks for at least 90 days after the last dose of study 
drug. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
14 T3, T4, TSH; at screening, then every other cycle starting from Cycle 2, and at the mandatory safety follow-up visit. Additional T3, T4 and TSH may be performed at the 
discretion of the investigator. 
15 If a paraprotein is present, testing will be repeated on all subsequent immunoglobulin assessments. IgA, IgG and IgM tests should be performed for all subjects at screening and 
only for those with significant abnormal findings at subsquent visits. EPG testing was removed with Amendment #4. 
16 Viral serologies include hepatitis B (HBsAg and total HB core antibody [anti-HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), HCV antibody (as well as 
HCV RNA by PCR if the subject is HCV antibody positive), and HIV. 
17 Administer 1 dose of zanubrutinib in the clinic (for the first dose only), review and dispense diary. If subjects discontinue tislelizumab but continue taking zanubrutinib, subjects 
are allowed to reduce visits after 1 year to every 2 months. 
18 Tumor assessments must be performed at screening, and then in conjunction with overall disease response assessments within 7 days of the end of every 4 cycles, and at disease 
progression. Assessments by PET-CT scan with IV contrast of neck, chest, abdomen, and pelvis and any other disease sites for non-Hodgkin lymphoma classifications that are 
reliably FDG-avid (includes MCL, FL, DLBCL, transformed FL, Richter’s transformation, and CNS lymphomas) must be performed at Screening, Cycles 4, 8, and 12, and at 
suspected PD or CR. After Cycle 12, standalone CT scans will be performed every 4 cycles. Screening findings will determine whether patients are followed with PET-CT-
based or CT-based assessments on study. (Refer to Section 7.2.4.)  
19 Tumor assessment including imaging scan required at a minimum of every 6 months, otherwise assessment via physical exam is acceptable. 
20 A bone marrow examination must be performed at screening for all subjects and within 7 days of the end of Cycle 4 for subjects with baseline marrow disease. 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 CR), a bone marrow 
aspirate and biopsy will be obtained to confirm the CR. Additional bone marrow examinations may be performed at the investigator’s discretion. Peripheral blood and/or bone 
marrow aspirate/biopsy with flow cytometry assessment(s) for minimal residual disease should be done 3 months after evidence of CR in all of the response parameters 
(i.e., hematology, CT scan). 
21 Overall disease response assessment will utilize components and guidelines specified per disease type in Appendix 4. They should accompany tumor assessments by imaging 
(CT, PET, etc.) as applicable. 
22 For subjects that enter efficacy follow-up, response assessments should be conducted every 3 months to identify potential progression. These response assessments may utilize 
physical examination rather than imaging provided an assessment utilizing imaging is conducted at least every 6 months. 
23 Subjects with CLL should have a blood sample sent at screening for interphase FISH for chromosomal abnormalities including 17p-, 11q-, 13q- and +12. Other analysis 
including IgVH and P53 mutational status is optional.  
24 Blood for anti-tislelizumab antibodies should be collected within 2 hours before start of Day 8 infusion on Cycle 1, Day 1 on Cycles 2, 4, 6, and every 4 cycles starting with 
Cycle 8 (Day 1), and also collected at the mandatory safety follow-up visit. In subjects who discontinue study therapy before 6 months, every effort should be made to analyze 
anti-tislelizumab antibodies approximately 6 months after the first dose. Corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are 
collected to assess the neutralizing capacity of ADA. Analysis will be performed by a central laboratory. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:39 of 132
 
Version 5.0: 02 May 2019 
25 Subjects with an accessible tumor lesion must agree to a fresh tumor biopsy at screening and another before drug administration on Cycle 1 Day 8 (unless deemed clinically 
unsafe), ideally taken from the same tumor lesion, for the biomarker analysis (up to the first 12 qualified subjects). Subjects with DLBCL must have archival tumor tissues or 
agree to a fresh tumor biopsy for the confirmation of the DLBCL subtype. For the rest of subjects, upon consent (optional), an archival tumor tissue or a fresh tumor biopsy if 
feasible, will be collected at screening for biomarker analysis. Optional biopsy will also be taken at the safety follow up visit for the subjects who have confirmed disease 
progression during the study from accessible tumor sites to obtain samples to explore resistance mechanism.  
26 Serial PK blood samples will be collected at the time points specified in Table 4-3. Procedures for collection of samples are described in the lab manual. In addition, 
corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are collected to assess the neutralizing capacity of ADA. 
27  Patients who are suspected or known to have serious respiratory concurrent illness or who exhibit significant respiratory symptoms unrelated to underlying cancer will also take 
a pulmonary function test, which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the Screening period to assist the determination 
of suitability for enrollment into the study (Refer to Section 7.1.2.  
28 Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of study drug initiation may be used rather than repeating tests. Eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeat assessments approximately every 15 weeks (± 7 days). 
29 The ophthalmologic assessments including eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) should only be performed once at either 
the EOT or during safety follow up, within 30 days of study treatment end. 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                        CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001 
IND number:  Not applicable
Protocol 
Page:40 of 132
 
Version 5.0: 02 May 2019 
Table 4-2 
Schedule of Assessments (Dose Expansion) 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy  
Follow-up4 
Survival 
Follow-up5 
Cycle 1 
(21 days) 
Cycle 2 Through Last Cycle 
(21 days) 
Days Window 
-28 to -1 
D1 
D8 
D1 ± 3 
30 ± 3 Days After 
Last Dose 
(Telephone 
Contacts 60 & 90 ± 
14 Days After Last 
Dose) 
Every 3 Months 
±7 Days 
Every 3 Months 
±7 Days 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographic/medical history 
X 
 
 
 
 
 
 
Vital signs/weight6 
X 
X 
X 
X 
X 
X 
 
B symptoms7  
X 
X 
 
X 
X 
X 
 
Complete physical examination8  
X 
 
 
 
 
 
 
Targeted physical examination8  
 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
X 
X 
 
 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
12-lead ECG9  
X 
X 
 
X 
X 
 
 
Review AEs and concomitant 
medications10 
X 
X 
X 
X 
X 
 
 
Hematology11  
X 
X 
X 
X 
X 
X 
 
Clinical chemistry12  
X 
X 
X 
X 
X 
X 
 
Coagulation parameters 
X 
X 
 
X 
X 
 
 
Urinalysis13  
X 
X 
X 
X 
X 
 
 
Pregnancy test14  
X 
X 
 
X 
 
 
 
Thyroid function15  
X 
 
 
X 
X 
 
 
IgA, IgG, IgM level16  
X 
 
 
X 
X 
X 
 
Viral serologies17 
X 
 
 
 
 
 
 
Tislelizumab administration (30 to 60 
minutes infusion)18 
 
X 
 
X 
 
 
 
Zanubrutinib administration19  
 
Orally every day 
 
 
 
Tumor assessment by CT scan20  
X 
Every 4 cycles 
X 
X21 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:41 of 132
 
Version 5.0: 02 May 2019 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy  
Follow-up4 
Survival 
Follow-up5 
Cycle 1 
(21 days) 
Cycle 2 Through Last Cycle 
(21 days) 
Days Window 
-28 to -1 
D1 
D8 
D1 ± 3 
30 ± 3 Days After 
Last Dose 
(Telephone 
Contacts 60 & 90 ± 
14 Days After Last 
Dose) 
Every 3 Months 
±7 Days 
Every 3 Months 
±7 Days 
MRI with gadolinium or CT with 
contrast of brain22 
X 
End of Cycles 2, 4, 6, 8, 10, 12, 14, and 16 
 
 
 
Lumbar puncture and/or Ommaya 
tap23 
X 
End of Cycles 2, 4, 6, 8, 10, 12, 14, and 16 
X 
 
 
CSF PK during lumbar puncture or 
Ommaya tap (optional)23 
 
End of Cycles 2, 6 and 12 
 
 
 
Ultrasound of testicles24 
X 
Repeat at suspected CR or CRu defined in 
Appendix 4 for SCNSL 
 
 
 
Mammogram of bilateral breast24 
X 
Repeat at CR or CRu defined in 
Appendix 4 for SCNSL 
 
 
 
 
 
 
 
 
 
Ocular assessment for CNS lymphoma 
cohort (PCNSL and SCNSL) 25 
X 
End of Cycles 4, 8, 12, and 16 for those 
with abnormality at Screening, and at 
suspected CR or CRu defined in 
Appendix 4  
 
 
 
Bone marrow evaluation26  
X 
 
End of Cycle 4  
 
To confirm CR (at any time, 
Cycle 4 or later) 
 
 
 
Overall disease response27 
 
Every 4 cycles 
 
X28 
 
Survival status 
 
 
 
 
 
 
X 
Anti-tislelizumab antibodies29  
 
X 
 
X30 
X 
 
 
Archival tumor tissues31  
X 
 
 
 
 
 
 
Fresh tumor tissues31  
X 
 
 
 
X 
 
 
PK blood sampling32  
 
X 
 
X 
 
 
 
Pulmonary function tests33 
X 
 
 
 
 
 
 
Optical coherence tomography (or 
equivalent diagnostic test) and visual 
acuity tests34, 35  
X 
 
 
X 
X 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:42 of 132
 
Version 5.0: 02 May 2019 
ADA = anti-drug antibody; D = day; AE = adverse event; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CLL = chronic lymphocytic leukemia; CR = 
complete response; CRu = complete response unconfirmed; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IgVH – immunoglobin variable region heavy chain; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition 
scan; PCNSL  = primary central nervous system (CNS) lymphoma; PCR = polymerase chain reaction; PD-1 = Programmed cell death-1; PD-L1 = Programmed Death Ligand-1; 
PD-L2 = Programmed Death Ligand-2; PET = positron emission tomography; PK = pharmacokinetic; QTc = corrected QT wave; RNA = ribonucleic acid; SCNSL = secondary 
CNS lymphoma; TSH = thyroid stimulating hormone; WBC = white blood cell. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified. 
1 Performed within 28 days prior to Day 1. Assessments that are performed as standard of care assessments may be used for screening.  
2 The maximum duration of treatment will be until disease progression.  
3 Performed within 30 days after the last dose of zanubrutinib (± 3 days).  If the patient continues on single-agent tislelizumab, a second safety follow-up should be performed 30 
days after last dose of tislelizumab. Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE 
or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of tislelizumab. 
4 Efficacy follow-up will apply only to subjects who discontinue study drug due to reasons other than disease progression. They will remain on study and should follow the 
guidance provided in Section 7.5. 
5 Once subjects progress or start the use of alternative anti-cancer therapy, subjects only need to establish survival status and are not required to come in for a visit (telephone call, 
medical records, etc.). 
6 Vital sign time points for PK sampling will be obtained per Table 4-4. 
7 Unexplained weight loss > 10% over previous 6 months, fever (>38°C), and/or drenching night sweats. 
8 Complete physical exam includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical relevance (i.e. 
cardiovascular, respiratory, lymph nodes, liver, and spleen) and those systems associated with clinical signs/symptoms. 
9 Perform a 12-lead ECG in triplicate at screening and at the treatment completion/early termination visit. ECG time points for PK sampling will be obtained as per Table 4-4. 
Additional ECGs may be required if there is a prolongation of QT or QTc, see Section 7.2.3. 
10 AEs will be recorded from the time of the first dose and all SAEs will be collected after informed consent has been signed but prior to administration of the study drug.  
Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or is a new anticancer therapy) at 60, 
and 90 days (±14 days) after the last dose of tislelizumab. All AEs and SAEs, regardless of relationship to study drug, will be recorded until up to 90 days after the last dose of 
study drug.  Beyond the safety follow up period, all drug-related SAEs will be recorded by investigator until patient death, or lost to follow up, whichever occurs first 
11 Hematology, including hemoglobin, reticulocyte count, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes) and platelet count. In the event of 
neutropenia (absolute neutrophil count < 1.0 × 109/L) or thrombocytopenia (platelets count < 50 ×109/L), assessments will be performed as frequent as the physician feels 
needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed with dosing; in 
these cases, a separate pre-treatment sample must still be taken 
12 Clinical chemistry includes sodium, potassium, chloride, bicarbonate (total CO2), glucose, urea, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequent as 
the physician feels needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed 
with dosing; in these cases, a separate pre-treatment sample must still be taken 
13 Collect urine dipstick, as well as urine microscopy, if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24-hour urine test for total protein and a random urine test for 
total protein and creatinine will be obtained and evaluated on the first occasion; subsequent need for 24-hour collection will be determined by the investigator. 
14 All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Laboratory-based highly sensitive pregnancy 
tests (urine or serum) will be performed at specified subsequent visits and continued every 4 weeks (locally is acceptable) for at least 90 days after the last dose of study drug. If 
a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
15 T3, T4, TSH; at screening, then every other cycle starting from Cycle 2, and at the mandatory safety follow-up visit. Additional T3, T4 and TSH may be performed at the 
discretion of the investigator. 
16 IgA, IgG and IgM tests should be performed for all subjects at screening and only for those with significant abnormal findings at subsquent visits.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:43 of 132
 
Version 5.0: 02 May 2019 
17 Viral serologies include hepatitis B (HBsAg and total HB core antibody [anti-HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), Hepatitis C virus (HCV) 
antibody (as well as HCV RNA by PCR if the subject is HCV antibody positive), and HIV. 
18 For Cohort 4A, subjects will not receive the combination dosing of zanubrutinib and tislelizumab until Cycle 5.  
19 Administer 1 dose of zanubrutinib in the clinic (for the first dose only), review and dispense diary. If subjects discontinue tislelizumab but continue taking zanubrutinib, subjects 
are allowed to reduce visits after 1 year to every 2 months. 
20 Tumor assessments for subjects with non-CNS lymphoma must be performed at screening, and then in conjunction with overall disease response assessments within 7 days of 
the end of every 4 cycles, and at disease progression. Assessments by PET-CT scan with IV contrast of neck, chest, abdomen, and pelvis and any other disease sites for non-
Hodgkin lymphoma classifications that are reliably FDG-avid (includes MCL, FL, DLBCL, transformed FL, Richter’s transformation, and CNS lymphomas) must be performed 
at Screening, Cycles 4, 8, and 12, and at suspected PD or CR. After Cycle 12, standalone CT scans will be performed every 4 cycles. Screening findings will determine whether 
patients are followed with PET-CT-based or CT-based assessments on study. (Refer to Section 7.2.4.). For the early termination visit, CT is required if the previous scan was 
performed more than 3 months ago.  Cycle 1, Day 1 laboratory assessments should be considered baseline.  
21 Tumor assessment including imaging scan required at a minimum of every 6 months, otherwise assessment via physical exam is acceptable. 
22 Only for subjects with PCNSL or SCNSL of breast or testicular origin (Cohort 4 of expansion part). MRI of gadolinium is preferred imaging modality. CT with contrast of brain 
may be substituted if contraindication to MRI (e.g. implanted metal or electronic device like pacemaker, insulin pump, claustrophobia). 
23 Cerebrospinal fluid will be obtained by lumbar puncture and/or Ommaya tap in subjects with PCNSL or SCNSL of breast or testicular origin only (Cohort 4 of Expansion part), 
and will include cytology, total cell count, protein level, and glucose level. Lumbar puncture should only be performed in subjects with PCNSL or SCNSL of breast or testicular 
origin who are not at risk of herniation. Cerebrospinal fluid analyses are required after Screening only if these studies were initially positive at Screening or if clinically indicated 
by new symptoms or signs. Patients with significant CSF abnormalities at baseline, are required to have both repeat lumbar puncture and Ommaya tap at suspected CR or CRu 
defined per Appendix 4. CSF fluid needs to be analyzed at the site local pathology laboratory. If subjects have CSF collected for disease assessment (post treatment) above, it is 
recommended to spare 2 mL of CSF for drug measurements (especially at Cycle 2). In this case, at end of Cycles 2, 6 and 12, subjects will take the morning dose of zanubrutinib 
at the clinic, and CSF collection will be performed around 2 hours (+/- 10 minutes) following zanubrutinib dose for measurement of zanubrutinib and tislelizumab concentration 
in CSF. On the same day of CSF collection, blood samples for measuring blood zanubrutinib and serum tislelizumab concentrations will be collected at pre-dose (prior to 
zanubrutinib dose) and at 2 hours (+/- 10 minutes) post zanubrutinib dose. CSF collection for PK samples is optional. 
24 Testicular ultrasound required only for male subjects with SCNSL of testicular origin and only if the PET/CT is positive for testicular disease. Bilateral mammogram required 
only for male or female subjects with SCNSL of breast origin. Repeat testicular ultrasound or bilateral breast mammogram required at suspected CR or CRu defined per for 
PCNSL or SCNSL. 
25 For PCNSL and SCNSL (Cohorts 4A and 4B), ophthalmologic examination includes a complete examination with dilated fundus and slit-lamp examinations. Color photography 
of the posterior pole should be obtained in those patients with ocular involvement. Fluorescein angiography may be helpful to confirm lymphomatous involvement of the retina. 
26 A bone marrow examination must be performed at screening for all subjects and within 7 days of the end of Cycle 4 for subjects with baseline marrow disease. In those subjects 
who had evidence of bone marrow disease at the time of enrollment, upon achieving a possible CR (e.g. physical exam or CT scan indicating a possible CR), a bone marrow 
aspirate and biopsy will be obtained to confirm the CR. Additional bone marrow examinations may be performed at the investigator’s discretion. Peripheral blood and/or bone 
marrow aspirate/biopsy with flow cytometry assessment(s) for minimal residual disease should be done at least 3 months after the last dose if there is evidence of CR in all of 
the response parameters (i.e., hematology, CT scan). 
27 Overall disease response assessment will utilize components and guidelines specified per disease type in Appendix 4. They should accompany tumor assessments by imaging 
(CT, PET, etc.) as applicable. 
28 For subjects that enter efficacy follow-up, response assessments should be conducted every 3 months to identify potential progression. These response assessments may utilize 
physical examination rather than imaging, provided an assessment utilizing imaging is conducted at least every 6 months. 
29 Blood for anti- tislelizumab antibodies should be collected within 2 hours before start of Day 1 infusion on Cycles 1, 2, 5, 9, and 17, and also collected at the mandatory Safety 
Follow-Up Visit. In subjects who discontinue study therapy before 6 months, every effort should be made to analyze anti-tislelizumab antibodies approximately 6 months after 
the first dose. Corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are collected to assess the neutralizing capacity of ADA. 
Analysis will be performed by a central laboratory. 
30 Collect at Day 1 of Cycles, 2, 3, 6 and every 4 cycles starting with Cycle 8 (Day 1).  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                          CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:44 of 132
 
Version 5.0: 02 May 2019 
31 Upon consent (optional), an archival tumor tissue or a fresh tumor biopsy if feasible, will be collected at screening for biomarker analysis. Optional biopsy will also be taken at 
the safety follow up visit for the subjects who have confirmed disease progression during the study from accessible tumor sites to obtain samples to explore resistance 
mechanism. 
32 Serial PK blood samples will be collected at the time points specified in Table 4-4. Procedures for collection of samples are described in the Lab Manual. In addition, 
corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are collected to assess the neutralizing capacity of ADA. 
33  Patients who are suspected or known to have serious respiratory concurrent illness or who exhibit significant respiratory symptoms unrelated to underlying cancer will also take 
a pulmonary function test, which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the Screening period to assist the determination 
of suitability for enrollment into the study. (Refer to Section 7.1.2.) 
34 Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of study drug initiation may be used rather than repeating tests. Eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test) will be assessed at the Screening Visit. Subjects will undergo repeat assessments approximately every 15 weeks (± 7 days). For subjects with PCNSL 
or SCNSL (Cohorts 4A and 4B), eye examinations performed for response evaluation do not need to be duplicated if they fall within the acceptable scheduling window for the 
eye exam, visual acuity test, and optical coherence tomography. 
35 The ophthalmologic assessments including eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) should only be performed once at either 
the EOT or during safety follow up, within 30 days of study treatment end. (Refer to Section 7.2.7.) 
 
 
 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                        CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001 
IND number:  Not applicable
Protocol 
Page:45 of 132
 
Version 5.0: 02 May 2019 
Table 4-3 
Pharmacokinetic/ADA Sampling and Safety Measurements From the First 30 Subjects (Dose Escalation) 
Procedure 
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Cycle 
1 
Day 
8 
Cycle 2  
Day 1 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
Cycles 6, 
8, 12, 
and 16 
Day 1 
Safety 
Follow-
up 
Hours 
Predose 
1 
2 
4 
7 
Predose 
 
Predose 
1 
2 
4 
7 
Predose 
4 
Predose 
4 
 
 
PK blood 
sampling for 
Zaubrutinib  
X1 
X2 
X3 
X3 
X4 
X1 
 
X1 
X2 
X2 
X2 
X4 
 
 
 
 
 
 
PK blood 
sampling for 
tislelizumab 
 
 
 
 
 
 
X1 
X1 
 
 
X3 
 
X1 
X3 
X1 
X3 
X1 
X 
ADA blood 
sampling for 
tislelizumab 
 
 
 
 
 
 
X1 
X1 
 
 
 
 
 
 
X1 
 
X 
X 
Vital signs and 
ECGs(in 
triplicate) 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
ADA = anti-drug antibody; ECG = electrocardiogram; PK = pharmacokinetics. 
General note:  When the two study drugs are administered on the same day (except on the days both PK samples to be collected), zanubrutinib should be taken at least 30 minutes 
before tislelizumab infusion. Except for predose PK, each PK sampling time point of tislelizumab and zanubrutinib will be in correspondence with the end of dosing of each agent, 
respectively. For tislelizumab, the time point relates to the end of the infusion. It is important that PK sampling occur as close as possible to the scheduled time. To achieve this, 
some other assessments scheduled at the same time need to be initiated prior to or after the time point to allow for these measurements to be completed with sufficient time for PK 
sampling at the designated time point. Thus, the sequence at a particular time point is: 1) scheduled ECG; 2) vital sign measurements; 3) PK blood samples (to be performed at the 
precise protocol scheduled time); and 4) any other scheduled or unscheduled measurements at that time point. 
1 Within 2 hours prior to dosing. 
2 Window of ±10 minutes. 
3 Window of ±20 minutes. 
4 Window of ±1 hour.  
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                                        CONFIDENTIAL 
BGB-3111_BGB-A317_Study_ 001 
IND number:  Not applicable
Protocol 
Page:46 of 132
 
Version 5.0: 02 May 2019 
Table 4-4 
Pharmacokinetic/ADA Sampling and Safety Measurements (Dose Expansion) 
Expansion Cohort 
Procedure 
Cycle 1 Day 1  
Cycle 2 
Day 1  
Cycles 2, 6, 12 
Day 21 
(optional)5 
Cycle 5 Day 1  
Cycle 9 
Day 1  
Cycle 17 
Day 1  
Safety 
Follow 
Up 
Hours  
Predose  
2 
hours 
Within 30 
min after 
the end of 
infusion 
Predose Predose 2 hours Predose 
2 
hours 
Within 30 
min after 
the end of 
infusion 
Predose  
Predose  
 
PK for Zanubrutinib   
X1 
X2 
 
 
X1 
X2 
X1 
X2 
 
  
 
 
PK for tislelizumab 
X1 
 
X3  
X1 
X1 
X2 
X1 
 
X3  
X1 
X1 
X 
ADA for tislelizumab 
X1 
 
 
X1 
 
 
X1 
 
 
X1 
X1 
X 
Vital signs and ECGs 
 (in triplicate)4 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
ADA = anti-drug antibody; ECG = electrocardiogram; PK = pharmacokinetics. 
General note: When the 2 study drugs are administered on the same day (except on the days both PK samples to be collected), zanubrutinib should be taken at least 30 minutes 
before tislelizumab infusion. Except for predose PK, each PK sampling time point of tislelizumab and BGB-290 will be in correspondence with the end of dosing of each agent, 
respectively. For tislelizumab, the time point relates to the end of the infusion. It is important that PK sampling occur as close as possible to the scheduled time. To achieve this, 
some other assessments scheduled at the same time need to be initiated prior to or after the time point to allow for these measurements to be completed with sufficient time for PK 
sampling at the designated time point. Thus, the sequence at a particular time point is: 1) scheduled ECG; 2) vital sign measurements; 3) PK blood samples (to be performed at the 
precise protocol scheduled time); and 4) any other scheduled or unscheduled measurements at that time point. 
1 Within 2 hours prior to dosing. 
2 Window of ±20 minutes. 
3 Within 30 minutes after the end of infusion of tislelizumab. 
4  In the first 30 subjects only. 
5 If subjects have CSF collected for disease assessment, it is recommended to spare 2 mL of CSF for drug measurements (especially at Cycle 2). In this case, at end of Cycles 2, 6, 
and 12, subjects will take the morning dose of zanubrutinib at the clinic, and CSF collection will be performed around 2 hours (± 10 minutes) following zanubrutinib dose for 
measurement of zanubrutinib and tislelizumab concentration in CSF. On the same day of CSF collection, blood samples for measuring blood zanubrutinib and serum tislelizumab 
concentrations will be collected at pre-dose (prior to zanubrutinib dose) and at 2 hours (± 10 minutes) post zanubrutinib dose. CSF collection for drug measurement is optional.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                CONFIDENTIAL                   
BGB-3111_BGB-A317_Study_001 
IND number:  Not applicable      
Protocol 
          Page:47 of 132 
 
Version 5.0: 02 May 2019 
4.2 
Selection of Study Population 
Approximately 85 subjects will be required to complete the Phase 1b study of zanubrutinib in 
combination with tislelizumab.  
4.2.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Dose escalation for Dose Levels 1, 2, and 3: Subjects with relapsed or refractory World 
Health Organization (WHO) classification-defined B-lymphoid malignancy following at least 
1 line of therapy, with no therapy of higher priority available, including CLL/SLL, MCL, FL, 
HCL, MZL, non-germinal center B-cell (GCB) DLBCL, GCB DLBCL, transformed FL, and 
Richter’s transformation (NOTE: subjects with WM are excluded from enrollment as of 
Amendment 3). 
2. Dose expansion for Cohorts 1 to 4: Subjects with either of the following relapsed or 
refractory WHO-classified lymphoid malignancies who have received at least 1 prior line of 
standard therapy:   
a. Cohort 1: GCB DLBCL, with cell of origin defined by either immunohistochemistry 
or gene expression profiling. 
b. Cohort 2: non-GCB DLBCL, with cell of origin defined by either 
immunohistochemistry or gene expression profiling. Subjects who have transformed 
to DLBCL from another histology may be enrolled into Cohort 3. 
c. Cohort 3: Transformed lymphoid malignancy, including but not limited to: 
i. 
Large cell transformation of chronic lymphocytic leukemia (Richter’s 
transformation). 
ii. 
Large cell transformation of other WHO-classified indolent non-Hodgkin’s 
lymphoma, including FL, or MZL. 
d. Cohort 4: Histologically confirmed PCNSL or SCNSL of breast or testicular origin: 
i. 
Must be able to tolerate lumbar puncture and/or Ommaya taps. 
ii. 
Must have received at least 1 prior central nervous system (CNS)-directed 
therapy. 
iii. 
Presence of brain parenchymal and/or leptomeningeal disease. 
3. Aged ≥ 18 years, able and willing to provide written informed consent and to comply with the 
study protocol. 
4. Measurable disease for non-Hodgkin lymphoma defined as ≥ 1 nodal lesion that is > 15 mm 
in the longest diameter and can be accurately measured in at least 2 dimensions with 
computed tomography (CT) scan, or ≥ 1 extra-nodal lesion that is > 10 mm in the longest 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:48 of 132
 
Version 5.0: 02 May 2019 
diameter and can be accurately measured in at least 2 dimensions with CT scan, except for 
PCNSL or SCNSL. 
5. Subjects with an accessible tumor lesion must agree to a tumor biopsy at screening and 
another before the drug administration on Cycle 1 Day 8, ideally taken from the same tumor 
lesion, for biomarker analysis (up to first 12 qualified subjects), except for PCNSL. 
Additionally, subjects with DLBCL must have archival tumor tissue or agree to a tumor 
biopsy for confirmation of the DLBCL subtype.  
6. Laboratory parameters as specified below: 
a. Hematologic: Platelet count ≥ 50 × 109/L; absolute neutrophil count ≥ 1.0 × 109 
cells/L; subjects with neutrophils < 1.0 × 109/L unless cytopenias are a direct 
result of active leukemia or lymphoma, in which case platelet count ≥ 35 × 109/L, 
absolute neutrophil count ≥ 0.75 × 109/L are allowed. (Note: Platelet transfusion 
administered ≤ 7 days of screening to raise pre-treatment platelet count to ≥ 35 x 
109/L is prohibited.) 
b. Hepatic: Total bilirubin ≤ 1.5 the ULN or ≤ 2.0 × ULN for subjects with Gilbert 
syndrome, AST, and ALT ≤ 3 × ULN. 
c. Renal: Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault 
equation or as measured by nuclear medicine scan or 24-hour urine collection). 
Subjects requiring hemodialysis will be excluded. 
7. Anticipated survival of at least 4 months. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 
9. Female subjects of childbearing potential and nonsterile males must practice at least 1 of the 
following methods of birth control with partner(s) throughout the study and for ≥ 3 months 
after discontinuing study drug: total abstinence from sexual intercourse, double-barrier 
contraception, intrauterine device or hormonal contraceptive initiated at least 3 months prior 
to first dose of study drug. 
10. Male subjects must not donate sperm from initial study drug administration until 180 days 
after drug discontinuation. 
4.2.2 
Exclusion Criteria 
Subjects will not be entered in the study for any of the following reasons: 
1. Known, active, CNS lymphoma or leukemia, except for Cohorts 4. 
2. Diagnosis with Waldenstrom’s macroglobulinemia (WM). 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:49 of 132
 
Version 5.0: 02 May 2019 
3. For PCNSL and SCNSL (Cohorts 4): 
a. Require corticosteroid therapy > 16 mg dexamethasone daily or equivalent.  
b. Corticosteroid therapy ≤ 16 mg dexamethasone daily or equivalent at study entry  
from which, in the Investigator’s opinion, it is expected that the subject cannot be 
tapered off after the first 4 weeks of study treatment. 
c. Intraocular PCNSL without evidence of brain disease. 
d. SCNSL actively receiving treatment for extra-CNS disease. 
e. PCNSL actively receiving concomitant local or systemic therapy for CNS disease. 
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. 
5. History of stroke or cerebral hemorrhage within 6 months of enrollment. 
6. History of significant cardiovascular disease, defined as: 
a. Congestive heart failure greater than New York Heart Association (NYHA) 
class II according to the NYHA functional classification. 
b. Unstable angina or myocardial infarction with 6 months of enrollment. 
c. Serious cardiac arrhythmia or clinically significant ECG abnormality: corrected 
QT wave (QTcF) > 480 msec based on the Fridericia’s formula or other ECG 
abnormalities including second-degree atrioventricular block type II, third-degree 
atrioventricular block. Subjects who have a pacemaker will be allowed on study 
despite ECG abnormalities or the inability to calculate the QTc. 
7. Severe or debilitating pulmonary disease (dyspnea at rest, significant shortness of breath, 
congestive obstructive pulmonary disease). 
8. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy. 
9. Prior BTK inhibitor or anti-PD-1/anti-PD-L1 treatment. 
10. Any illness or condition that in the opinion of the investigator may affect safety of 
treatment or evaluation of any study endpoint. 
11. Active autoimmune diseases or history of severe autoimmune diseases ; these include but 
are not limited to a history of immune related neurologic disease, multiple sclerosis, 
autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis, 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:50 of 132
 
Version 5.0: 02 May 2019 
systemic lupus erythematosus, rheumatoid arthritis, connective tissue diseases, 
scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune 
hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, or clinically manifest 
antiphospholipid syndrome. Note: Subjects are permitted to enroll if they have vitiligo, 
eczema, type I diabetes mellitus, or endocrine deficiencies, including thyroiditis managed 
with replacement hormones including physiologic doses of corticosteroids. Subjects with 
Sjögren’s syndrome and psoriasis controlled with topical medication and subjects with 
positive serology, such as antinuclear antibodies or antithyroid antibodies should be 
evaluated for the presence of target organ involvement and potential need for systemic 
treatment but should otherwise be eligible. 
12. A condition requiring systemic treatment with either corticosteroids (> 20 mg daily 
prednisone or equivalent) or other immunosuppressive medications within 14 days of 
study drug administration, except for PCNSL and SCNSL. Note: adrenal replacement 
doses ≤ 20 mg daily prednisone or equivalents are permitted in the absence of active 
autoimmune disease; subjects are permitted to use topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic absorption). 
13. History of interstitial lung disease or noninfectious pneumonitis, except for those induced 
by radiation therapy. 
14. Requirement for medications which strong cytochrome P450 (CYP)3A inhibitors or 
inducers. 
15. Vaccination with a live vaccine within 28 days of the initiation of treatment. 
16. A candidate for hematopoietic stem cell transplantation or have received prior autologous 
hematopoietic stem cell transplant within the past 6 months. Subjects are excluded if they 
had received prior allogeneic stem cell transplantation.  
17. Participated in any investigational drug study within 28 days or not recovered from 
toxicity of any prior chemotherapy to Grade ≤ 1. 
18. History of other active malignancies within 2 years of study entry, with the exception of 
adequately treated in-situ carcinoma of cervix; localized basal cell or squamous cell 
carcinoma of skin; or previous malignancy confined and treated locally (surgery or other 
modality) with curative intent. 
19. Major surgery in the past 4 weeks prior to the first day of screening. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:51 of 132
 
Version 5.0: 02 May 2019 
20. Active and symptomatic fungal, bacterial, and/or viral infection; human T-cell 
lymphotropic virus type 1 seropositive status. 
21. Human immunodeficiency virus (HIV) infection, or active hepatitis B (eg, hepatitis B 
surface antigen [HBsAg] reactive) or hepatitis C (eg, hepatitis C virus [HCV] ribonucleic 
acid [RNA] detected.   
 Hepatitis B/C serologic markers and 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 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 (≥ 15 IU/mL) are not eligible.  Subjects 
negative for HBsAg, HBcAb positive, and HBV DNA negative must undergo 
monthly HBV DNA screening by PCR.  Subjects positive for HCV antibody but 
negative for HCV RNA (defined as < 15 IU) must undergo monthly HCV RNA 
screening. 
22. Inability to comply with study procedures. 
23. Pregnant or nursing women. 
24. Men or women of childbearing potential who refuse to use an adequate measure of 
contraception, unless they have past medical history of surgical sterilization. 
25. Currently taking or plan to take CNS penetrant therapy such as thiotepa, cytarabine, or 
partially CNS penetrant agents known to be active in lymphoid tumors, such as rituximab. 
26. Has taken or plans to take any chemotherapy, immunotherapy (eg, interleukin, interferon, 
thymoxin), or any investigational therapies to treat leukemia or lymphoma within 28 days 
or 5 half-lives (whichever is shorter) of the first study drug administration, including CNS 
penetrating agents. Has received radiotherapy to treat leukemia or lymphoma within 
21 days of the first study drug administration. 
4.2.3 
Other Eligibility Criteria Considerations 
To assess any potential impact on subject eligibility with regard to safety, the investigator must 
refer to the IB for zanubrutinib and the IB for tislelizumab for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the 
investigational product being used in this study. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:52 of 132
 
Version 5.0: 02 May 2019 
4.2.4 
Subject Completion and Withdrawal 
4.2.4.1 
Subject Completion 
Study treatment duration is not limited and continues until one of the events listed in 
Section 4.2.4.3 occurs. Since there is no maximum treatment duration, a subject will be 
considered complete if he/she has completed at least 1 full cycle of zanubrutinib plus tislelizumab 
treatment and has not withdrawn from the study prior to completing the first cycle. A subject who 
discontinues due to a DLT before completing the first cycle will be considered complete as well. 
Incomplete subjects may result in additional enrollment, as needed (i.e. to meet minimum number 
of DLT-evaluable subjects in dose-escalation cohorts). 
If a subject discontinues from the study, the procedures will be followed as described in 
Section 4.2.4.2. 
Subjects continuing to show clinical benefit at study closure will be allowed to participate in the 
long-term extension study at the discretion of the sponsor/investigator. 
4.2.4.2 
Subject Withdrawal/Discontinuation 
Subjects may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject may be withdrawn by the 
investigator or the sponsor if he/she violates the study plan or for administrative and/or other 
safety reasons. When a subject discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse experiences which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 9.0. 
In the event that a subject is prematurely discontinued from the study at any time due to an AE 
(as defined in Section 9.1), the procedures stated in Section 9.0 must be followed.  
Subjects that are part of dose escalation cohorts who drop out or are withdrawn for any reason 
that does not fall under DLT will be considered for replacement in the cohort after due 
consideration from the sponsor and safety committee.  
Discontinuing one or both study drugs does not require the subject to discontinue the study: 
subjects should still continue with study procedures, either on study drug or in follow-up, as 
appropriate (see Section 4.1.3). 
4.2.4.3 
Subject Withdrawal from the Investigational Product  
Treatment with both zanubrutinib and tislelizumab will permanently discontinue when one of the 
following events occurs: 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:53 of 132
 
Version 5.0: 02 May 2019 
 Confirmed disease progression (refer to Section 7.7) 
 Need for prohibited medication 
 Subject withdrawal of consent 
 Subject is lost to follow-up 
 Pregnancy in subject 
 Lack of compliance with the study and/or study procedures (eg, administration 
instructions, study visits) 
 Study closure  
Treatment with either zanubrutinib or tislelizumab (per drug, as applicable) will permanently 
discontinue when one of the following events occurs: 
 
Unresolved toxicity leading to a treatment delay of more than 21 days (unless Investigator 
and Sponsor Medical Monitor approval was obtained) 
 
Treatment delay of more than 42 days for reasons unrelated to unresolved toxicity (with 
the exception of subjects whose delays are related to prophylactic vaccinations or to 
specific consultation and agreement between the investigator and the sponsor Medical 
Monitor, in settings where benefit/risk may justify continued study therapy) 
 
Unacceptable adverse experiences (see Section 9.0) 
 
Intercurrent illness that prevents further administration of treatment 
 
If, in the opinion of the investigator, a change or discontinuation of therapy would be in 
the best interest of the subject 
 
Discontinuation of study drug by the sponsor 
Treatment with zanubrutinib will permanently discontinue if one of the following occurs: 
 
Adverse events as indicated in Section 9.14.1. 
 
Subject cannot tolerate 80 mg QD. 
Treatment with tislelizumab will permanently discontinue if any adverse events indicated in 
Section 9.14.2 occur. 
In the event that a subject is prematurely discontinued from study drug at any time due to an AE 
(as defined in Section 9.1), the procedures stated in Section 9.0 must be followed. The 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:54 of 132
 
Version 5.0: 02 May 2019 
investigator or study coordinator must notify the sponsor immediately when a subject has been 
discontinued / withdrawn due to an adverse experience.  
Subjects who discontinue study drug due to reasons other than disease progression will remain on 
study and should be follow the guidance provided in Section 7.4. 
5.0 STUDY TREATMENTS 
5.1 
Description of Investigational Product  
Subjects will receive zanubrutinib orally as 80-mg white, opaque capsules.  
Subjects will receive tislelizumab by intravenous (IV) infusion using a single-use vial (20R glass, 
USP Type I) containing a total of 100 mg antibody in 10-mL isotonic solution. 
5.2 
Dosage and Administration 
Zanubrutinib will be administered orally every day with or without food. Tislelizumab will be 
administered intravenously (2.0 mg/kg, 5.0 mg/kg, or 200 mg flat dose, depending on assigned 
dose level cohort) Q3W. When the 2 study drugs are administered on the same day (except on the 
days both PK samples are collected), zanubrutinib should be taken at least 30 minutes before 
tislelizumab infusion. 
For dose escalation, Cycle 1 will be 28 days and all subsequent cycles will be 21 days. 
Zanubrutinib will be administered on Cycle 1 Day 1 and then continuously every 
day.Tislelizumab will be administered on Cycle 1 Day 8 and then on Day 1 of all subsequent 
cycles. The period for DLT assessment is 21 days from Cycle 1 Day 8 to Cycle 1 Day 28. 
For dose expansion, all cycles will be 21 days. On Day 1 of each cycle, zanubrutinib and 
tislelizumab will be administered on the same day, except for 10 subjects of the CNS lymphoma 
cohort (Cohort 4A) as described below.  
For PCNSL and SCNSL (Cohorts 4A and 4B), 10 subjects (Cohort 4A) will initially receive 
single-agent tislelizumab for 4 cycles at 200 mg intravenously Q3W. On Day 1 of Cycle 5 and 
thereafter, these 10 subjects will receive combination zanubrutinib and tislelizumab at the RP2D 
defined by dose escalation. For Amendment 5.0, Cohort 4A is being discontinued.  There were no 
safety or tolerability signals that led to the discontinuation of Cohort 4A. Cohort 4B will be 
immediately activated with Amendment 5.0. As of March 2019, 3 subjects with CNSL have been 
enrolled in Cohort 4A; however, no subjects remain on study treatment in this cohort, which is 
now closed to treatment and further enrollment. For Cohort 4B, 10 subjects with PCNSL and 
SCNSL will receive combination zanubrutinib and tislelizumab at the RP2D defined by the dose 
escalation starting at Day 1 of Cycle 1 and all cycles thereafter. When the 2 study drugs are 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:55 of 132
 
Version 5.0: 02 May 2019 
administered on the same day (except on the days both PK samples are collected), zanubrutinib 
should be taken at least 30 minutes before tislelizumab infusion. All cycles will be 21 days.  
Subjects will continue to take zanubrutinib and tislelizumab as scheduled until one of the events 
listed in Section 4.2.4.3 occurs.  
5.2.1 
Zanubrutinib 
Zanubrutinib will be administered orally every day (320 mg QD or 160 mg BID) with or without 
food. When the 2 study drugs are administered on the same day (except on the days both PK 
samples are collected), zanubrutinib should be taken at least 30 minutes before tislelizumab 
infusion. Subjects will be advised that if a dose of zanubrutinib 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 zanubrutinib should not be taken to make up for the missed dose. 
Subjects will continue to take zanubrutinib until one of the events listed in Section 4.2.4.3 occurs. 
Subjects may discontinue tislelizumab  for toxicity and continue on a single-agent of zanubrutinib 
. 
5.2.2 
Tislelizumab 
Tislelizumab will be administered intravenously (2.0 mg/kg, 5.0 mg/kg, or 200 mg flat dose, 
depending on assigned dose level cohort) Q3W, using a volumetric pump through an IV line 
containing a sterile, nonpyrogenic, low-protein binding 0.2 micron in-line or add-on filter. 
Specific instructions for product preparation and administration are provided below; refer to 
Pharmacy Manual for additional details. 
There will be no dose adjustments allowed for tislelizumab. In the case that an infusion cannot be 
administered at a scheduled visit, it is to be administered as soon as possible. If there is a dosing 
delay of between 1 and 10 days, the procedures at the original scheduled visit should be 
performed. If the delay is more than 10 days, the tislelizumab study drug infusion should be held 
and administered on Day 1 of the next planned cycle. The infusion at the original scheduled visit 
will be considered a missed dose. Subjects with infusion delays > 42 days should discontinue 
treatment (with some exceptions, see Section 4.2.4.3).   
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of immune-related AEs are provided in detail in Section 9.14.2.4. 
Subjects will continue to take tislelizumab until one of the events listed in Section 4.2.4.3 occurs. 
Should subjects discontinue zanubrutinib for toxicity, tislelizumab monotherapy may be 
continued.   
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:56 of 132
 
Version 5.0: 02 May 2019 
As a routine precaution, subjects who were enrolled in this study must be observed for 2 hours 
after the initial infusion, in an area with resuscitation equipment and emergency agents. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. For management of toxicity, refer to Section 9.14.2. 
5.2.3 
Dose Escalation 
The purpose of dose escalation is to determine the MTD for this study. During dose escalation, 
three dose levels will be explored in the following order (sequentially): 
 Dose level 1: zanubrutinib 320 mg once a day (QD) in combination with 
tislelizumab 2.0 mg/kg Q3W. If dose level 3 has cleared, subjects will be 
converted to dose level 3 dosing.  
o Dose level -1 (applicable only if dose level 1 exceeds MTD): zanubrutinib 
160 mg QD in combination with tislelizumab 2.0 mg/kg Q3W. Further 
reductions of zanubrutinib or tislelizumab dose levels may be allowed until 
a safe dose combination is identified.  
 Dose level 2: zanubrutinib 320 mg QD with tislelizumab 5.0 mg/kg Q3W. If dose 
level 3 has cleared, subjects will be converted to dose level 3 dosing. 
 Dose level 3: zanubrutinib 160 mg BID with tislelizumab 200 mg flat dose Q3W. 
Dose escalation will follow the same principles as stipulated for a standard 3+3 dose escalation 
design, with each cohort evaluated for safety based on the number of DLTs observed. DLTs are 
defined in Section 4.1.1. Evaluation of a cohort of at least 3 subjects completing the DLT 
assessment at any given dose level is required prior to determining the next dose level and dose 
regimen for the subsequent cohort. Three subjects in the cohort are sufficient if no DLTs are 
observed within the DLT window for all 3 subjects. More than 3 subjects are required per cohort 
depending on the number of observed DLTs as follows: 
 < 6 subjects enrolled in the cohort:  
o 1 subject experiences a DLT during the DLT assessment period: the cohort must 
enroll a minimum of 6 subjects evaluable for DLT.   
o ≥ 2 subjects experience a DLT during the DLT assessment period: the MTD is 
considered to have been exceeded, and no additional subjects will be treated at the 
current or higher doses.   
 ≥ 6 subjects enrolled in the cohort: 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:57 of 132
 
Version 5.0: 02 May 2019 
o 1 subject experiences a DLT during the DLT assessment period: the cohort is 
considered tolerable and to not exceed the MTD. 
o  ≥ 33% of subjects (eg, 2 out of 6) experience a DLT during the DLT assessment 
period: the MTD is considered to have been exceeded, and no additional subjects 
will be treated at the current or higher doses.  
Additional subjects, may be enrolled to each dose escalation cohort beyond the minimum 
necessary (3 for 0 DLT, 6 for 1 DLT).  
The MTD is considered the dose level below that at which ≥ 2 (or ≥ 33%) subjects experience a 
DLT. If that does not occur at any dose level, the MTD is considered not to be reached. The 
RP2D will be selected by taking into account the MTD, safety, tolerability, and PK profile, under 
the guidance of the SMC (Section 7.3.1). 
5.2.4 
Dose Escalation for Safety Expansion (Additional Subject Enrollment for Dose 
Levels 1, 2, and 3) 
Once a dose level has been determined not to have exceeded the MTD, up to 9 additional subjects 
may be enrolled to that dose level cohort (eg, a total of 15 subjects for a dose level found 
tolerable in a dose escalation cohort of 6 subjects) to provide additional safety information on that 
dose level prior to proceeding to the dose expansion of the study. More than 9 additional subjects 
may be enrolled if requested by the SMC for additional safety information (see Section 7.3.1). If 
dose level 3 has cleared, these subjects will be converted to dose level 3 dosing. 
5.2.5 
Dose Expansion 
In the dose expansion, there will be 4 dose expansion cohorts at the RP2D for the combination of 
tislelizumab and zanubrutinib (see Section 4.2.1 for the specific inclusion requirements of each 
cohort): 
 Cohort 1 (n = 10): GCB DLBCL  
 Cohort 2 (n = 10): non-GCB DLBCL  
 Cohort 3 (n = 20): Transformed lymphoid malignancy  
 Cohort 4: Primary CNS lymphoma or SCNSL of breast or testicular origin 
o Cohort 4A (n = 10): begin with 4 cycles of single-agent tislelizumab at 200 mg 
Q3W, combination of zanubrutinib and tislelizumab starting Cycle 5 
o Cohort 4B (n = 10): combination of zanubrutinib and tislelizumab starting Cycle 1 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:58 of 132
 
Version 5.0: 02 May 2019 
The dose and schedule of combination zanubrutinib and tislelizumab will be the RP2D as 
determined by the SMC for the non-CNS disease types (Cohorts 1 to 3). The dose and schedule 
of single-agent tislelizumab will be 200 mg IV Q3W for Cohort 4, followed by the RP2D for the 
combination. Approximately 10 to 20 subjects each per classification of non-Hodgkin lymphoma 
will be enrolled in dose expansion. Cohorts 1, 2, 3, and 4A will open simultaneously once the 
RP2D has been determined.  
5.3 
Treatment Assignment 
Each study subject will be identified by a unique subject number, which will be assigned after the 
subject signs the informed consent. Each subject receiving zanubrutinib and/or tislelizumab will 
also receive a treatment allocation number. Subject and treatment numbers will be assigned in 
chronological order, starting with the lowest number. Once a subject number and treatment 
number have been assigned to a subject, it cannot be reassigned to any other subject. 
If a subject needs to be replaced in a cohort, a new subject will be enrolled for this purpose.  
5.4 
Packaging and Labeling 
The capsule of zanubrutinib will be provided in a child-resistant closure and be labeled with 
space to enter the subject number and name of investigator. Tislelizumab will be provided in 
aseptic glass vials with a Flurotec-coated butyl rubber stopper and an aluminum cap packaged in 
cartons.  
The primary labels on the zanubrutinib and tislelizumab packaging will be in accordance with all 
applicable local regulatory requirements. 
5.5 
Handling and Storage 
The investigational products 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. 
Investigational product must be dispensed or administered according to procedures described 
herein. Only subjects enrolled in the study may receive investigational product, in accordance 
with all applicable regulatory requirements. Only authorized study center personnel may supply 
or administer investigational product. All investigational products 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 investigational product-specific requirements. 
Zanubrutinib must be kept at the condition as specified on the labels or according to the latest 
version of the IBs. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:59 of 132
 
Version 5.0: 02 May 2019 
Tislelizumab does not contain a preservative. Unreconstituted vials should be stored at a 
temperature between 2°C to 8°C (36°F to 46°F) and protected from light. Refer to the Pharmacy 
Manual for details regarding IV administration, accountability, and disposal.  Please also refer to 
the Investigator’s Brochure for other details regarding tislelizumab.  
5.6 
Product Accountability 
The investigator is responsible for investigational product accountability, reconciliation, and 
record maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study center personnel must maintain investigational product accountability records 
throughout the course of the study. This person will document the amount of investigational 
products received from the sponsor and the amount supplied and/or administered to and returned 
by subjects, if applicable. 
After completion of the study, all unused zanubrutinib and tislelizumab will be inventoried and 
packaged for return shipment by the hospital unit pharmacist. The inventoried supplies will be 
returned to the sponsor or destroyed on site, after receiving written sponsor approval. 
5.7 
Assessment of Compliance 
On all visits to the study center, subjects will be questioned in regard to compliance with study 
instructions. 
5.8 
Treatment of Investigational Product Overdose 
Overdose is defined as the subject having taken (accidentally or intentionally) a dose exceeding 
the dose prescribed in the protocol by 20%. Subjects with a suspected overdose should be 
managed with appropriate supportive therapy as determined by the investigator in consultation 
with the medical monitor. Any AEs occurring as a result of an overdose should be reported to the 
medical monitor.  
5.9 
Occupational Safety 
The investigational products are not expected to pose significant occupational safety risk to the 
study center personnel under normal conditions of use and administration. A material safety data 
sheet describing occupational hazards and recommended handling precautions will be provided to 
the investigator, where this is required by local laws, or will be available upon request from the 
sponsor.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:60 of 132
 
Version 5.0: 02 May 2019 
6.0 CONCOMITANT MEDICATIONS AND NONDRUG 
THERAPIES 
6.1 
Permitted Medications 
For prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted; treatment course 
should not last longer than 2 weeks and should be discussed with the medical monitor unless 
given for an immune-mediated reaction. 
Patients with hematologic malignancies, particularly those having received prior 
lymphodepleting chemotherapy or having prolonged corticosteroid exposure, are pre-disposed to 
opportunistic infections as a result of disease and treatment-related factors. In patients with a high 
risk for opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP), prophylaxis 
should be considered as per institutional standards. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription medications, over-the-counter medications, herbal supplements, and IV 
medications and fluids. If changes occur during the study period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of study medication 
and 28 days after the last infusion of study medication should be recorded.  
The eCRF entry must include the dose, regimen, route, indication, and start and stop dates of use 
of the prior and concomitant medication. 
6.2 
Prohibited Medications 
Subjects should not receive other anticancer therapy (cytotoxic, biologic, or hormone other than 
for replacement) while on treatment in this study. Other anticancer therapy should not be 
administered until disease progression (as per clinical practice standards at the study center), 
unmanageable toxicity, or no further clinical benefit occurs which requires permanent 
discontinuation of the investigational product. Bisphosphonate use is permitted if the subject has 
already been on it for 3 or more months and on a stable dose. Corticosteroid courses of limited 
duration (2 weeks or less) and dose (< 10 mg prednisone per day or equivalent) are permitted, if 
used to treat a concomitant (noncancer) medical condition. Corticosteroid treatment of longer 
duration for management of tislelizumab-related infusion reaction or immune-mediated AEs is 
permitted (see Section 6.3.2 and Section 9.14.2.4). 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:61 of 132
 
Version 5.0: 02 May 2019 
6.3 
Medications to Be Used with Caution 
6.3.1 
Zanubrutinib 
Administration of zanubrutinib with strong/moderate CYP3A inhibitors or CYP3A inducers 
(refer to Table 6-1 for a list of these medications) and grapefruit juice and Seville oranges should 
be used with caution as they may affect the metabolism of zanubrutinib.  If at all possible, 
patients are encouraged not to use strong/moderate CYP3A inhibitors and inducers and consider 
using alternative agents. If these agents will be used, follow the dose modification table in Table 
6-1.  The medical monitor should be consulted in these situations. Please refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list. 
Table 6-1 
Dose Modification for Zanubrutinib when Co-Administered with 
Strong/Moderate CYP3A Inhibitors or Inducers 
 
CYP3A 
Co-administered Drug 
Recommended use 
Inhibition 
Strong CYP3A inhibitor (eg, ketoconazole, 
conivaptan, clarithromycin, indinavir, 
itraconazole, lopinavir, ritonavir, telaprevir, 
posaconazole, voriconazole) 
80 mg once daily 
Moderate CYP3A inhibitor (eg, erythromycin, 
ciprofloxacin, diltiazem, dronedarone, 
fluconazole, verapamil, aprepitant, imatinib, 
grapefruit products) 
80 mg twice daily 
Induction 
Strong CYP3A inducer (eg, carbamazepine, 
phenytoin, rifampin, St. John’s wort) 
Avoid concomitant use; Consider alternative 
agents with less induction potential. 
Moderate CYP3A inducer (eg, bosentan, 
efavirenz, etravirine, modafinil, nafcillin) 
160 mg twice daily, use with caution; Monitor 
for potential lack of efficacy. 
 
Clinical drug-drug interaction study indicated that zanubrutinib is a mild inducer of CYP3A4 and 
CYP2C19 (Section 1.2). Narrow therapeutic index drugs that are metabolized by CYP3A4 
(alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should be used with caution, as 
zanubrutinib may decrease the plasma exposures of these drugs.   
6.3.2 
Tislelizumab 
Subjects may be pretreated with H1 blockers (diphenhydramine 50 mg IV, or equivalent), and 
paracetamol (500 to 650 mg oral or IV), 30 to 60 minutes prior to each tislelizumab infusion. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:62 of 132
 
Version 5.0: 02 May 2019 
Systemic corticosteroids required for the control of infusion reactions or AEs must be tapered and 
be at nonimmunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) for at least 
2 weeks before the next study drug administration (see Section 9.14.2.2 for further details). The 
use of steroids as prophylactic treatment for subjects with allergies to diagnostic imaging contrast 
dyes will be permitted. 
7.0 SAFETY, PHARMACOKINETIC, EFFICACY, AND OTHER 
ASSESSMENTS 
A signed, written informed consent must be obtained prior to screening assessments and before 
any study-specific assessments are initiated. The study-specific assessments and procedures are 
shown in Table 4-1 and Table 4-2, and the procedures schedule for pharmacokinetic sampling 
time points is presented in Table 4-3 and Table 4-4.  
7.1 
Screening: Demographic and Baseline Assessments 
Having given consent, subjects will be required to undergo a medical screening to determine 
whether they are eligible to participate in the study according to the criteria in Section 4.2.1 and 
Section 4.2.2. Screening assessments will be performed within 28 days prior to Day 1 (first 
dosing) and will include the following: 
 
Demographic data (includes date of birth, race, height [cm], body weight [kg], and body mass 
index [kg/m2]) 
 
General medical history 
 
Vital signs 
 
B symptoms (unexplained weight loss > 10% over the previous 6 months, fever > 38ºC, 
and/or drenching night sweats) 
 
Complete physical examination 
 
ECOG performance status 
 
Echocardiogram or multigated acquisition (MUGA) scan 
 
12-lead ECG 
 
Review of concomitant medications 
 
Hematology testing (Appendix 2) 
 
Clinical chemistry testing (Appendix 2) 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:63 of 132
 
Version 5.0: 02 May 2019 
 
Coagulation parameters testing (Appendix 2) 
 
Urinalysis 
 
Pregnancy tests (for women of childbearing potential) 
 
IgA, IgG, and IgM level (Appendix 2) 
 
Viral serologies (HBV, HCV antibody, and human immunodeficiency virus [HIV]) 
 
CT scan for tumor assessment 
 
MRI with gadolinium or CT with contrast of brain (Cohort 4 of expansion part only) 
 
Lumbar puncture or Ommaya tap for CSF analyses (Cohort 4 of expansion part only) 
 
Complete ophthalmologic examination with slit lamp (Cohort 4 of expansion part only) 
 
Ultrasound of testicle for male subjects with SCNSL of testicular origin and only if the 
positron emission tomography (PET)/CT scan is positive for testicular disease for Cohort 4 
only 
 
Mammogram of bilateral breast for male or female subjects with SCNSL of breast origin for 
Cohort 4 only 
 
Bone marrow aspirations or biopsy 
 
CLL prognostic factors 
 
Archival tumor tissues 
 
Fresh tumor tissues (additional consent required) 
The abovementioned data will be captured in the source documents. Any results outside the 
normal range, the test will be repeated at the discretion of the investigator. 
7.1.1 
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.  If, during monthly monitoring of HBV DNA by PCR, the value is between 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:64 of 132
 
Version 5.0: 02 May 2019 
20 IU/mL and 100 IU/mL then the HBV DNA level should be rechecked within 2 weeks.  Study 
drug should be held and anti-viral therapy initiated if the repeat level is between 20IU/mL and 
100 IU/mL. If the HBV DNA by PCR is 100IU/mL or higher then study drug should be stopped 
and anti-viral therapy initiated. Subjects positive for HCV antibody but negative for HCV RNA 
must undergo monthly HCV RNA screening. Subjects with HIV infection are excluded from the 
study. Subjects with HCV RNA of 15 IU/mL or greater should stop study drug and anti-viral 
therapy should be initiated.  The medical monitor should be informed of any suspected Hep B or 
Hep C reactivation and both tislelizumab and zanubrutinib should be held.  Resuming either drug 
should only occur after discussion with the medical monitor; consultation with a specialist in 
hepatitis B may be also requested. 
Table 7-1 shows how the results for HBV and HBV testing at screening relate to inclusion and 
exclusion criteria. 
Table 7-1:  
Active Hepatitis B or Hepatitis C Infection (Detected Positive by Polymerase 
Chain Reaction)  
Screening 
Assessment 
Meets Inclusion Criteria 
To be Excluded 
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) and HBcAb (+) 
HBV DNA “Not detected”  
 
Perform monthly monitoring of HBV DNA  
HBsAg (-) and HBcAb (+) 
HBV DNA detected 
HCV 
Antibody (-) or Antibody (+) 
HCV RNA “Not-detected” (< 15 IU/mL) 
 
Perform monthly monitoring of HCV RNA  
Antibody (+) 
HCV RNA Detected (≥ 15 IU/mL)  
HBsAg: Hepatitis B surface antigen; HBcAb: Hepatitis B core antibody; HBV: Hepatitis B virus; HCV: Hepatitis C virus; DNA: 
deoxyribonucleic acid; RNA: ribonucleic acid 
 
7.1.2 
Pulmonary Function Tests 
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit 
significant respiratory symptoms unrelated to the underlying cancer will undergo pulmonary 
function testing which may include but is not limited to spirometry and assessment of diffusion 
capacity done during the Screening period to assist the determination of suitability on the study 
(refer to Section 4.1.3 for details). 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:65 of 132
 
Version 5.0: 02 May 2019 
7.2 
Assessments During Treatment 
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 is presented in Table 4-1 and Table 
4-2. 
7.2.1 
Local Laboratory Evaluation 
Laboratory assessments should be performed at a local certified laboratory (or a certified central 
laboratory if local laboratory is not feasible) on Day 1 before investigational product 
administration. Laboratory assessments need not be repeated on Day 1 if these assessments were 
completed for screening within 24 hours of the first administration. Required assessments are 
listed in Appendix 2. 
Clinical chemistry, hematology, coagulation, urinalysis, and immunoglobulin, viral serologies, 
and thyroid function assessments will be performed at the time points specified in Table 4-1 and 
Table 4-2. 
Clinical chemistry will include sodium, potassium, chloride, bicarbonate (total CO2), glucose, 
urea, creatinine, calcium phosphorus, magnesium, total and direct bilirubin, total protein, 
albumin, ALT, AST, lactate dehydrogenase, 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 needed until toxicity resolves to ≤ Grade 2. 
Hematology will include red blood cell count, hemoglobin, reticulocyte count, white blood cell 
count, absolute differential count (neutrophils, eosinophils, lymphocytes) and platelet count. In 
the event of neutropenia (absolute neutrophil count < 1.0 × 109/L) or thrombocytopenia (platelet 
count < 50 × 109/L), these assessments will be conducted as frequently as the investigator feels 
needed until toxicity resolves to ≤ Grade 2. 
Results of blood tests taken within 24 hours may be used to allow the investigator to make the 
decision to proceed with dosing; in these cases, a separate pre-treatment sample must still be 
taken.  
For urinalysis, a urine dipstick will be collected as well as microscopy if the dipstick is abnormal. 
If urine protein is ≥ 2+ by dipstick, a 24-hour urine test for total protein and a random urine test 
for total protein and creatinine will be obtained and evaluated on the first occurrence. 
Viral serologies should be performed during screening for all subjects. Viral serologies will 
include hepatitis B (HBsAg and total HB core antibody as well as HBV DNA by polymerase 
chain reaction if the subject is HB core antibody positive), HCV antibody (as well as HCV RNA 
by polymerase chain reaction if the subject is HCV antibody positive), and HIV. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:66 of 132
 
Version 5.0: 02 May 2019 
Thyroid testing of T3, T4, and thyroid stimulating hormone will be performed at screening, then 
every other cycle starting from Cycle 2, and at the safety follow-up visit or early discontinuation 
visit. Additional T3, T4, and TSH may be performed at the discretion of the investigator. 
Cerebrospinal fluid will be obtained by lumbar puncture and/or Ommaya tap in subjects with 
PCNSL or SCNSL of breast or testicular origin and will include cytology, total cell count, protein 
level, and glucose level. Lumbar puncture should only be performed in subjects with PCNSL or 
SCNSL of breast or testicular origin who are not at risk of herniation. Cerebrospinal fluid 
analyses are required after screening only if these studies were initially positive at screening or if 
clinically indicated by new symptoms or signs. Patients with significant CSF abnormalities at 
baseline, are required to have lumbar puncture and Ommaya tap at suspected CR or unconfirmed 
complete response defined per for PCNSL or SCNSL.  For subjects with CSF collection (at end 
of Cycles 2, 6 and 12), subjects will take the morning dose of zanubrutinib at the clinic, and CSF 
collection will be performed around 2 hours (+/- 10 minutes) following zanubrutinib dose for 
measurement of zanubrutinib and tislelizumab concentration in CSF. On the same day of CSF 
collection, blood samples for measuring plasma zanubrutinib and serum tislelizumab 
concentrations will be collected at pre-dose (prior to zanubrutinib dose) and at 2 hours (+/- 10 
minutes) post zanubrutinib dose. CSF collection for PK samples is optional. 
7.2.2 
Physical Examination, Vital Signs, and B Symptoms 
A complete or targeted physical examination, vital signs (systolic and diastolic blood pressure, 
pulse rate, temperature, and respiratory rate), weight, and B symptoms examination will be 
performed at the time points specified in Table 4-1 and Table 4-2. 
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 (i.e., cardiovascular, 
respiratory, lymph nodes, liver, and spleen), and those systems associated with clinical 
signs/symptoms.  
7.2.3 
Electrocardiogram and Cardiac Function 
A 12-lead ECG in triplicate will be performed at screening and upon treatment completion or 
early termination visit and at the time points specified in Table 4-1, Table 4-2, Table 4-3, and 
Table 4-4. Note: not all required ECGs are indicated in these tables; additional ECGs may be 
required if there is a prolongation of QT or QTc (see below). If prolongation of QT or QTc is 
noted during the first 8 days, ECGs will be performed weekly during the first 2 cycles, and then 
on Day 1 every cycle onward for the remaining duration of treatment.  
Significant QTc prolongation will be defined as an interval ≥ 500 msec (corrected based on the 
Fridericia’s formula) or an interval that increases by ≥ 60 msec over baseline. Either of these 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:67 of 132
 
Version 5.0: 02 May 2019 
conditions should be documented on 2 or more ECG tracings separated by at least 5 minutes. The 
ECG tracing should be examined and a manual measurement by a trained physician should be 
performed to assess the accuracy of the equipment being used. 
If a subject has significant QTc prolongation： 
 The investigational product administration will be suspended. 
 The subject will be medically assessed, treated appropriately, and closely followed until the 
QT and QTc interval returns to within 30 msec of baseline.  
 The medical monitor will be consulted prior to administering further doses or rechallenging.  
 The medical monitor will be consulted prior to administering higher doses.  
An assessment of left ventricular ejection fraction (LVEF) will be performed and documented at 
screening and as medically indicated. Note: an echocardiogram or MUGA scan are acceptable. 
7.2.4 
Positron Emission Tomography (PET)-Computed Tomography (CT) and CT 
with Contrast Computed Tomography 
Tumor assessments by PET-CT scan with IV contrast of neck, chest, abdomen, and pelvis and 
any other disease sites for non-Hodgkin lymphoma classifications that are reliably FDG-avid 
(includes MCL, FL, DLBCL, transformed FL, Richter’s transformation, and CNS lymphomas) 
must be performed at Screening, within 7 days of Cycles 4, 8, and 12, and at suspected PD or CR. 
After Cycle 12, standalone CT scans will be performed every 4 cycles. Screening findings will 
determine whether patients are followed with PET-CT-based or CT-based assessments on study. 
That is, patients whose disease is not PET-avid will be followed by CT-based assessments alone 
while patients whose disease is PET-avid will be followed by an integration of PET-CT and CT-
based assessments.  
Ideally, contrast-enhanced CT should occur during a single visit combined with PET-CT. 
Combined PET-CT may be used in lieu of a CT with contrast only if the CT of the combined 
PET-CT has been performed with diagnostic quality and contrast is administered. An MRI may 
be used in place of CT only for patients who cannot undergo CT due to contrast allergy. 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 patient’s 
course on study. These images may be collected and reviewed by an independent review 
committee if required in the future. 
7.2.5 
Magnetic Resonance Imaging with Gadolinium of Brain 
Tumor assessment by MRI with gadolinium of brain required for subjects in Cohort 4 of 
expansion per the schedule of assessments. A computed tomography scan with contrast of brain 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:68 of 132
 
Version 5.0: 02 May 2019 
may be substituted if MRI is contraindicated (eg, implanted metal or electronic device such as 
pacemaker or insulin pump, or claustrophobia). 
7.2.6 
Bone Marrow Evaluation 
A bone marrow aspirate/biopsy must be performed at screening for all participants and within 7 
days of the end of Cycle 4 for subjects with baseline marrow disease. 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 CR), a bone marrow aspirate and biopsy will be 
obtained to confirm the CR. Additional bone marrow examinations may be performed at the 
investigator’s discretion. Peripheral blood and/or bone marrow aspirate/biopsy with flow 
cytometry assessments for minimal residual disease should be done at least 3 months after the last 
dose if there is evidence of CR in all of the response parameters (i.e., hematology, CT scan). 
7.2.7 
Ophthalmologic Examination 
For all subjects, an eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test) will be assessed by an appropriate specialist at Screening. Eye exam, 
visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal 
examination) captured as standard of care prior to obtaining written informed consent or within 
28 days of study drug initiation may be used for the Screening evaluation. Patients will undergo 
repeat assessments by an appropriate specialist approximately every 15 weeks (± 7 days) during 
study treatment and a final assessment < 30 days after the last dose of study treatment.   
In addition, Investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance. 
For subjects with PCNSL and SCNSL (Cohorts 4A and 4B), ophthalmologic examination as 
part of response criteria includes a complete examination with dilated fundus and slit-lamp 
examinations. Color photography of the posterior pole should be obtained in those patients with 
ocular involvement. Fluorescein angiography may be helpful to confirm lymphomatous 
involvement of the retina. Eye examinations performed for response evaluation do not need to be 
duplicated as part of the safety evaluations (specified above for all subjects) if they fall within the 
acceptable scheduling window for the safety-based eye exam, visual acuity test, and optical 
coherence tomography. 
7.2.8 
Ultrasound of Testicles 
Ultrasound examination of the testicles is required for male subjects with SCNSL of testicular 
origin as per the schedule of assessments if the PET/CT scan is positive for testicular disease 
(Table 4-2).  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:69 of 132
 
Version 5.0: 02 May 2019 
7.2.9 
Bilateral Breast Mammogram 
Bilateral breast mammogram is required for male or female subjects with SCNSL of breast origin 
as per the schedule of assessments (Table 4-2). 
7.2.10 
Adverse Events 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. All AEs and SAEs, regardless of the relationship to the investigational 
product, will be collected from initiation of study drug and throughout the study.  
7.2.11 
Overall Disease Response Assessments 
Overall response to study drug for each patient will be assessed using disease-standard criteria as 
specified in Appendix 4. Depending on disease, this assessment will incorporate several 
components listed in Section 7.2, including imaging, physical exam, laboratory evaluations, vital 
signs, bone marrow evaluation, and B-symptoms.  
Response should be assessed against baseline unless otherwise noted by Appendix 4. Overall 
disease response will be used in assessments of study efficacy (Section 7.6). 
7.3 
Safety 
Measurements used to evaluate safety will include vital signs, B symptoms, other signs and 
symptoms related to the disease or its treatment, clinical laboratory tests (hematology, clinical 
chemistry, coagulation, urinalysis, and immunoglobulin assessment), 12-lead ECG, physical 
examinations, and ECOG performance status. Throughout the study, the study center personnel 
will be monitoring AEs. Adverse events and toxicities will be graded according to NCI-CTCAE, 
Version 4.03.20 
7.3.1 
Safety Monitoring 
The continuous safety monitoring will be performed by the investigators, the CRO medical 
monitors, and the sponsor. The SMC will be established for the evaluation of subjects’ safety and 
determination of dose levels to be administered during dose escalation and the dose regimens in 
this study. Details of the safety monitoring process will be specified in a dedicated SMC charter. 
The SMC consists of the coordinating investigator, selected recruiting investigators, the sponsor’s 
medical monitor, and the contract research organization’s (CRO) medical monitor. Ad hoc 
members will be consulted as needed and may include, but are not restricted to, the biostatistician 
and clinical pharmacologist.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:70 of 132
 
Version 5.0: 02 May 2019 
7.3.1.1 
SMC during Dose Escalation 
Before moving to the next dose level, the SMC will review all safety data available to determine 
whether recruitment to the next cohort should be initiated. At the conclusion of the dose 
escalation, the SMC will determine the RP2Ds to be further investigated, based on the MTD and 
other relevant information. 
The SMC will determine when no further dose escalation is appropriate and a RP2D is 
determined.  
In dose escalation, the SMC will meet for cohort safety reviews after all subjects in a dosing level 
have completed the first treatment cycle. All available safety data will also be provided for 
subjects who discontinue prior to this time. Safety data from prior cohorts may also be presented. 
The decision to escalate dose and the determination of the RP2D will be based on the cohort 
safety reviews. The SMC will review any protocol violations that may have impacted evaluation 
of potential DLT. The SMC may weigh collective evidence and may determine a DLT for 
reasons in addition to those explicitly stated in the final protocol. 
Response from all SMC members, including investigators with subjects enrolled in the study, or 
their designees, shall be required for each escalation/review. 
Enrollment in subsequent dose levels will be put “on hold” during each review period, pending 
the decision of the SMC. 
The SMC decision may fall into 1 of the categories detailed below: 
 
Escalate to a higher dose 
 
Recruit an additional 3 subjects into existing dose level 
 
Stop escalation and investigate lower dose(s) 
 
End part of the study 
 
End the overall study 
Decisions will be made using the criteria defined within the protocol. 
7.3.1.2 
SMC during Dose Expansion 
In the dose expansion, the SMC will meet at a minimum of every 6 months to review the safety 
status for all subjects enrolled or when there is a significant safety finding.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:71 of 132
 
Version 5.0: 02 May 2019 
7.3.2 
Pregnancy 
7.3.2.1 
Pregnancy Testing 
A serum pregnancy test will be performed at screening in women of childbearing potential. 
Laboratory-based highly sensitive pregnancy tests (urine or serum) will be performed at specified 
subsequent visits. Pregnancy tests must be continued every 4 weeks (cycle) and for at least 
90 days after the last dose of study drug (local laboratory assessment is acceptable after Safety 
Follow Up visit). If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test. Any 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.  
The results of pregnancy tests will not be recorded in the database.  
7.3.2.2 
Time Period for Collecting Pregnancy Information 
The time period for collecting information on whether a pregnancy occurs is every 4 weeks from 
screening to the 90 days after the last dose visit or early discontinuation from the study. 
Information on pregnancies identified prior to the investigational product administration does not 
need to be reported to the sponsor. 
7.3.2.3 
Action to Be Taken If a Pregnancy Occurs 
A subject who has a positive pregnancy test result at any time after the investigational product 
administration will be immediately withdrawn from participation in the study. All post-study 
assessments will be collected at the time of discontinuation as described in Section 4.2.4.2. 
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 2 weeks of learning of a subject’s pregnancy. The subject 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. Generally, follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any premature termination of the pregnancy will be 
reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE, as 
described in Section 9.7 and will be followed as described in Section 9.9. 
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 9.0. Furthermore, any SAE occurring as a result of a post-study pregnancy that is 
considered reasonably related to the investigational product by the investigator will be reported to 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:72 of 132
 
Version 5.0: 02 May 2019 
the sponsor as described in Section 9.12. While the investigator is not obligated to actively seek 
this information in former subjects, he/she may learn of an SAE through spontaneous reporting. 
7.4 
Safety Follow-up 
Approximately 30 ± 3 days after the last administration of the investigational product, all subjects 
should return for a final evaluation. Assessments to be performed include vital signs, evaluation 
for B symptoms, targeted physical examination, ECOG performance status, 12-lead ECG, LVEF 
assessment (echocardiogram or MUGA), review of AEs, review of concomitant medications, 
laboratory tests (hematology, clinical chemistry, coagulation parameters, urinalysis, thyroid 
function, immunoglobulin, serum tumor markers (if appropriate), and tumor assessment by CT 
scan (if appropriate). In addition, telephone contacts with patients should be conducted to assess 
AEs and concomitant medications (if appropriate, ie, associated with an AE or is a new 
anticancer therapy) at 60, and 90 days (±14 days) after the last dose of tislelizumab, regardless of 
whether or not the patient starts a new anticancer therapy. Beyond 90 days, Investigators should 
continue to report any SAEs that are believed to be related to study drug(s) if they become aware 
of them. 
Any abnormal finding of clinical consequence not related to the disease progression will be 
monitored until resolution or baseline status. 
The same assessments for early discontinuation will be performed as for safety follow-up. 
7.5 
Efficacy Follow-up 
Subjects who discontinue study drug due to reasons other than disease progression will remain on 
study and be followed every 3 months until subject exhibits first progression, starts new 
anti-cancer therapy, death, or study closure, whichever occurs first. 
7.6 
Survival Follow-up 
Once subjects progress or start the use of alternative anti-cancer therapy, clinic visits are no 
longer required. Subjects only need to establish survival status every 3 months (telephone call, 
medical records, etc.). 
7.7 
Treatment Beyond Disease Progression 
There is evidence that a minority of subjects treated with anti-PD1 therapies, such as 
tislelizumab, may derive clinical benefit despite initial documentation of PD by the response 
criteria in Section 14.0, Appendix 4. 
Pseudo-progression may occur due to immune cell infiltration and other mechanisms, as 
manifested by apparent increase of existing tumor masses or appearance of new tumor lesions. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:73 of 132
 
Version 5.0: 02 May 2019 
These subjects may go on to exhibit a partial response at a later time point. It is the responsibility 
of the investigator to determine if the subject should be considered for treatment beyond 
progression due to clinical benefit. This decision should be considered carefully so as to permit 
subjects who are likely to be benefitting to continue treatment while at the same time preventing 
prolonged exposure of a futile therapy in subjects who may not be benefitting. Any decisions to 
continue treatment beyond initial progression must be discussed with the medical monitor and 
documented in the study records.  
Subjects with documented progression in tumor burden or the appearance of new lesions in the 
absence of significant clinical deterioration (decline in performance status and/or laboratory 
values) are permitted to continue with treatment until confirmation of PD with repeat imaging at 
least 4 weeks later or at the next regularly scheduled imaging time point. The next imaging to 
confirm disease progression must not exceed 12 weeks from initial documentation of PD. 
If PD is suspected by the investigator to possibly reflect early pseudo-progression, subjects can 
be considered for treatment continuation until subsequent confirmation of PD as long as the 
following criteria are met: 
 
Absence of unmanageable clinical manifestations of toxicity (including worsening laboratory 
values) 
 
Stable ECOG performance status 
 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, cord compression) that necessitates urgent alternative medical intervention 
7.8 
Efficacy 
Efficacy is not a primary objective of the study. Nevertheless, the following efficacy endpoints 
will be assessed:  
 The number and proportion of subjects who achieve objective tumor response (CR, PR, and 
CR+PR) or SD 
 PFS 
 Overall survival (OS) 
 Duration of response for responders (CR or PR) and duration of SD 
Efficacy assessments will use the applicable response criteria with CT (or PET if applicable) for 
tumor assessments (see Section 7.2.4). Subjects who are at increased risk of allergic reaction to 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:74 of 132
 
Version 5.0: 02 May 2019 
iodinated contrast media should not have enhanced CT but should instead be provided MRI with 
gadolinium enhancement. 
7.9 
Pharmacokinetics 
Blood in a subset of subjects will be collected to describe the PK profile of zanubrutinib and 
tislelizumab. 
Blood samples for PK analysis will be collected at time points for zanubrutinib and for 
tislelizumab as described in Table 4-3 and Table 4-4. Total blood volume is presented in 
Appendix 3. 
The actual time each sample was collected will be captured to the nearest minute in the eCRF and 
recorded in the database. 
Details concerning handling of the PK blood samples, including labeling and shipping 
instructions, will be provided in the Study Manual.  
Samples will be shipped to the central laboratory, where all samples will be analyzed for blood 
zanubrutinib and tislelizumab concentrations using validated methods. 
For subjects with CSF collection (at end of Cycles 2, 6 and 12), subjects will take the morning 
dose of zanubrutinib at the clinic, and CSF collection will be performed around 2 hours 
(+/- 10 minutes) following zanubrutinib dose for measurement of zanubrutinib and tislelizumab 
concentration in CSF. On the same day of CSF collection, blood samples for measuring plasma 
zanubrutinib and serum tislelizumab concentrations will be collected at pre-dose (prior to 
zanubrutinib dose) and at 2 hours (+/- 10 minutes) post zanubrutinib dose. 
7.10 Other Assessments 
7.10.1 
Archival/Fresh Tumor Tissue 
Subjects with an accessible tumor lesion must agree to a fresh tumor biopsy at screening and 
another before the drug administration on Cycle 1 Day 8 (unless clinically unsafe), ideally taken 
from the same tumor lesion, for the biomarker analysis including but not limited to 
immunohistochemistry of PD-1, PD-L1, and T lymphocyte infiltration (up to first 12 qualified 
subjects). Written subject consent is required.  
Subjects with DLBCL must have the archival tumor tissues or agree to a fresh tumor biopsy for 
confirmation of DLBCL subtype and biomarker analysis if they do not provide the tumor 
biopsies during screening. Written subject consent is required for collection of archival tumor 
tissue. Specific instructions for tissue collection and shipment are provided in the lab manual. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:75 of 132
 
Version 5.0: 02 May 2019 
For the rest of subjects, upon consent (optional), an archival tumor tissue or a fresh tumor biopsy, 
if feasible, will be collected for the biomarker analysis. Upon consent, subjects who have disease 
relapse at any time will be asked to undergo rebiopsy of representative tumor sites to obtain 
samples for studying mechanisms of resistance. These studies may include phosphoprotein 
analysis of relevant pathways, whole exome or genome sequencing, and assessments of RNA 
expression. 
7.10.2 
Anti-Tislelizumab Antibodies 
Immunogenic responses to tislelizumab combined with zanubrutinib will be assessed to 
determine occurrence of anti-drug antibody.  Blood for anti-tislelizumab antibodies should be 
collected within 2 hours before start of infusion. Refer to Table 4-3 and Table 4-4 for details on 
the collection schedule. In subjects who discontinue study therapy before 6 months, every effort 
should be made to analyze anti-tislelizumab antibodies approximately 6 months after the first 
dose. Analysis will be performed by a central laboratory. 
7.10.3 
Biomarkers in the Blood 
Other candidate biomarkers that will be investigated in the study may include, but are not limited 
to, proteomics and ctDNA profiling in peripheral blood. Specific instructions for sample 
collection and shipment are provided in the lab manual. 
7.11 Appropriateness of Measurements 
All safety and PK assessments used in this study are standard (i.e., widely used and generally 
recognized as reliable, accurate, and relevant).  
8.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the International Conference on Harmonisation Note for Guidance on Good 
Clinical Practice, July 1996, the sponsor is responsible for implementing and maintaining quality 
assurance and quality control systems with written Standard Operating Procedures (SOPs).  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 
Investigator meeting(s) 
 
Certified local laboratories for laboratory measurements and ECGs 
 
Study center initiation visit 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:76 of 132
 
Version 5.0: 02 May 2019 
 
Early study center visits post-enrollment 
 
Routine study center monitoring 
 
Ongoing study center communication and training 
 
Data management quality control checks 
 
Continuous data acquisition and cleaning 
 
Internal review of data 
 
Quality control check of the final clinical study report 
In addition, the sponsor and/or the CRO clinical quality assurance department may conduct 
periodic audits of the study processes, including, but not limited to, the study center, study center 
visits, central laboratories, vendors, clinical database, and the final clinical study report. When 
audits are conducted, access must be authorized for all study-related documents including 
medical history and concomitant medication documentation to authorized sponsor’s 
representatives and regulatory authorities. 
8.1 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor procedures, the sponsor has 
engaged the services of a CRO to perform all monitoring functions within this clinical study. 
Monitors will work in accordance with the sponsor or CRO SOPs and have the same rights and 
responsibilities as monitors from the sponsor’s organization. Monitors will establish and maintain 
regular contact between the investigator and the sponsor. 
During these contacts, the monitor will: 
 Check the progress of the study 
 Review study data collected 
 Conduct source document verification 
 Identify any issues and address their resolution 
This will be done in order to verify that the: 
 Data are authentic, accurate, and complete 
 Safety and rights of subjects are being protected 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:77 of 132
 
Version 5.0: 02 May 2019 
 Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her personnel to the monitor to discuss findings and any 
relevant issues. 
At study closure, monitors will also conduct all activities described in Section 12.1. 
8.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
data management department of the CRO. 
An electronic data capture system will be used for this study, meaning that all eCRF data will be 
entered in electronic forms at the study center. Data collection will be completed by authorized 
study center personnel designated by the investigator. Appropriate training and security measures 
will be completed with the investigator and all authorized study center personnel prior to the 
study being initiated and prior to any data being entered into the system for any subjects. 
The eCRFs should always reflect the latest observations of the subjects participating in the study. 
Therefore, the eCRFs are to be completed as soon as possible during or after the subject’s visit. 
To avoid interobserver variability, every effort should be made to ensure that the same individual 
who made the initial baseline determinations completes all safety evaluations. The investigator 
must verify that all data entries in the eCRFs are accurate and correct. If some assessments are 
not done, or if certain information is not available or not applicable or unknown, the investigator 
should indicate this in the eCRF. The investigator will be required to electronically sign off on 
the clinical data once complete.  
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections, and alterations are to be made by the responsible 
investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data 
have been entered into the eCRF, any corrections or alterations to the data fields will be traceable 
via an audit trail, meaning that the reason for change, the name of the person who performed the 
change, together with time and date will be logged. Roles and rights of the study center personnel 
responsible for entering the clinical data into the eCRF will be determined in advance. If 
additional corrections are needed, the responsible monitor or data manager will raise a query in 
the electronic data capture application. The appropriate study center personnel will respond to 
any queries raised. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:78 of 132
 
Version 5.0: 02 May 2019 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria, and all records covering the subject’s 
participation in the study. They include laboratory notes, ECG results, memoranda, pharmacy 
dispensing records, subject files, etc. 
The investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. The investigator must submit a 
completed eCRF for each subject who receives the investigational product, regardless of the 
duration. All supportive documentation submitted with the eCRF, such as laboratory or hospital 
records, should be clearly identified with the study and subject number. Any personal 
information, including subject name, should be removed or rendered illegible to preserve 
individual confidentiality. 
Electronic CRF records will be automatically appended with the identification of the creator, by 
means of their unique user ID. Specified records will be electronically signed by the investigator 
to document his/her review of the data and acknowledgment that the data are accurate. This will 
be facilitated by means of the investigator’s unique user ID and password; date and time stamps 
will be added automatically at the time of the electronic signature. If an entry on an eCRF 
requires change, the correction should be made in accordance with the relevant software 
procedures. All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 17.0 or the latest version. Concomitant medications will be coded using the WHO Drug 
Dictionary. Concomitant diseases/medical history will be coded using the MedDRA Version 17.0 
or the latest version. 
8.3 
Quality Assurance Audit 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:79 of 132
 
Version 5.0: 02 May 2019 
9.0 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
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. 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 90 
days after the last study treatment of the study drug, regardless of initiation of new anticancer 
therapy. 
9.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation 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 an investigational product. 
Examples of an AE include: 
 Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, duration, and/or that has an association with a significantly worse 
outcome 
 New conditions detected or diagnosed after investigational product 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 investigational 
product or a concurrent medication 
 Significant failure of expected pharmacological or biological action. See Section 9.3 for 
additional information 
Given that the mechanism of action by tislelizumab involves immune regulatory function, 
particular attention should be given to immune-related AEs, which include pruritus, vitiligo, 
pruritic rash, macular rash, hypopigmentation, other skin disorders, hypo- and hyperthyroidism, 
hypophysitis, pneumonitis, hepatitis, nephritis, allergic rhinitis, diarrhea, abdominal pain, fatigue, 
hypersensitivity, and any other immune-related AEs. For suspected immune-mediated adverse 
reactions, adequate evaluation should be ensured to confirm etiology or exclude other causes. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:80 of 132
 
Version 5.0: 02 May 2019 
9.2 
Definition of a Serious Adverse Event 
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 that 
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 preexisting condition that did not worsen from 
baseline, or for social/logistical reasons only, is not considered an SAE. 
 Results in disability/incapacity 
NOTE: The term “disability” means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 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 1 of the other outcomes listed in the above 
definition.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:81 of 132
 
Version 5.0: 02 May 2019 
9.3 
Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE. The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including 
clarifications). 
9.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events  
Abnormal laboratory findings (eg, clinical chemistry, hematology, coagulation, urinalysis) or 
other abnormal assessments (eg, ECGs, X-rays, vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs, as defined in Section 9.1, or SAEs, as defined in 
Section 9.2. This includes clinically significant abnormal laboratory findings or other abnormal 
assessments that are present at baseline and significantly worsen during the study.   The 
definition of clinically significant is left to the judgment of the investigator; in general, these are 
the abnormalities that are associated with clinical signs or symptoms, require active medical 
intervention, or lead to dose interruption or discontinuation, or require close observation, or more 
frequent follow-up assessments, or further diagnostic investigation. 
9.5 
Time Period, Frequency, and Method of Detecting Adverse Events and 
Serious Adverse Events 
9.5.1 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 90 days after the last study treatment of study drug, regardless of initiation of new 
anticancer therapy. After this period, the investigator should report any SAEs that are believed to 
be related to prior study drug treatment. 
9.5.2 
Eliciting Adverse Events 
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?  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:82 of 132
 
Version 5.0: 02 May 2019 
9.6 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events 
9.6.1 
Disease Progression  
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an event term.  
Instead, the symptoms, signs or clinical sequelae that result from disease progression should be 
reported as the events.  
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of disease 
progression. If a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression”. 
9.6.2 
Death 
Death is an outcome and not usually considered an AE. If the only information available is death 
and the cause of death is unknown, then the death is reported as an event, e.g. “death”, “death of 
unknown cause”, or “death unexplained”. 
9.7 
Recording of Adverse Events and Serious Adverse Events 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, 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.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:83 of 132
 
Version 5.0: 02 May 2019 
9.8 
Evaluating Adverse Events and Serious Adverse Events 
9.8.1 
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 NCI-CTCAE, 
Version 4.03. Subjects who initiate treatment with an absolute neutrophil count < 1000/µL will 
not be considered evaluable for neutrophil toxicity as outlined in the 2008 International 
Workshop on Chronic Lymphocytic Leukemia guidelines.14 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living  
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living  
 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities, as described in Section 9.2. 
9.8.2 
Assessment of Causality  
The investigator is obligated to assess the relationship between the investigational product 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 investigational 
product 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 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:84 of 132
 
Version 5.0: 02 May 2019 
information, amending the SAE eCRF accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is at least “a reasonable possibility” that the 
AE may have been caused by the study drug (i.e., there are facts, evidence, or arguments to 
suggest possible causation, or a causal relationship between t he  A E  and the drug cannot be 
ruled out). A number of factors should be considered in making this assessment, including: 
 Temporal relationship of the AE to the administration of study treatment/study procedure 
 Whether an alternative etiology has been identified  
 Mechanism of action of the study drug 
 Biological plausibility 
An AE should be considered related to study drug if any of the following are met: 
 There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. 
 There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
 There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of other 
factors may have contributed to the AE (eg, the subject’s clinical condition or other 
concomitant AEs). 
An AE should be considered unrelated to study drug if any of the following are met: 
 An unreasonable temporal relationship between administration of the study drug and the 
onset of the AE (eg, the AE occurred either before or too long after administration of the 
product for it to be considered product related) 
 A causal relationship between the study drug and the AE is biologically implausible (eg, 
death as a passenger in an automobile accident) 
 A clearly more likely alternative explanation for the AE is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related AE) 
9.9 
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. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:85 of 132
 
Version 5.0: 02 May 2019 
All AEs and SAEs will be followed until resolution, the condition stabilizes, the event is 
otherwise explained, the subject is lost to follow-up, or the subject withdraws consent. 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 
postmortem findings, including histopathology.  
New or updated information will be recorded on the originally completed SAE eCRF, with all 
changes signed and dated by the investigator. The updated SAE eCRF should be resent to the 
sponsor within the time frames outlined in Section 9.10. 
9.10 Prompt Reporting of Serious Adverse Events 
9.10.1 
Timeframes for Submitting Serious Adverse Events 
Serious adverse events will be reported promptly to the sponsor as described in Table 9-1 once 
the investigator determines that the event meets the protocol definition of a SAE. 
Table 9-1 
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 eCRF 
As soon as possible 
Updated SAE 
eCRF 
SAE: serious adverse event; eCRF: electronic case report form 
9.10.2 
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 9.10.1. The SAE eCRF will 
always be completed as thoroughly as possible with all available details of the event, signed by 
the investigator (or designee), 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. The investigator will always 
provide an assessment of causality at the time of the initial report as described in Section 9.8.2. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:86 of 132
 
Version 5.0: 02 May 2019 
In case the electronic data capture system is nonoperational, facsimile transmission of the SAE 
eCRF 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 eCRF sent by overnight mail. Initial notification via the 
telephone does not replace the need for the investigator to complete and sign the SAE eCRF 
within the time frames outlined in Section 9.10.1. After the electronic data capture system 
becomes operational again, the investigator will enter the information in the system. 
The sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone 
numbers, and mailing addresses. 
9.11 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 9.10. 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 toward 
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) application with the U.S. 
FDA. Once active, a given SAE may qualify as an IND safety report if the SAE is both 
attributable to the investigational product 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 investigational product and unexpected. The purpose of the report is to fulfill 
specific regulatory and GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised IB) from the sponsor, the responsible person according to local requirements is required 
to promptly notify his/her IRB or IEC.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:87 of 132
 
Version 5.0: 02 May 2019 
9.12 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 reporting 
period. 
Investigators are not obligated to actively collect AEs or SAEs from 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. 
9.13 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 (see Section 9.10). 
9.14 Management of AE of Special Interest 
9.14.1 
Zanubrutinib  
9.14.1.1 
Tumor Lysis Syndrome 
Subjects with a high tumor burden (circulating absolute lymphocyte counts ≥ 25 × 109/L or bulky 
lymphadenopathy) should receive prophylaxis for tumor lysis syndrome prior to the initiation of 
treatment. These subjects must be well hydrated. It is desirable to maintain a fluid intake of 
approximately 3 L per day, 1 to 2 days before the first dose of zanubrutinib. All such subjects 
with high tumor burden must be treated with allopurinol (≥ 300 mg/day orally) or a suitable 
alternative treatment (eg, rasburicase) starting at least 12 to 24 hours prior to the first dose of 
zanubrutinib. Subjects should continue to receive repeated prophylaxis with allopurinol and 
adequate hydration prior to each dosing, if deemed appropriate by the investigator. 
9.14.1.2 
Immune-related Adverse Events 
Both zanubrutinib and tislelizumab should be held for immune-related events, regardless of 
causality.  
 
Pneumonitis: Monitor subjects for signs and symptoms of pneumonitis. Evaluate subjects 
with suspected pneumonitis with radiographic imaging and administer corticosteroids for 
Grade 2 or greater pneumonitis. Withhold zanubrutinib for moderate (Grade 2) pneumonitis: 
permanently discontinue zanubrutinib if the toxicity does not resolve within 12 weeks of last 
dose or with inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks. Permanently discontinue zanubrutinib for severe (Grade 3) or life-
threatening (Grade 4) pneumonitis. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:88 of 132
 
Version 5.0: 02 May 2019 
 
Colitis: Monitor subjects for signs and symptoms of colitis. Administer corticosteroids for 
Grade 2 or greater colitis. Withhold zanubrutinib for moderate (Grade 2) or severe (Grade 3) 
colitis: permanently discontinue zanubrutinib if the toxicity does not resolve within 12 weeks 
of last dose or with inability to reduce corticosteroid to 10 mg or less of Prednisone or 
equivalent per day within 12 weeks. Permanently discontinue zanubrutinib for life-
threatening (Grade 4) colitis. 
Other tislelizumab immune-related holds: zanubrutinib should be held anytime tislelizumab is 
required to be held for an immune-related event (see Section 9.14.2.4). Zanubrutinib may be 
restarted after resolution of the event with approval of the medical monitor. 
9.14.2 
Tislelizumab 
9.14.2.1 
Tumor Lysis Syndrome 
Treatment for tumor lysis syndrome is presented in Section 9.14.1.1. 
9.14.2.2 
Infusion-related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness 
or hypertension.  Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock.  Patients should be closely monitored 
for such reactions. Immediate access to an intensive care unit (ICU) or equivalent environment 
and appropriate medical therapy (including epinephrine, corticosteroids, IV antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions.   
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 9-2.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:89 of 132
 
Version 5.0: 02 May 2019 
Table 9-2 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 or 2 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Any worsening is 
closely monitored.  Medical management as needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 hrs 
Stop infusion.  Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to at least grade 1 in severity.  
Any worsening is closely monitored. Proper medical 
management should be instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication.  If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued and the patient should be withdrawn from 
tislelizumab treatment. 
CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted, as 
indicated per type of the reaction.  This includes but is not limited to an anti-histamine (eg, 
diphenhydramine or equivalent), anti-pyretic (eg, paracetamol or equivalent), and if considered 
indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen.  In the next cycle, 
patients should receive oral premedication with an antihistamine (eg, diphenhydramine or 
equivalent) and an antipyretic (eg, paracetamol or equivalent), and they should be closely 
monitored for clinical signs and symptoms of an infusion reaction.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:90 of 132
 
Version 5.0: 02 May 2019 
CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction.  This includes but is not limited to 
oral or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
9.14.2.3 
Severe Hypersensitivity Reactions and Flu-like Symptoms 
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Subjects should be instructed to report any delayed reactions to the investigator immediately.  
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen and characterized by respiratory distress; 
laryngeal edema; and/or intense bronchospasm [often followed by vascular collapse or shock 
without antecedent respiratory difficulty]; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the subject 
discontinued from the study drug.  
Subjects will be administered with epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed, and then the subject should be placed on monitor 
immediately and ICU alerted for possible transfer if needed.  
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of tislelizumab IV infusion. 
Alternative treatments for fever (i.e., paracetamol) may be given to subjects at the discretion of 
the investigator. 
9.14.2.4 
Immune-related Adverse Events 
Immune-related AEs are of special interest in this study.  If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but is not limited to serologic, immunologic, and 
histologic (biopsy) data.  If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy and is consistent with an 
immune mediated mechanism of action, the irAE indicator in the eCRF AE page should be 
checked. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:91 of 132
 
Version 5.0: 02 May 2019 
A list of potential irAEs is shown below in Table 9-3.  All conditions similar to those listed 
should be evaluated in patients receiving tislelizumab tislelizumab to determine whether they are 
immune-related.  
Recommendation for diagnostic evaluation and management of irAEs is based on a recent ESMO 
guideline (Haanen et al 2017) and common immune-related toxicities are detailed in Appendix 6.  
For any adverse events not included in Appendix 6, please refer to the recent ESMO guideline 
(Haanen et al 2017) for further guidance on diagnostic evaluation and management of immune-
related toxicities.    
Table 9-3 
Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase (ALT/AST) 
elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent diabetes 
mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
 
Dose modification and management for irAEs are detailed in Appendix 6. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:92 of 132
 
Version 5.0: 02 May 2019 
9.15 Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs, 
and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference documents: 
 Zanubrutinib (BGB-3111) Investigator’s Brochure  
 Tislelizumab (BGB-A317) Investigator’s Brochure 
10.0 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
10.1 Sample Size Considerations 
The number of dose levels in the dose escalation and the emerging zanubrutinib and/or 
tislelizumab toxicities will determine the sample size. It is anticipated that approximately 
15 subjects per dose level will be required to complete the dose escalation of the study, and 
approximately 60 subjects (anticipated that approximately 10 subjects per cohort for Cohorts 1 
and 2 and 20 subjects per cohort for Cohorts 3 and 4) will be required to complete the dose 
expansion of the study. Subjects dropping out before completion will be replaced by enrolling a 
new subject. 
10.2 General Considerations for Data Analysis 
Complete details will be documented in the reporting and statistical analysis plan. 
10.2.1 
Analysis Set 
The following analysis sets will be analyzed: 
All subjects enrolled set (ENR): Includes all subjects who provide informed consent for this 
study. The ENR analysis set will be used to summarized and describe the subject disposition, 
deaths, unless stated otherwise. 
Safety analysis set (SAF): Includes all subjects in the ENR set who receive at least 1 dose of 
zanubrutinib and/or tislelizumab. The SAF analysis set will be used for all summaries (except 
DLTs). 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:93 of 132
 
Version 5.0: 02 May 2019 
DLT analysis set (DLTS): Includes all subjects who experienced a DLT during DLT 
observation period plus subjects who received at least 80% of the planned doses of treatment 
during the DLT observation period (Cycle 1) and had sufficient safety evaluation.  
PK analysis set (PKS): Includes subjects who have received at least the first dose of tislelizumab 
plus zanubrutinib and provided PK samples as per protocol following first dosing on Day 1. 
10.2.2 
Interim Analysis 
No formal interim analysis is planned for this study. Since this is a dose escalation study, safety, 
PK, and preliminary efficacy data will be evaluated on an ongoing basis. 
10.2.3 
Withdrawal 
Subjects who dropout will be replaced whenever possible.  
10.3 Efficacy Analyses 
The responses will be assessed using the applicable response criteria in Appendix 4. Objective 
response rates will be determined along with 95% confidence intervals. 
Progression free survival and OS are defined as the time from first dose of zanubrutinib, to 
disease progression, or death. Kaplan-Meier methodology will be used to estimate median PFS 
and OS and 95% confidence interval. Kaplan-Meier curves will be constructed to provide a visual 
description of the PFS and OS change with time. 
All subjects who take investigational products and have a baseline tumor assessment will be 
included in the efficacy analysis set.  
Study drug exposure data, including the number of cycles using study drug and dose intensity, 
will be summarized. 
10.3.1 
Primary Analysis 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE, Version 
4.03, and laboratory values (eg, hematology, clinical chemistry, urinalysis). Vital signs and 
physical examinations will also be used in determining safety. Descriptive statistics will be used 
to analyze all safety data by study part (dose escalation vs. dose expansion) in the SAF. In the 
dose escalation, DLT will be summarized at each dosing cohort in the DLT set. Maximum 
tolerated dose may not be reached in the 4 planned dose levels. RP2D will be determined based 
on overall safety profile of each dose level. In the dose expansion part, efficacy and safety will be 
summarized by cohort and overall. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:94 of 132
 
Version 5.0: 02 May 2019 
10.3.2 
Efficacy Analysis 
The secondary efficacy endpoints, including ORR, DOR, and PFS, will be summarized by part 
and by cohort within dose expansion part, in the clinical study report (CSR).  
Objective response rate and its binomial exact 95% confidence interval will be calculated.     
Duration of response and PFS will be estimated using the Kaplan-Meier method. Its 95% 
confidence interval will be constructed using Greenwood’s formula. Duration of response and 
PFS censoring rule will follow US FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007). Only subjects who have achieved objective 
responses will be included in the analysis of DOR.  
Kaplan-Meier curves of DOR and PFS in each dose expansion cohort will be plotted and 
percentages of maximum decrease of sum of target lesions in each subject will be calculated and 
displayed in waterfall plots.  
PK samples will be collected in this study, and PK analyses are detailed in Section 10.5. 
Incidence of development of anti-drug antibody to tislelizumab and its 95% confidence interval 
will be summarized. 
10.3.3 
Exploratory Analysis 
10.4 Safety Analyses 
All subjects who are exposed to zanubrutinib and/or tislelizumab will be evaluated for safety. 
Adverse event rates and changes in laboratory results by dose levels will be summarized in 
tabular form. Adverse events representing clear evidence of disease progression will not be 
considered relevant to the assessment of toxicity. 
Adverse events and toxicities will be graded according to NCI-CTCAE, Version 4.03. Subjects 
who initiate treatment with an absolute neutrophil count < 1000/μL will not be considered 
evaluable for neutrophil toxicity as outlined in the 2008 International Workshop on Chronic 
Lymphocytic Leukemia Guidelines.14 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:95 of 132
 
Version 5.0: 02 May 2019 
Summaries of the number of toxicity grades for both laboratory and nonlaboratory data will be 
presented by dose levels. Adverse events of special interest will be defined in the statistical 
analysis plan. 
Hematology, clinical chemistry, coagulation, and urinalysis values will be listed for each subject 
and flagged as high or low relative to the normal range, where applicable. Predose values will be 
used to assess laboratory shifts occurring at postdose. A comparison of prestudy and poststudy 
values will be performed to identify any parameters that have not returned to prestudy levels. 
Adverse events will be coded and grouped using the MedDRA Version 17.0 or the latest version. 
All AEs will be listed. 
10.4.1 
Extent of Exposure 
Extent of exposure to zanubrutinib and/or tislelizumab will be calculated for each subject. Overall 
exposure will also be summarized by dose levels. 
10.4.2 
Electrocardiogram 
All ECG parameters, including the QT interval corrected for heart rate (QTc), will be listed for 
each subject and summarized by dose level and assessment time. Change from baseline will also 
be summarized. The relationship between dose level and QTc changes will be explored by 
graphs. The QTc will be calculated using Fridericia’s formula.  
10.5 Pharmacokinetics Analyses 
For dose escalation cohorts (zanubrutinib PK data collected on C1D1 and C2D1), PK parameters 
of zanubrutinib will be derived using standard noncompartmental methods with WinNonlin 
Professional, Version 5.2 or higher (Pharsight Corp., Mountain View, CA). Nominal sampling 
times will be used for interim PK parameter calculations, while actual sampling times will be 
used in the final PK parameter calculations. Sampling times are displayed in Table 4-3 and Table 
4-4. Sparse PK data of tislelizumab in dose escalation and sparse PK data of zanubrutinib and 
tislelizumab in dose expansion will be used in the PK analysis set and will be reported separately. 
For subjects with PCNSL or SCNSL only (Cohort 4 of Expansion Phase), CSF obtained by 
lumbar puncture and/or Ommaya tap (at end of Cycles 2, 6 and 12), may be assessed for 
measurement of zanubrutinib and tislelizumab concentrations. On the same day of CSF 
collection, blood samples for measuring zanubrutinib and serum tislelizumab concentrations will 
be collected at pre-dose (prior to zanubrutinib dose) and at 2 hours (+/- 10 minutes) post 
zanubrutinib dose. See Table 4-4 for additional details on collection procedures and times. 
AUC0-infinity 
Area under the plasma concentration-time curve from zero extrapolated to 
infinity calculated using the linear up/log down trapezoidal method 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:96 of 132
 
Version 5.0: 02 May 2019 
AUClast and AUCss 
Area under the plasma concentration-time curve from zero to the last 
quantifiable concentration 
Cmax and Cmax,ss 
Maximum plasma concentration 
tmax and tmax,ss 
Time of maximum plasma concentration 
λz 
Terminal rate constant 
t1/2 
Terminal half-life 
CL/F 
Apparent systemic plasma clearance 
Vz/F 
Apparent volume of distribution during the terminal phase 
RAUC 
AUC accumulation ratio (AUC Cycle 2 Day 1/AUC Cycle 1 Day 1) 
RCmax 
Cmax accumulation ratio (Cmax Week 2 Day 1/Cmax Week 1 Day 1) 
Where possible, the following diagnostic parameters of the plasma PK analysis will be calculated 
and listed, but not summarized: 
Interval 
The time interval (hours) of the log-linear regression used to determine λz 
n 
Number of data points included in the log-linear regression analysis to 
determine λz (a minimum of 3 points will be used) 
Rsq 
R-square; coefficient of determination for calculation of λz. If Rsq is < 
0.800, then λz and related parameters will not be reported 
%AUCex 
Percentage of AUC obtained by extrapolation; if > 20%, then AUC and 
related parameters will not be reported 
Blood zanubrutinib and tislelizumab concentration-time data will be summarized and displayed 
in both tabular and graphical form. Concentration-time data will be analyzed with standard 
noncompartmental and/or compartmental PK methods. The PK parameters for a single dose 
profile (AUClast, AUC, Cmax, tmax, t1/2, CL/F, and Vd/F) and after steady-state (AUClast,ss, Cmax,ss, 
tmax,ss), will be calculated, if there are sufficient data. Individual subject parameter values, as well 
as a descriptive summary (mean, standard deviation, median, minimum, maximum, and the 
standard deviation and geometric mean of log-transformed parameters) by treatment group will 
be reported. Individual subject parameter values will be plotted against dose.  
In the dose escalation, Cmax, Ctrough, Tmax, AUClast or other applicable PK parameters for 
zanubrutinib  may be derived for each cycle at which pharmacokinetics are to be measured; 
Ctrough may be derived for tislelizumab, where applicable (as specified in Table 4-3). In the dose 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:97 of 132
 
Version 5.0: 02 May 2019 
expansion part of the study, PK parameters such as Ctrough may be derived for both zanubrutinib  
and tislelizumab for each cycle at which pharmacokinetics are to be measured, where applicable 
(as specified in Table 4-4). 
Additional PK analyses will be conducted as appropriate in all subjects for whom valid 
tislelizumab and zanubrutinib PK parameters can be estimated.  
Summary statistics of the calculated PK parameters will be provided. Graphical, 
noncompartmental and 
 
 
  
 
 
 
 
 
 
. 
10.6 
Immunogenicity Analyses 
Samples to assess anti-tislelizumab antibodies will be collected in patients receiving tislelizumab 
and in sites that are able to adequately perform sampling, handling and processing procedures 
outlined in the Laboratory Manual. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs. The incidences of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 
10.7 Biomarker Analyses 
Clinical response to zanubrutinib and tislelizumab will be evaluated for possible correlation with 
established genomic and clinical risk factors.  
The primary predictive biomarker analysis is based on a subset of the subjects with both a valid 
PD-L1 expression and/or TIL measurement and at least 1 disease assessment post-treatment. A 
supportive analysis is based on subjects with a valid PD-L1 expression and/or TIL measurement, 
irrespective of the availability of post-treatment disease assessments. In this analysis, those 
without post-treatment disease assessments will be imputed with the worst outcome in tumor 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:98 of 132
 
Version 5.0: 02 May 2019 
response. 
 
 
For subjects with paired tumor biopsies, changes in the tumor tissues, including but not limited to 
PD-L1 expression and TIL levels, following zanubrutinib treatment will be analyzed.  
11.0 ETHICS 
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 before the study is 
initiated at a study center in that country. 
11.2 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 documents/data that are needed for IEC/IRB review and approval of the study. 
Before the investigational products can be shipped to the study center, the sponsor must receive 
copies of the IEC/IRB approval, the approved informed consent form, and any other information 
that the IEC/IRB has approved for presentation to potential 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. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:99 of 132
 
Version 5.0: 02 May 2019 
11.3 Informed 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. 
11.4 Investigator Reporting Requirements 
As indicated in Section 9.10, 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. 
12.0 STUDY ADMINISTRATION 
12.1 Study and Study Center Closure 
Study closure is anticipated to occur approximately 1 year following initiation of the last study 
subject. 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 investigational products 
 Review of study records for completeness 
 Return of treatment codes to the sponsor 
 Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to 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 noncompliance. 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 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:100 of 132
 
Version 5.0: 02 May 2019 
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 investigational products 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. 
12.2 Records Retention 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating 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 archival at an off-site facility and transfer of ownership of the records in the 
event the investigator leaves the study center. 
12.3 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 treatment 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 subjects. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:101 of 132
 
Version 5.0: 02 May 2019 
The sponsor will not routinely inform the investigator or subject of 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.  
12.4 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. This will be determined by the sponsor as other details on publications are provided. 
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 confidential 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 
without the prior written consent of the sponsor.  
These restrictions do not apply to: 
 Information that becomes publicly available through no fault of the investigator or study 
center personnel 
 Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
 Information that is necessary to disclose in order to provide appropriate medical care to a 
subject 
 Study results that may be published 
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. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:102 of 132
 
Version 5.0: 02 May 2019 
12.4.1 
Study Report and Publication Policy  
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 International Conference on 
Harmonisation Guideline for Structure and Content of Clinical Study Reports (International 
Conference on Harmonisation E3).  Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (sponsor), 
regardless of the outcome of the trial.  The data generated in this clinical trial are the exclusive 
property of the sponsor and are confidential.  As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor.  Thereafter, any secondary publications will reference the original 
publication(s).  Authorship will be determined by mutual agreement, and all authors must meet 
the criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors, 2013). 
Each investigator agrees to submit all manuscripts, or congress abstracts, and posters, 
publications, and presentations (both oral and written) to the sponsor for review before 
submission or presentation in accordance with the clinical study agreement.  This allows the 
sponsor to protect proprietary information, provide comments based on information from other 
studies that may not yet be available to the investigator, and ensure scientific and clinical 
accuracy.  Each investigator agrees that, in accordance with the terms of clinical study agreement, 
a further delay of the publication/presentation may be requested by the sponsor to allow for 
patent filings in advance of the publication/presentation.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:103 of 132
 
Version 5.0: 02 May 2019 
13.0 REFERENCES 
1. Rickert RC. New insights into pre-BCR and BCR signaling with relevance to B cell 
malignancies. Nat Rev Immunol 2013. 13(8):578-91. 
2. Advani, RH et al. Bruton tyrosine kinase inhibitor ibrutinib ((PCI-32765) has significant 
activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31(1):88-
94. 
3. Ibrutinib approved for mantle cell lymphoma. Cancer Discov, 2014, 4(1):OF1. 
4. Ibrutinib (Imbruvica) for chronic lymphocytic leukemia. Med Lett Drugs Ther, 2014; 
56(1440): 29-30. 
5. Byrd JC et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N 
Engl J Med 2013:369(1):32-42. 
6. Wang ML, et al., Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med 2013; 369(6):507-16. 
7. McDermott DF, Atkins M B, PD-1 as a potential target in cancer therapy. Cancer Med 2013; 
2(5):662-73. 
8. Hawkes EA, Grigg A, Chong G. Programmed cell death-1 inhibition in lymphoma. Lancet 
Oncol 2015; 16(5):e234-e245. 
9. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in 
combination with rituximab in patients with relapsed follicular lymphoma: a single group, 
open-label, phase 2 trial. Lancet Oncol 2014;15: 69–77. 
10. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of 
nivolumab (BMS-936558) in subjects with relapsed or refractory lymphoid malignancies. 
Blood 2014; 124:Abstr 291. 
11. Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 blockade with the monoclonal antibody 
pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab 
vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Blood 2014; 
124:Abstr 290. 
12. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed 
death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, 
and immunologic correlates. J Clin Oncol 2010; 28(19):3167-75. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:104 of 132
 
Version 5.0: 02 May 2019 
13. Topalian SL, Hodi F S, Brahmer JR, et al., Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med, 2012; 366(26):2443-54. 
14. Hallek M et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a 
report from the International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111(12):5446-556. 
15. Hamid O, Robert C, Daud A, et al., Safety and tumor responses with lambrolizumab (anti-
PD-1) in melanoma. N Engl J Med, 2013; 369(2):134-44. 
16. Wolchock JD et al. Nivolumab plus ipilumumab in advanced melanoma. N Engl J Med 2013; 
369(2):122-33. 
17. Keytruda (pembrolizumab) [package insert]. Whitehouse, NJ: Merck, 2014. 
18. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb, 2014. 
19. Bai et al. 2012 
20. US Department of Health and Human Services, National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03. Washington, DC. 
14 June 2010. 
21. Cheson BD; International Harmonisation Project on Lymphoma. Revised response criteria for 
malignant lymphoma. J Clin Oncol 2007; 25(5):579-86. 
22. Abrey LE, Batchelor TT, Ferreri AJM, et al., Report of an International Workshop to 
Standardize Baseline Evaluation and Response Criteria for Primary CNS Lymphoma. J Clin 
Oncol 2005;23(22):5034-43. 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:105 of 132
 
Version 5.0: 02 May 2019 
14.0 APPENDICES 
APPENDIX 1: 
SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
A Phase 1b, Open Label, Multiple Dose, Dose Escalation, and 
Expansion Study to Assess Safety, Tolerability, and Antitumor 
Activities of the Combination of BGB-3111 with BGB-A317 in 
Subjects with B-Cell Lymphoid Malignancies  
PROTOCOL NO: 
 
BGB-3111_BGB-A317_Study_001 
This protocol is a confidential communication of BeiGene Aus Pty 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 Aus 
Pty 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 PAREXL International. 
 
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: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:106 of 132
 
Version 5.0: 02 May 2019 
APPENDIX 2: 
CLINICAL LABORATORY ASSESSMENTS 
Clinical 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Immunoglobulin 
Assessment and 
Thyroid Testing 
Cerebrospinal 
fluidb 
Alkaline 
phosphatase 
ALT 
AST 
Albumin 
Bicarbonate 
(Total CO2) 
Calcium 
Chloride 
Creatinine 
Glucose 
LDH 
Magnesium 
Phosphorus 
Total protein 
Potassium 
Sodium 
Total and direct 
bilirubin 
Urea 
Uric acid 
Hemoglobin 
Reticulocyte 
count 
Platelet counts 
WBC count 
with 
differential 
Neutrophil 
count 
Bands 
(optional) 
Lymphocyte 
count 
Eosinophil 
count 
 
Prothrombin time 
Partial 
thromboplastin 
time 
International 
normalized ratio 
pH  
Specific gravity 
Glucose 
Protein 
Ketones 
Blood  
24-hour 
proteina 
Random urine 
protein to 
creatinine ratioa 
IgA  
IgG 
IgM 
T3 
T4 
TSH 
Cell count 
Total protein 
Glucose 
Cytology 
ALT = alanine aminotransferase; AST = aspartate aminotransferase;LDH = lactate dehydrogenase; TSH = thyroid stimulating 
hormone; WBC = white blood cell. 
a On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample (on the first occurrence) for total 
protein and a random urine sample for total protein and creatinine to determine a protein to creatinine ratio. 
b Only for subjects with primary or secondary central nervous system lymphoma of breast or testicular origin (Cohort 4 of 
expansion part). 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:107 of 132
 
Version 5.0: 02 May 2019 
APPENDIX 3: 
BLOOD REQUIREMENTS 
Blood Requirements for Safety Evaluation of Zanubrutinib in Combination with 
Tislelizumab  During Dose Escalation 
Time point 
Assessment 
Total blood volume (mL) 
Screening 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
Thyroid function 
3 
 
IgA, IgG, and IgM level  
5 
 
Pregnancy test 
Virology 
CLL prognostic factors 
3.5 
5 
5 
 
Total 
32 
Cycle 1, Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
 
 
 
PK for zanubrutinib (5 samples @ 4 mL each) 
20 
 
Total 
30.5 
Cycle 1, Day 2 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
PK for zanubrutinib (1 sample @ 4 mL) 
4 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Anti-tislelizumab 
2 
 
Total 
9.5 
Cycle 1, Day 15 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Total 
7.5 
Cycle 1, Day 22 
 
 
 
Clinical chemistry 
Hematology 
 
5 
2.5 
 
Total 
7.5 
Cycle 2, Day 1  
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM level 
Thyroid function 
Anti-tislelizumab 
5 
3 
2 
 
PK for zanubrutinib (5 samples @ 4 mL each) 
20 
 
PK for tislelizumab (2 samples @ 5 mL each) 
10 
 
Total 
50.5 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:108 of 132
 
Version 5.0: 02 May 2019 
Time point 
Assessment 
Total blood volume (mL) 
Cycle 3, Day 1 
 
 
 
Clinical chemistry 
Hematology 
Coagulation 
IgA, IgG, and IgM level  
Thyroid function 
PK for tislelizumab (2 samples @ 5 mL each) 
5 
2.5 
3 
5 
3 
10  
 
Total 
28.5 
Cycle 4, Day 1  
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM level  
5 
 
Thyroid function 
Anti-tislelizumab 
PK for tislelizumab (2 samples @ 5 mL) 
3 
2 
10 
 
Total 
30.5 
Cycle 5+, Day 1 
 
 
 
Clinical chemistry 
Hematology 
Coagulation 
IgA, IgG, and IgM level  
Thyroid function 
Anti-tislelizumab1 
5 
2.5 
3 
5 
3 
2 
 
Total 
20.5 
Safety Follow-up 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM  
Thyroid function 
Anti-tislelizumab 
5 
3 
2 
 
Total 
20.5 
Survival Follow-up 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, and IgM level  
5 
 
Total 
12.5 
PK = pharmacokinetic 
1 Blood samples will be collected on Day 1 of Cycles 6, 8, 12, and 16.    
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:109 of 132
 
Version 5.0: 02 May 2019 
Blood Requirements for Safety Evaluation of Zanubrutinib in Combination with 
Tislelizumab During Dose Expansion 
Time point 
Assessment 
Total blood volume (mL) 
Screening 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
Thyroid function 
3 
 
IgA, IgG, and IgM level  
5 
 
Pregnancy test 
Virology 
CLL prognostic factors 
3.5 
5 
5 
 
Total 
32 
Cycle 1, Day 1 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
Anti-tislelizumab 
2 
 
PK for zanubrutinib (2 samples @ 4 mL each) 
PK for tislelizumab (2 samples @ 5 mL each) 
8 
10 
 
Total 
30.5 
Other Cycles,  
Day 1 (± 3 days) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM level  
Thyroid function 
5 
3 
 
Total 
18.5 
Cycle 2, 5, 9, 17 
Day 1 (± 3 days) 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM level 
5 
 
Thyroid function 
3 
 
Anti-tislelizumab (Note: Cycle 5 has 2 samples @ 
2 mL each) 
2 (4 for Cycle 5) 
 
PK for zanubrutinib (Note: Cycle 5 has 2 samples @ 
4 mL each) 
4 (8 for Cycle 5) 
 
PK for tislelizumab (Note: Cycle 5 has 2 samples @ 
5 mL each) 
5 (10 for Cycle 5) 
 
Total 
29.5 (40.5 for Cycle 5) 
End of Cycles 2, 6, 
12 (optional)1 
 
 
 
For Cohort 4 subjects with CSF collection: 
 
 
PK for zanubrutinib (Note: has 2 samples @ 4 mL 
each) 
8 
 
PK for tislelizumab (Note: has 2 samples @ 5mL 
each) 
10 
 
Total 
18 
Safety Follow-up 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:110 of 132
 
Version 5.0: 02 May 2019 
Time point 
Assessment 
Total blood volume (mL) 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
Coagulation 
3 
 
IgA, IgG, and IgM level 
Thyroid function 
Anti-tislelizumab 
PK for tislelizumab 
5 
3 
2 
5 
 
Total 
25.5 
Efficacy Follow-up 
 
 
 
Clinical chemistry 
5 
 
Hematology 
2.5 
 
IgA, IgG, and IgM level  
5 
 
Total 
12.5 
CSF = cerebrospinal fluid; PK = pharmacokinetic 
 
1 CSF collection for drug measurements is optional for end of Cycles 2, 6, and 12. 
 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:111 of 132
 
Version 5.0: 02 May 2019 
APPENDIX 4: 
RESPONSE CRITERIA 
Note: increases and decreases are relative to baseline unless otherwise indicated. 
A) CHRONIC LYMPHOCYTIC LEUKEMIA  
Response* 
Group A 
Group B 
Bone 
Marrow‡ 
Lymphadenopathy† 
Physical 
Exam 
(Liver, 
Spleen) 
Blood 
lymphocytes 
Peripheral Blood 
 
CR 
None > 1.5 cm 
Normal 
< 4 x 109/L 
Platelets > 100 x 
109/L 
Hemoglobin > 
11.0 g/dL 
ANC > 1.5 x 109/L 
Normocellular, 
< 30% 
lymphocytes 
No B-
lymphoid 
nodules, 
hypocellular 
marrow 
defines CRi* 
CRi 
None > 1.5 cm 
Normal 
< 4 x 109/L 
Persistent anemia, 
thrombocytopenia, 
or neutropenia 
related to drug 
toxicity 
PR 
Decrease ≥ 50% in 
lymphadenopathy 
Decrease ≥ 
50% in 
spleen or 
liver 
enlargement  
< 5 x 109/L 
OR 
Decrease ≥ 50%  
Platelets > 100 x 
109/L or ≥ 50% 
improvement over 
baseline 
OR 
Hemoglobin 
> 11.0 g/dL or 
>50% 
improvement over 
baseline 
OR 
ANC > 1.5 x 109/L 
or > 50% 
improvement over 
baseline 
50% reduction 
in marrow 
infiltrate 
PRL 
Decrease ≥ 50% in 
lymphadenopathy 
Decrease ≥ 
50% in 
spleen or 
liver 
enlargement  
Decrease < 50% 
or increase from 
baseline 
Platelets > 100 x 
109/L or 50% 
improvement over 
baseline 
50% reduction 
in marrow 
infiltrate, or B-
lymphoid 
nodules 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:112 of 132
 
Version 5.0: 02 May 2019 
OR 
Hemoglobin 
> 11.0 g/dL or 
50% improvement 
over baseline 
OR 
ANC > 1.5 x 109/L 
or > 50% 
improvement over 
baseline 
SD 
Absence of PD and failure to achieve at least a PR 
PD** 
Increase ≥ 50% in 
lymphadenopathy 
from nadir 
OR 
new lesion 
Increase ≥ 
50% in 
splenomegaly 
OR 
Increase ≥ 
50% in 
hepatomegaly 
 Not assessed 
Platelets decrease 
≥ 50% from 
baseline secondary 
to CLL 
OR 
Hemoglobin 
decrease of > 2 
g/dL from baseline 
secondary to CLL 
 
Abbreviations: ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; CR = complete remission 
(response); CRi = CR with incomplete bone marrow recovery; PD = progressive disease; PR = partial remission 
(response); PRL = partial remission (response) with lymphocytosis; SD = stable disease. 
Group A criteria define the tumor load, group B criteria define the function of the hematopoietic system (or marrow). 
*CR: all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR: at least 
2 of the criteria of group A (lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes) plus 1 of the criteria 
of group B (platelets, hemoglobin, or ANC) have to be met; PRL: presence of lymphocytosis, plus ≥ 50% reduction 
in lymphadenopathy and/or in spleen or liver enlargement, plus 1 of the criteria for platelets, hemoglobin, or ANC 
have to be met; SD: is absence of PD and failure to achieve at least a PR; PD: at least 1 of the above PD criteria has 
to be met.  
**Note: Isolated elevation of treatment-related lymphocytosis by itself will not be considered PD unless patient 
becomes symptomatic as a result from this per Cheson 2012. 
a. 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal 
b. Without need for exogenous growth factors 
c. 
If the sum products of ≤ 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected 
before therapy and no increase in any lymph node or new enlarged lymph nodes 
† Sum of the products of multiple lymph nodes (as evaluated by CT scans, or by physical examination) 
‡ These parameters are irrelevant for some response categories 
References: 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic 
lymphocytic leukemia. J Clin Oncol 2012;30:2820-2. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
Version
.0
VV-CLIN-012535
2






BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:115 of 132
 
Version 5.0: 02 May 2019 
Increase by ≥50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions> 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by >50% 
of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen 
must increase to > 16 cm).  If not prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
 
 
New or recurrent splenomegaly 
Nonmeasured lesion 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation).  If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extra nodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = 
longest transvers diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; 
PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = 
sum of the product of the perpendicular diameters for multiple lesions. 
a 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan.  However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to six 
of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters.  nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs).  GI involvement, cutaneous lesions, or those noted on palpation.  Nonmeasured 
lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.  In 
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow).  FDG uptake may be greater than the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic 
uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
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. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:116 of 132
 
Version 5.0: 02 May 2019 
non-Hodgkin lymphoma 
 
 
C) HAIRY CELL LEUKEMIA (HCL) 
Response Criteria 
 Complete response (CR) is defined as the absence of hairy cells from the 
peripheral blood and bone marrow along with resolution of organomegaly and 
cytopenia. In CR immunohistochemistry reveals no clustering (≥ 3 cells) of 
CD20-positive or DBA.44-positive cells. 
 Partial response (PR) is defined as a normalization of cytopenia along with a 
minimum 50% improvement in both organomegaly and bone marrow infiltration 
with no circulating hairy cells. 
Consensus resolution: proposed criteria for evaluation of response to treatment in hairy cell 
leukemia (Author anonymous). Leukemia. 1987;1:405. 
D) 
CNS LYMPHOMAS (PCNSL and SCNSL) Response Criteria 
Radiographic Response Assessment 
Radiographic criteria will be assessed using gadolinium-enhanced magnetic resonance imaging 
(MRI) of brain (contrast-enhanced CT may be substituted in patients in whom MRI is medically 
contraindicated), in accordance with the criteria developed in the International Workshop to 
Standardize Baseline Evaluation and Response Criteria in Primary CNS Lymphoma.22 Thorough 
evaluation to determine full extent of disease in subjects with PCNSL or SCNSL is critical and 
includes whole body PET/diagnostic CT scan with contrast (refer to Table 4-2). Whole body 
PET/diagnostic CT will be required at screening, and if positive, at specified timepoints during 
study treatment, to evaluate for presence of extra-CNS disease in PCNSL and primary site 
disease (i.e., breast or testes) in SCNSL. Response criteria will be assessed in accordance with the 
Lugano Classification (Cheson et al, 2014). 
Ocular Response Assessment 
A detailed ophthalmologic examination with dilated fundus examination and slit-lamp 
examination should be done to exclude vitreous, retinal, or optic nerve involvement. Fluorescein 
angiography may be helpful to confirm lymphomatous involvement of the retina. Color 
photography of the posterior pole of the eye should be obtained in those patients with ocular 
involvement to follow and document response to therapy. 
CSF Cytology Assessment 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:117 of 132
 
Version 5.0: 02 May 2019 
Cerebrospinal fluid will be obtained by lumbar puncture and/or Ommaya tap, and will include 
cytology, total cell count, protein level, and glucose level. Total protein has been identified as an 
important prognostic factor and should be analyzed in all patients. Ideally, CSF protein levels 
should be assessed on lumbar puncture samples because ventricular CSF has a lower normal 
value. Lumbar puncture though should only be performed in subjects who are not at risk of 
herniation. Cerebrospinal fluid analyses are required after screening only if these studies were 
initially positive at screening or if clinically indicated by new signs/symptoms, or to confirm CR 
or CRu.  
 
Response 
Whole Body 
Imaging 
Brain Imaging 
Corticosteroid 
Doseb 
Eye Examinationc 
CSF 
Cytologyd 
CR 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on CR status 
No contrast 
enhancement 
None 
Normal 
Negative 
CRu 
No contrast 
enhancement 
Any 
Normal 
Negative 
 
Minimal 
abnormality 
Any 
Minor RPE 
abnormality 
Negative 
PRe 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on PR status 
50% decrease in 
enhancing tumor 
Irrelevant 
Minor RPE 
abnormality or 
normal 
Negative 
No contrast 
enhancement 
Irrelevant 
Decrease in vitreous 
cells or retinal 
infiltrate 
Persistent or 
suspicious 
SD 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on No 
Response or 
SD status 
Does not meet conditions specified in responses or PD; defined as less than a 
PR but is not PD 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:118 of 132
 
Version 5.0: 02 May 2019 
PDf 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on PD status 
25% increase in 
lesion 
Irrelevant 
Recurrent or new 
ocular disease 
Recurrent 
or positive 
Any new site of 
disease: central 
nervous system or 
systemic 
 
 
 
CR: complete response; CRu: unconfirmed complete response; NHL = non-Hodgkin lymphoma; RPE: retinal pigment 
epithelium; PR: partial response; SD: stable disease; PD: progressive disease 
a 
Repeat testicular ultrasound for male subjects or bilateral breast mammogram for female or male subjects are required at 
suspected CR or CRu for SCNSL only. 
b 
At the time a CR is determined, the patient should have discontinued use of all corticosteroids for ≥ 2 weeks (rare 
exceptions may be made for those receiving corticosteroids for another diagnosis). 
c 
All CRs should be confirmed by repeat imaging; CR in the eyes should be confirmed by repeat evaluation. 
d 
In the setting of primary leptomeningeal disease, PR is not recognized; all patients should be categorized as CR, CRu, 
SD, or PD. 
e 
For subjects with PCNSL or SCNSL, repeat lumbar puncture and Ommaya tap are both required at suspected CR or Cru 
or if clinically indicated by new symptoms or signs. 
f 
For classification of PD, confirmation of any of the listed conditions would qualify as having met PD criteria. 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                                CONFIDENTIAL                  
BGB-3111_BGB-A317_Study_001 
IND number:  Not applicable      
Protocol 
          Page:119 of 132 
 
Version 5.0: 02 May 2019 
 
Version
.0
VV-CLIN-012535
2






BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:122 of 132
 
Version 5.0: 02 May 2019 
APPENDIX 6: 
IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE are intended as a 
guidance.  This document should be used in conjunction with expert clinical judgement (by 
specialist physicians experienced in the treatment of cancer using immunological agents), and 
individual institutional guidelines or policies. 
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs.  In addition to the results of these tests, the following 
factors should be considered when making an irAE diagnosis:  
 What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
 How did the patient respond to withdrawal of tislelizumab? 
 Did the event recur when tislelizumab was reintroduced? 
 Was there a clinical response to corticosteroids? 
 Is the event an autoimmune endocrinopathy? 
 Is disease progression or an alternative diagnosis a more likely explanation? 
 When alternative explanations to autoimmune toxicity have been excluded, the irAE field 
associated with the AE in the eCRF should be checked.  
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:123 of 132
 
Version 5.0: 02 May 2019 
Recommended Diagnostic Tests in the Management of Possible Immune-related AEs 
Immune-related 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform pituitary and 
whole brain MRI in patients with headache, visual disturbance, unexplained fatigue, asthenia, 
weight loss and unexplained constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such as an upper 
respiratory infection, new cough, shortness of breath or hypoxia should be assessed by high-
resolution CT.  Consider pulmonary function test including DLCO.  
Radiographic appearance is often nonspecific.  Depending on the location of the abnormality, 
bronchoscopy and bronchoalveolar lavage or lung biopsy may be considered.  Consult with a 
respiratory medicine physician for cases of uncertain cause.  
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS symptoms; 
review alcohol history and other medications.  Conduct a diabetic screen, and assess blood 
B12/folate, HIV status, TFTs, and consider autoimmune serology.  Consider the need for 
brain/spine MRI/MRA and nerve conduction study for peripheral neuropathy.  Consult with a 
neurologist if there are abnormal findings. 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, including the 
following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and culture, viral PCR, Clostridium 
difficile toxin, cryptosporidia (drug-resistant organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan.  If a patient experiences 
bleeding, pain or distension, consider colonoscopy with biopsy and surgical intervention, as 
appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, blurred vision, or 
other visual disturbances, refer the patient urgently to an ophthalmologist for evaluation and 
management.   
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on severity of the AE 
(eg, daily if Grade 3-4; every 2-3 days if Grade 2, until recovering).  Review medications (eg, 
statins, antibiotics) and alcohol history.  Perform liver screen including Hepatitis A/B/C serology, 
Hepatitis E PCR and assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies.  Consider imaging, 
eg, ultrasound scan for metastases or thromboembolism.  Consult with a hepatologist and 
consider liver biopsy.  
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  Consider renal 
ultrasound scan, protein assessment (dipstick/24-hour urine collection), or phase-contrast 
microscopy.  Refer to nephrology for further management assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology referral for 
skin biopsy. 
Rheumatology 
Conduct musculoskeletal history and perform complete musculoskeletal examination.  Consider 
joint X-ray and other imaging as required to exclude metastatic disease.  Perform autoimmune 
serology and refer to rheumatology for further management assistance.  
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal examination. Consider 
joint X-ray and other imaging as required to exclude metastatic disease. Perform autoimmune 
serology and refer to rheumatology for further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, troponin and 
consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, troponin, and refer to a cardiologist. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:124 of 132
 
Version 5.0: 02 May 2019 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; 
CNS, central nervous system; CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon 
monoxide; FBC, full blood count; HIV, human immunodeficiency virus; INR, international normalized ratio; LCI, liver cystolic 
antigen; LFT, liver function test; LKM, liver kidney microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance 
angiogram; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth 
muscle antibody; T4, thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC,  urea electrolytes and 
creatinine 
 
Treatment of Immune-Related Adverse Events 
 Immune-related AEs can escalate quickly; study treatment interruption, close monitoring, 
timely diagnostic work-up and treatment intervention, as appropriate, with patients is 
required 
 Immune-related AEs should improve promptly after introduction of immunosuppressive 
therapy.  If this does not occur, review the diagnosis, seek further specialist advice and 
contact the study medical monitor 
 For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after consultation 
with the study medical monitor 
 Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
 Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy 
 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.   
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
Hold study treatment; 
resume when 
resolved/improved to 
grade 0-1. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:125 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
the suggested starting dose is 0.5 
µg/kg/day).  Add oral prednisolone 
0.5 mg/kg/day for thyroid pain.  
Thyrotoxic patients require treatment 
with a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  
Initiate pulse IV methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation.  Convert to 
oral prednisolone and taper over at 
least 1 month.  Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:126 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 2 
months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day.  Taper over at least 4 
weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:127 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no perforation, 
sepsis, TB, hepatitis, NYHA grade 
III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/ sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 
2 
Rash covers 10%-30% 
of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch. Consider a 
short course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:128 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:   
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day. When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
 
If on oral prednisolone, change to pulsed IV methylprednisolone 
 
If on IV, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection.  Discuss with 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:129 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy.  If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 4 
weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-      
13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week.  Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose value 
> 500 mg/dL; > 27.8 
mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
Continue study 
treatment or hold 
treatment if symptoms 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:130 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
symptoms 
course of oral steroids. 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the study medical 
monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
As per local guidelines, treat with 
analgesics, topical treatments and 
Continue study 
treatment. 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:131 of 132
 
Version 5.0: 02 May 2019 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
oral intake, limited 
instrumental activities 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care.  Consider IV corticosteroids if 
not contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus IV (methyl)prednisolone and1-
2 mg/kg/day maintenance for severe 
activity restriction or dysphagia. If 
symptoms do not improve add 
immunosuppressant therapy. Taper 
oral steroids over at least 4 weeks 
Hold study treatment 
until improved to grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
1 
Asymptomatic but 
abnormal CK-MB, 
cardiac troponin or 
intraventricular 
conduction delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac symptoms 
or any increase in cardiac serum 
markers to the coronary care unit. 
Initiate oral prednisolone or IV 
(methyl)prednisolone at 1-
2 mg/kg/day. Manage symptoms of 
cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin 
Hold study treatment 
until completely 
resolved or myocarditis 
has been ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
has been excluded and 
symptoms have 
completely resolved 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, chronic heart failure; INR, international normalized ratio; IV, intravenous; LFT, liver function 
Version
.0
VV-CLIN-012535
2


BeiGene Aus Pty Ltd                                   CONFIDENTIAL 
BGB-3111_BGB-A317_Study_001
IND number:  Not applicable
Protocol 
Page:132 of 132
 
Version 5.0: 02 May 2019 
test; MMF, mycophenolate mofetil; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of 
normal. 
 
Version
.0
VV-CLIN-012535
2

SAP_001.pdf: 
BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 1 of 49  
CONFIDENTIAL 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-3111_BGB-A317_Study_001 
Study Protocol 
Title: 
A Phase 1b, Open Label, Multiple Dose, Dose Escalation, and Expansion 
Study to Assess Safety, Tolerability, and Antitumor Activities of the 
Combination of BGB-3111 with BGB-A317 in Subjects with B-Cell 
Lymphoid Malignancies Version 5.0, 02 May 2019 
 
Date: 
25 November 2020 
Version: 
 
 
 
 
 
 
 
 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
SIGNATURE PAGE 
Author: 
 
               Director, Biostatistics 
                
 
 
 
 
 
Signature 
Date:  ______________ 
 
 
 
Approval 
 
 
 
 
 
 
 
 
Vice President, Biometrics 
 
 
 
 
 
Signature 
Date: ________________ 
 
Chief Medical Officer 
 
 
 
 
 
Signature 
Date: ________________ 
 
Senior Director, Clinical Science 
 
 
 
Signature 
Date: ________________ 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
3 
STUDY OBJECTIVES 
9 
3.1 
Primary Objectives 
9 
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 
12 
6.2.1 
Definitions and Computations 
14 
6.2.2 
Conventions 
14 
6.2.3 
Handling of Missing Data 
15 
6.2.4 
Adjustment for Covariates 
15 
6.2.5 
Multiplicity Adjustment 
15 
6.2.6 
Data Integrity 
15 
6.3 
Subject Characteristics 
16 
6.3.1 
Subject Disposition 
16 
6.3.2 
Protocol Deviations 
16 
6.3.3 
Demographic and Other Baseline Characteristics 
16 
6.3.4 
Disease History 
16 
6.3.5 
Medical History 
17 
6.3.6 
Prior Anti-Cancer Drug Therapies and Surgeries 
17 
6.3.7 
Prior and Concomitant Medications 
17 
6.4 
Efficacy Analysis 
17 
6.4.1 
Primary Endpoint 
17 
6.4.2 
Secondary Endpoints 
17 
6.4.2.1 
Best Overall Response (BOR) and Overall Response 
Rate (ORR) 
18 
6.4.2.2 
Progression Free Survival (PFS) 
19 
6.4.2.3 
Duration of response (DOR) 
19 
6.4.3 
Additional Efficacy Endpoints 
20 
6.4.3.1 
Time to Response 
20 
6.4.3.2 
Overall Survival (OS) 
20 
6.4.3.3 
MRD for CLL 
20 
6.5 
Safety Analyses 
20 
6.5.1 
Extent of Exposure 
20 
6.5.2 
Adverse Events 
21 
6.5.2.1 
Death 
23 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
6.5.2.2 
Dose Limiting Toxicities 
23 
6.5.3 
Laboratory Values 
23 
6.5.4 
Vital Signs 
24 
6.5.5 
Physical Examination 
24 
6.5.6 
Echocardiogram 
24 
6.5.7 
Electrocardiograms (ECG) 
24 
6.5.8 
ECOG 
24 
6.5.9 
Ophthalmologic exam 
24 
7 
INTERIM ANALYSIS 
24 
8 
SUMMARY OF MODIFICATIONS 
25 
8.1 
Modifications from the Approved Clinical Study Protocol 
25 
8.2 
Modifications from the Approved Statistical Analysis Plan 
26 
9 
REFERENCES 
26 
10 
APPENDIX 
27 
10.1 
Schedule of Assessments 
27 
10.1.1 
A Brief summary of efficacy assessments’ frequencies 
37 
10.2 
Response Criteria 
38 
10.2.1 
CHRONIC LYMPHOCYTIC LEUKEMIA 
38 
10.2.2 
NON-HODGKIN LYMPHOMA (including SLL) 
40 
10.2.3 
HAIRY CELL LEUKEMIA (HCL) 
43 
10.2.4 
CNS LYMPHOMAS (PCNSL and SCNSL) Response Criteria 
44 
10.3 
Definition of DLT 
46 
10.4 
Missing Data Imputation Rule 
47 
10.4.1 
Prior/Concomitant Medications/Procedures 
47 
10.4.2 
Adverse Events 
47 
10.4.3 
Deaths 
48 
10.4.4 
Date of diagnosis or date of progression to most recent prior 
therapy 
48 
10.5 
Clinical Laboratory Assessments 
49 
 
 
 
 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BOR 
Best overall response 
BP 
Blood pressure 
BMI 
Body mass index 
CLL 
Chronis lymphoid lymphoma 
CR 
Complete response 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
CNSL 
Central nervous system lymphoma 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose limiting toxicity 
DLTS 
DLT analysis set 
DOR 
Duration of response 
EAS 
Efficacy evaluable analysis set 
ECG 
Electrocardiograms 
ENR 
All subjects enrolled set 
FL 
Folic lymphoma 
GCB 
Germinal center B-cell 
HCL 
Hairy cell leukemia 
MedDRA 
Medical dictionary for regulatory activities 
MR 
Marginal response 
MTD 
Maximum tolerable dose 
NE 
Not evaluable 
NHL 
Non-Hodgkin’s lymphoma 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PCNSL 
Primary central nervous system lymphoma 
PR 
Partial response 
PT 
Preferred term 
QD 
Once-daily 
Q3W 
One every 3 weeks 
PET 
Positron emission tomography 
RP2D 
Proposed phase 2 dose 
RT 
Richter’s transformation 
SAP 
Statistical analysis plan 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
SCNSL 
Secondary central nervous system lymphoma 
SD 
Sustained disease 
SMC 
Safety Monitor Committee 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor-infiltrating lymphocytes 
VGPR 
Very good partial response 
WHO DD 
World health organization drug dictionary 
WM 
Waldenstrom macroglobulinemia  


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
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 protocol BGB-3111_BGB-
A317_Study_001: A Phase 1b, Open-Label, Multiple-Dose, Dose Escalation, and Expansion 
Study to Assess Safety, Tolerability, and Antitumor Activities of the Combination of BGB-3111 
with BGB-A317 in Subjects with B-Cell Lymphoid Malignancies. This SAP is based on the 
clinical study protocol Version 5.0, dated 02 May 2019.  
The focus of this SAP is for the planned final analysis specified in the study protocol. This SAP 
documents the planned final primary statistical analyses of efficacy and safety data in the study 
protocol and describes the corresponding data presentations. It also documents additional efficacy 
and safety analyses not specified in the protocol, which will provide supplementary information 
to further support the safety and efficacy of the combination therapy of BGB-3111 (Zanubrutinib) 
and BGB-A317 (Tislelizumab).  
The study also evaluates the Pharmacokinetic (PK), Pharmacodynamics, Pharmacogenomics and 
 The analysis details for PK, pharmacodynamics, and 
are not 
described within this SAP.  
The BeiGene Biostatistics and Statistical Programming will perform the statistical analysis 
detailed in this SAP; SAS (Version 9.3 or higher) will be used to generate all statistical outputs 
(tables, figures, listings, and datasets). The SAP will be finalized and approved prior to final 
database lock.  
2 
STUDY OVERVIEW 
Study BGB-3111_BGB-317_Study 001 (hereafter referred to as Study 001) is a Phase 1b study to 
evaluate safety, tolerability, and preliminary efficacy of zanubrutinib in combination with 
tislelizumab in subjects with B-cell malignancies, including relapsed/refractory CLL/SLL, MCL, 
non-GCB DLBCL, GCB DLBCL, FL, MZL, HCL, transformed FL, Richter’s transformation 
(RT), primary central nervous system lymphoma (PCNSL), and secondary central nervous 
system lymphoma (SCNSL) of breast or testicular origin (Note: WM subjects are excluded from 
enrollment as of Amendment 3). The study is divided into a dose escalation and dose expansion.  
Study Treatment: 
Zanubrutinib will be administered orally every day (either once daily or twice a day) with or 
without food. Tislelizumab will be administered intravenously (2.0 mg/kg, 5.0 mg/kg, or 200 mg 
flat dose, depending on assigned dose level cohort) every 21 days (Q3W). When the 2 study 
drugs are administered on the same day (except on the days both PK samples are collected), 
zanubrutinib should be taken at least 30 minutes before tislelizumab infusion.  
For dose escalation, Cycle 1 will be 28 days and all subsequent cycles will be 21 days. 
Zanubrutinib will be administered on Cycle 1 Day 1 and then continuously every day. 
Tislelizumab will be administered on Cycle 1 Day 8 and then on Day 1 of all subsequent cycles. 
The period for DLT assessment is 21 days from Cycle 1 Day 8 to Cycle 1 Day 28. 
For dose expansion, all cycles will be 21 days. On Day 1 of each cycle, zanubrutinib and 
tislelizumab will be administered on the same day, except for 10 subjects of the CNS lymphoma 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
cohort (Cohort 4A). For PCNSL and SCNSL (Cohorts 4A and 4B), 10 subjects (Cohort 4A) will 
initially receive single-agent tislelizumab for 4 cycles at 200 mg intravenously Q3W. On Day 1 
of Cycle 5 and thereafter, these 10 subjects will receive combination zanubrutinib and 
tislelizumab at the RP2D defined by dose escalation.  
Subjects will continue to take zanubrutinib and tislelizumab as scheduled until one of the events 
listed in protocol Section 4.2.4.3 occurs. There is no maximum duration of treatment as specified 
in the protocol. Subjects who discontinue study drug due to reasons other than disease 
progression will remain on study and be followed every 3 months for the survival follow-up.    
Dose Escalation 
The purpose of dose escalation is to determine the maximum tolerable dose (MTD) for this study. 
During dose escalation, three dose levels will be explored in the following order: 
• Dose level 1: zanubrutinib 320 mg QD in combination with tislelizumab 2.0 mg/kg Q3W. 
If Dose Level 3 has cleared, subjects will be converted to dose level 3 dosing. 
o Dose level -1 (applicable only if dose level 1 exceeds MTD): zanubrutinib 160 mg 
QD in combination with tislelizumab 2.0 mg/kg Q3W. Further reductions of 
zanubrutinib or tislelizumab dose levels may be allowed until a safe dose combination 
is identified.  
• Dose level 2: zanubrutinib 320 mg QD with tislelizumab 5.0 mg/kg Q3W. If dose level 3 
has cleared, subjects will be converted to dose level 3 dosing. 
• Dose level 3: zanubrutinib 160 mg BID with tislelizumab 200 mg flat dose Q3W 
Dose escalation will follow the same principles as stipulated for a standard 3+3 dose escalation 
design, with each cohort evaluated for safety based on the number of dose-limiting toxicities 
(DLTs) observed (See Appendix 10.3). Evaluation of a cohort of at least 3 subjects completing 
the DLT assessment at any given dose level is required prior to determining the next dose level 
and dose regimen for the subsequent cohort. Three subjects in the cohort are sufficient if no 
DLTs are observed within the DLT window for all 3 subjects. More than 3 subjects are required 
per cohort depending on the number of observed DLTs as follows: 
• < 6 subjects enrolled in the cohort:  
o 1 subject experiences a DLT during the DLT assessment period: the cohort must 
enroll a minimum of 6 subjects evaluable for DLT.   
o ≥ 2 subjects experience a DLT during the DLT assessment period: the MTD is 
considered to have been exceeded, and no additional subjects will be treated at the 
current or higher doses.   
• ≥ 6 subjects enrolled in the cohort: 
o 1 subject experiences a DLT during the DLT assessment period: the cohort is 
considered tolerable and to not exceed the MTD. 
o  ≥ 33% of subjects (i.e., 2 out of 6) experience a DLT during the DLT assessment 
period: the MTD is considered to have been exceeded, and no additional subjects will 
be treated at the current or higher doses.  


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
Additional subject(s) may be enrolled to each dose escalation cohort beyond the minimum 
necessary (3 for 0 DLT, 6 for 1 DLT).  
The MTD is considered the dose level below that at which ≥ 2 (or ≥ 33%) subjects experience a 
DLT. If that does not occur at any dose level, the MTD is considered not to be reached. The 
RP2D will be selected by taking into account, the MTD, safety, tolerability, and PK profile, 
under the guidance of the Safety Monitoring Committee ([SMC]). 
Once a dose level has been determined to have not exceeded the MTD, up to 9 additional subjects 
may be enrolled to that dose level cohort (e.g., a total of 15 subjects for a dose level found 
tolerable in a dose escalation cohort of 6 subjects) to provide additional safety information on that 
dose level prior to proceeding to the dose expansion part of the study. More than 9 additional 
subjects may be enrolled if requested by the SMC for additional safety information. 
Dose Expansion 
In the dose expansion, there will be 4 dose expansion cohorts at the RP2D for the combination of 
tislelizumab and zanubrutinib: 
• Cohort 1 (n = 10): GCB DLBCL 
• Cohort 2 (n = 10): Non-GCB DLBCL 
• Cohort 3 (n = 20): Transformed lymphoid malignancy 
• Cohort 4: PCNSL or SCNSL of breast or testicular origin 
o Cohort 4A (n = 10): begin with 4 cycles of single-agent tislelizumab at 200 mg Q3W, 
combination of zanubrutinib and tislelizumab starting Cycle 5 
o Cohort 4B (n = 10): combination of zanubrutinib and tislelizumab starting Cycle 1 
The dose and schedule of combination zanubrutinib and tislelizumab will be the RP2D as 
determined by the SMC for the non-CNS disease types (Cohorts 1 to 3). The dose and schedule 
of single-agent tislelizumab will be 200 mg IV Q3W for Cohort 4 followed by the RP2D for the 
combination. Approximately 10 to 20 subjects each per classification of non-Hodgkin lymphoma 
will be enrolled in dose expansion. Cohorts 1, 2, 3, and 4A will open simultaneously once the 
RP2D has been determined. For Amendment 5.0, Cohort 4A is being discontinued. There were 
no safety or tolerability signals that led to the discontinuation of Cohort 4A. As of March 2019, 3 
subjects with CNSL have been enrolled in Cohort 4A; however, no subjects remain on treatment 
in this cohort, which is closed to treatment and further enrollment. Cohort 4B was to be 
immediately activated with Amendment 5.0. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
• To determine the MTD and/or RP2D of tislelizumab when given in combination with 
zanubrutinib. 
• To assess the safety and tolerability of zanubrutinib in combination with tislelizumab 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
(Cohorts 1 to 3 and 4B) or single-agent tislelizumab followed by the combination of 
zanubrutinib and tislelizumab (Cohort 4A) in previously treated subjects with B-cell 
malignancies. 
3.2 
SECONDARY OBJECTIVES  
• To assess the preliminary antitumor activity of zanubrutinib in combination with 
tislelizumab (Cohorts 1 to 3 and 4B) or a single-agent tislelizumab followed by the 
combination of zanubrutinib and tislelizumab (Cohort 4A) in previously treated subjects 
with B-cell malignancies. 
• To characterize the PK of zanubrutinib and tislelizumab when administered in 
combination. 
• To assess host immunogenicity to tislelizumab when administered in combination with 
zanubrutinib. 
3.3 
EXPLORATORY OBJECTIVES 
• 
• 
• 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• Dose escalation: The MTD and RP2D of tislelizumab in combination with zanubrutinib, 
as determined based on the incidence of protocol-defined dose-limiting toxicities, safety, 
tolerability, and PK profile. 
• Dose expansion: The safety and tolerability of combination zanubrutinib and tislelizumab 
(Cohorts 1 to 3 and 4B) or single-agent tislelizumab followed by combination 
zanubrutinib and tislelizumab (Cohort 4A) in previously treated subjects with B-cell 
malignancies, as assessed by the occurrence and severity of AEs (Common Terminology 
Criteria for Adverse Events [CTCAE], version 4.03). 
4.2 
SECONDARY ENDPOINTS 
• The antitumor activity of the combination of zanubrutinib and tislelizumab (Cohorts 1 to 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
3 and 4B), or single-agent tislelizumab, followed by combination zanubrutinib and 
tislelizumab (Cohort 4A) in previously treated subjects with specified B-cell 
malignancies, as determined by  
o overall response rate (ORR, defined as the proportion of subjects who had CR or PR 
by standard disease-specific response criteria),  
o duration of response ([DOR]; defined as the time from the date that a confirmed 
objective response is first documented to the date of PD or death due to any cause for 
those subjects with a confirmed PR or CR), and  
o progression-free survival ([PFS]; defined as the time from the first dose of study 
medication to objective disease progression or death).  
o drug antibody to tislelizumab when given in combination with zanubrutinib. 
4.3 
EXPLORATORY ENDPOINTS 
• 
• 
• 
5 
SAMPLE SIZE CONSIDERATIONS 
The number of dose levels in the dose escalation and the emerging zanubrutinib and/or 
tislelizumab toxicities will determine the sample size. It is anticipated that approximately 
15 subjects per dose level will be required to complete the dose escalation of the study, and 
approximately 60 subjects (anticipated that approximately 10 subjects per cohort for Cohorts 1 
and 2 and 20 subjects per cohort for Cohorts 3 and 4) will be required to complete the dose 
expansion of the study. Subjects dropping out before completion will be replaced by enrolling a 
new subject. 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
The following analysis sets will be defined, i.e., Safety analysis sets in dose escalation and in 
dose expansion, and DLT analysis set.  






BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
combining the dose escalation cohort and the dose expansion cohort, by the following disease 
types and overall: 
• 
Other B-cell lymphoid malignancies, including WM, CLL, MCL, MZL, and FL. If data 
indicates a particular malignancy is of interest, additional disease-specific analysis may be 
considered post hoc.  
• 
DLBCL 
• 
GCB DLBCL 
• 
Non-GCB DLBCL 
• 
Subtotal 
• 
RT 
• 
Transformed FL 
• 
CNS lymphoma, defined as subjects with either PCNSL or SCNSL. If data indicates a 
particular malignancy is of interest, additional disease-specific analysis may be 
considered post hoc.   
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, the date will appear partial or missing 
in the listings; Study day and any corresponding durations will be presented based on the 
imputations specified in Appendix 10.4 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the date and time of first dose.  
Unscheduled Visits: Unscheduled visit measurements will be included in listings and for 
derivation of 1) baseline values, and 2) the analysis of max/min values and max/min changes 
from baseline values and related shift tables. Unscheduled measurements will not be included in 
by-visit table summaries and graphs. 
Repeated Measurements: For repeated measurements, i.e., measurements with exact same 
collection date and time (if time is available) and source (central vs. local lab), the average of the 
repeated measurements will be used to reflect the value at the corresponding measurement date 
and time. Actual values will be presented in the data listings. 
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. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
• 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 response assessment dates per 
the investigators. 
• Missing efficacy or safety data will not be imputed unless otherwise specified. 
• For laboratory results collected as < or >, a numeric value, 0.0000000001 will be subtracted 
or added, respectively, to the value. 
• 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, Q1, Q3 and range (minimum and maximum). 
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 and 
prior/concomitant medications/procedures.  Specific rules for handling of missing or partially 
missing dates for adverse events and prior/concomitant medications/procedures are provided in 
Appendices 10.4. 
By-visit assessments 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. 
6.2.4 
Adjustment for Covariates 
With possible exception of exploratory analyses, no adjustments for covariates are planned for 
this study. 
 
6.2.5 
Multiplicity Adjustment 
Given the phase 1b, dose escalation and expansion study design, and the primary safety objective 
of the study, there is no multiplicity adjustment.  
6.2.6 
Data Integrity 
Before pre-specified interim or final statistical analysis begins, the integrity of the data should be 
reviewed to assure fit-for-purpose.  The data set for analysis should be an accurate and complete 
representation of the subjects' relevant outcomes from the clinical database.  All data should be 
complete and reviewed up to a pre-specified cutoff date.  Consistency checks and appropriate 
source data verification should be complete. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 
Subject Disposition 
The number (percentage) of subjects treated, discontinued from study treatment and discontinued 
from the study will be summarized. The primary reason for end of treatment for zanubrutinib and 
tislelizumab separately, and the primary reason for end of study will be summarized by 
categories.   
The study follow-up time, defined as the time from first dose of study treatment to study 
discontinuation will also be summarized. Survival status (alive, death, or lost to follow-up) at the 
study discontinuation will be summarized. 
6.3.2 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol deviations 
will be identified and documented before the database lock. Major protocol deviations will be 
summarized based on 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 population. Continuous variables include height, weight, BMI; categorical variables 
include the following 
• Sex, 
• Age (years) and age group (< 65 y ears vs. ≥ 65 years),  
• Race,  
• Ethnicity,  
• Geographic region and country (China vs. Australia),  
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Height (cm), weight (kg) and Body mass index (BMI in kg/m2) 
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. Disease characteristics include  
• Time from first diagnosis of B-cell lymphoid malignancies (months),  
• Disease type (CLL, NHL, WM) 
o For CLL, type, stage at initial diagnosis and at study entry; genotype status for 
del(17p), del(11q), del(13q), trisomy 12, IgVH mutation, and p53 mutation 
o For NHL, type, stage at initial diagnosis and at study entry 
o For WM, stage at initial diagnosis and at study entry 
A listing of disease characteristics/history will be provided. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
6.3.5 
Medical History 
Medical History will be coded using MedDRA (Version 22.0 or higher). 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 based on safety analysis set. A 
listing of medical history will be provided. 
6.3.6 
Prior Anti-Cancer Drug Therapies and Surgeries 
The number (percentage) of subjects with any prior systematic therapy, as recorded on the CRF, 
will be summarized. Number of prior regimens, both as continuous variable and in categories (1, 
2, 3, 4, 5, and >=6) will be summarized. Of the last therapy, their duration, best response, time 
from last therapy to first dose, and time from disease progression on most recent systemic therapy 
to first dose will be summarized as well.  
The number (percentage) of subjects with prior radiation therapy, the time from the last radiation 
therapy to first dose and site of the radiation therapy will be summarized.    
6.3.7 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes (Version B3 Sep 2018 or later) and will be further classified 
to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
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 drug and 
were continuing at the time of the first dose of study drug, or (2) started on or after the date of the 
first dose of study drug up to 30 days after the subject’s last dose or initiation of a new anti-
cancer therapy. For the purpose of determining if a medication should be noted as a concomitant 
medication, the imputation rules stated in Appendix 10.4.1 will be used.   
The number (percentage) of subjects reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term. A listing of prior and 
concomitant medications will be provided. 
6.4 
EFFICACY ANALYSIS 
6.4.1 
Primary Endpoint 
The study’s primary objectives and endpoints are all related to safety. Please refer to Section 6.5 
for the primary safety analyses. The section below describes the analyses for the secondary 
endpoints on efficacy, including ORR, DOR, and PFS, and additional endpoints including OS 
and others. 
6.4.2 
Secondary Endpoints 
Note: Response related analyses will be based on the disease response page, with PD based on 
disease progression page. Given the design of disease progression page, if a subject reported 
‘Yes’ to disease progression but only ‘Death’ is checked as the ‘primary method of detection of 
progression disease’, the subject will not be considered as having PD. Instead the information 
will be summarized in the summary of death.   


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
All efficacy analyses will be based on Safety Analysis Set, unless specified otherwise. 
6.4.2.1 
 Best Overall Response (BOR) and Overall Response Rate (ORR) 
The response and progression status were determined by the investigator using the appropriate 
disease-specific criteria defined in the protocol. Please refer to Appendix 10.1 for the schedule of 
related assessments. 
A subject’s best overall response is the best disease response recorded throughout the study. The 
assessment after documented disease progression will be excluded from the BOR derivation. 
Disease responses recorded after initiation of new anti-cancer treatment will not be considered for 
best overall response.  Subjects without postbaseline disease assessments will be grouped as NE 
and considered as non-responders.  The best overall response (number [%]) will be summarized.   
Note that for NHL, the response may be evaluated by either PET or CT, and the response results 
were collected separately. In the response analyses, these responses will be combined as in the 
first column in Table 6-2. The BOR will be derived combining results from PET and CT. 
Table 6-2 NHL responses either by PET or by CT (per Investigator) 
Response 
NHL per PET 
NHL response per CT 
CR 
CMR 
CR 
PR 
PMR 
PR 
SD 
NMR 
SD 
PD 
PMD 
PD 
NE 
NE 
NE 
ORR is the proportion of subjects with best overall responses in the categories constituting 
response for each disease type.  For each specific disease,  Table 6-3 shows the response 
categories included in ORR by diseases. ORR will be summarized, along with Clopper Pearson 
2-sided 95% confidence interval.  
Table 6-3 ORR response categories by diseases 
Responses included in ORR 
   WM 
CR, VGPR, PR, MR 
   CLL* 
CR, PR 
   NHL (except below) 
CR, PR 
       PCNSL + SCNSL 
CR, CRu, PR 
*For CLL subjects, potential nPR or PR-L were not collected in the database 




BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
DOR. DOR will be determined using the same censoring rules as those specified for PFS in 
Section 6.4.2.2. DOR will be analyzed using the same methods as in the analysis of PFS.   
A similar analysis will be conducted for duration of response for complete responders. 
6.4.3 
Additional Efficacy Endpoints 
6.4.3.1 
Time to Response 
Time to response (TTR) for responders is defined as time (in months) from the start of the study 
treatment to the date of the earliest qualifying response.  Time to overall responses, and time to 
complete responses will be summarized by descriptive statistics.   
6.4.3.2 
Overall Survival (OS) 
OS is defined as the time from the date of first study dose to death. Subjects who remained alive 
before discontinuation of the study (discontinued study due to reasons other than “Death”) will be 
censored at the last date the subject was known to be alive. Kaplan-Meier curve will be used to 
estimate OS at different time points. 
6.4.3.3 
MRD for CLL 
MRD data will only be listed for subjects with CLL because there are only 2 CLL subjects 
enrolled. 
6.5 
SAFETY ANALYSES 
Two sets of analyses will be performed. One set will be for dose escalation by doses based on 
safety analysis set in dose escalation cohort for selection analyses as specified in Section 6.1; the 
main analyses will be performed combining dose escalation cohort and expansion cohort, by 
disease subtypes, based on safety analysis set.  
The incidence of treatment-emergent adverse events (TEAEs), as defined in Section 6.5.2, will be 
summarized. Laboratory test results, vital signs and their changes from baseline will be 
summarized using descriptive statistics (e.g., n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum for continuous variables; n [%] for categorical variables.  These results will 
be listed. Abnormal values will be flagged. 
6.5.1 
Extent of Exposure 
The treatment exposure will be summarized separately for zanubrutinib and tislelizumab 
separately. For both drugs, their cumulative dose administered, planned dose intensity, actual 
dose intensity, and relative dose intensity will be summarized respectively.  
For zanubrutinib, 
• The duration of treatment (days) is calculated as (date of the last dose – date of first dose + 1). 
In addition to the continuous summary, it will also be summarized by categories (< 3months, 
3-<6 months, 6-<9 months, 9-<12 months, 12-<24 months and >24 months). 
• The planned dose intensity is defined as the planned starting zanubrutinib dose per day (320 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
mg/day).   
• The actual dose intensity is defined as the cumulative dose (mg) taken based on the total daily 
dose divided by the duration of zanubrutinib treatment (days).   
For tislelizumab, 
• 
The duration of treatment (weeks) is calculated as (date of last dose + 21 days – date of first 
dose)/7 
• 
The planned dose intensity (mg/wk) is defined as the planned dose per week: 
o For subjects in dose escalation dose levels 1 and 2 with some subjects later switched to 
the 200 mg /kg Q3W dosing schedule, the planned dose intensity will be the ratio of 
cumulative planned dose/(number of cycles x 3). The cumulative planned dose will be 
calculated as the sum of last weight prior to infusion x (2.0 or 5.0) mg/kg for all relevant 
cycles plus 200 mg times number of cycles after dosing switch) divided 3 (Q3W 
schedule);  
o For subjects in dose escalation dose level 3 and in dose expansion, the planned dose 
intensity is 200 mg Q3W (66.7 mg/wk).  
• 
The actual dose intensity is defined as the cumulative dose (mg) divided by the duration of 
treatment (mg/wk). 
For both zanubrutinib and tislelizumab 
• 
The relative dose intensity (RDI) is defined as the ratio of the actual dose intensity to the 
planned dose intensity in percentage.   
In addition, for zanubrutinib, the number (percentage) of subjects with dose change and the 
number of dose change per subject; the number (percentage) of subjects with dose interruption, 
the number of dose interruption per subject, and duration of dose interruption; the number of 
subjects with dose missed and the number of dose missed per subject will be summarized.  
For tislelizumab, a listing of dose interruption will be provided. Dose delays were not captured in 
the data and can only be inferred based on relative dose intensity described above. The cycle in 
which the first dose interruption/delay occurred 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 Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be coded to the 
MedDRA (Version 22.0 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. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date during 
the treatment-emergent period, defined as from the first dose date of Zanubrutinib or 
Tislelizumab (whichever is earlier) through 30 days after the last dose (permanent 
discontinuation of study drug) of Zanubrutinib or 90 days after the last dose of Tislelizumab, 
whichever is later, or prior to initiation of new anti-cancer therapy. Treatment-related SAEs and 
any worsening of a TEAE by PT post treatment-emergent period will be also be counted as 
TEAEs. 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 number (percentage) of subjects with the following, will be 
provided.  
• TEAEs, 
• TEAEs with grade 3 or above,  
• Treatment-emergent serious adverse events (SAEs),  
• TEAEs that led to treatment discontinuation,  
• TEAEs that lead to treatment modification, by dose reduction vs. dose interruption.  
• TEAEs that led to death  
And 
• Treatment-related TEAEs, 
• Treatment-related TEAEs with grade 3 or above,  
• Treatment-related Treatment-emergent serious adverse events (SAEs),  
• Treatment-related TEAEs that led to treatment discontinuation,  
• Treatment-related TEAEs that lead to treatment modification, by dose reduction vs. dose 
interruption.  
• Treatment-related TEAEs that led to death  
Treatment-related AEs or SAEs include those events considered by the investigator to be related 
to either Zanubrutinib or Tislelizumab or with missing assessment of the causal relationship.   
TEAEs that lead to treatment discontinuation, dose reduction or dose interruption include those 
events that lead to discontinuation, dose reduction or dose interruption of either Zanubrutinib or 
Tislelizumab. The worst action (in the order of treatment reduction < interruption < 
discontinuation) will be selected as the action in the summary.  
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 the following will be summarized by SOC and PT.  
• TEAEs 
• TEAEs with grade 3 or above,  


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
• SAEs 
• TEAEs that led to treatment discontinuation,  
• TEAEs that lead to dose modifications, including dose reduction or dose interruption  
• TEAEs that led to death  
• Treatment-related TEAEs,  
• Treatment-related SAEs,  
TEAEs with grade 3 or above will also be summarized by PT in descending order.  
Additional AEs of Special Interest (AESIs) for Zanubrutinib and Immuno-related AEs (irAEs) 
will be identified per the Search strategy for the corresponding compound. Both AESIs and irAE 
will be summarized by SOCs and PTs. 
Subject data listings of all AEs, SAEs, treatment-related AEs, grade 3 or above AEs, AEs that led 
to death and AEs that led to treatment discontinuation of either Zanubrutinib or Tislelizumab will 
be provided. 
6.5.2.1 
Death 
A summary of the number of deaths and the cause of death, classified by deaths within 30 days of 
last dose of Zanubrutinib or within 90 days of Tislelizumab, whichever is later, and deaths more 
than that after the last dose, will be provided.   
6.5.2.2 
Dose Limiting Toxicities 
The database was not built to identify the subject with DLT. A subset of subjects enrolled into the 
dose escalation were reviewed by SMC. The DLTs were identified based on SMC review and 
meeting minutes and will be described in the CSR directly without further analyses. 
6.5.3 
Laboratory Values 
Laboratory safety tests were evaluated per protocol (Appendix 10.5). Descriptive summary 
statistics for laboratory parameters (clinical chemistry, hematology, and coagulation results) and 
their changes from baseline will be summarized by visit. 
Laboratory parameters (ALP, ALT, AST, total bilirubin, albumin, hemoglobin, platelet counts, 
WBC count, neutrophil and lymphocyte) 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 will be summarized separately.  
Subject data listings of selected hematology and serum chemistry parameters, urinalysis and 
coagulation will be provided. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
6.5.4 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], pulse 
rate, temperature, and weight) and changes from baseline will be presented by visit.  Vital signs 
will be listed by subjects and visits. 
6.5.5 
Physical Examination 
Subjects with abnormal physical exams will be listed. 
6.5.6 
Echocardiogram  
The overall evaluation and LVEF (%) at screening will be listed without summary.   
6.5.7 
Electrocardiograms (ECG) 
ECG will be performed at the baseline and multiple time points after the start of treatment. ECG 
findings at baseline, post-baseline visits and change from baseline will be summarized. 
6.5.8 
ECOG 
A shift table from baseline to worst post-baseline in ECOG performance score will be 
summarized. ECOG scores will be summarized by visit. 
6.5.9 
Ophthalmologic exam 
Ophthalmologic exams were added in the protocol amendment and only limited number of 
subjects have both baseline and post baseline assessments. No further tabulation will be 
generated for Ophthalmologic results.  
Subjects’ ophthalmologic exam will be listed.  
7 
INTERIM ANALYSIS 
There were no formal interim analyses conducted for this study. As specified in the Protocol 
Section 4.1.2, the continuous safety evaluation was performed by the sponsor, the coordinating 
investigator, and investigators, and the Safety Monitoring Committee (SMC). Please refer to 
SMC charter and meeting minutes for related information as needed.  
Additional analyses were conducted to support multiple publication purposes.  


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
8 
SUMMARY OF MODIFICATIONS 
8.1 
MODIFICATIONS FROM THE APPROVED CLINICAL STUDY PROTOCOL 
Protocol 
Section 
Protocol Language 
SAP Section and Language 
Rationale 
NA 
NA 
Section 6.1 
The safety analysis set will 
be used primarily for all 
summaries, both safety and 
efficacy analyses, except 
selected DLTs and AE 
summaries as described in 
Section 6.2.  
Section 6.2  
Driven by the small number 
of subjects with different B-
cell lymphoid malignancies 
under different doses, the 
primary safety analyses will 
primarily be performed 
based on safety analysis set.   
Per protocol, the 2nd bullet 
of the primary objective and 
the secondary endpoints 
implies the analyses will be 
based on subjects from dose 
expansion only. However, 
driven by the fact that there 
was no observed difference 
in subjects’ safety/efficacy 
profile by doses during dose 
escalation, and to increase 
the number of subjects for 
different diseases to make 
the analyses more 
interpretable, the analyses 
will be based on safety 
analysis set combining 
subjects from dose 
escalation and expansion.  
10.2.1  
Analysis Set 
All subjects 
enrolled set 
(ENR): Includes all 
subjects who 
provide informed 
consent for this 
study. 
Removed 
Subjects sign informed 
consent at screening. 
Original language includes 
screen failure subjects.  
Given the open label study 
nature, the enrolled subjects 
are all dosed. The Safety 
analysis set defined in 
Section 6.1 will meet the 
analyses need.  
10.2.1  
Analysis Set 
DLT analysis set 
(DLTS): Includes 
all subjects who 
DLT analysis set (DLTS): 
Includes all subjects 
evaluated by the Study 
DLT review is performed 
and identified by SMC. The 
analyses of DLTS and 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
 
experienced a DLT 
during DLT 
observation period 
plus subjects who 
received at least 
80% of the planned 
doses of treatment 
during the DLT 
observation period 
(Cycle 1) and had 
sufficient safety 
evaluation 
Monitor Committee (SMC) 
for DLTs. The database was 
not built to capture whether 
a given patient experienced 
a DLT. Both DLT analysis 
set and AEs considered 
DLTs were identified by 
SMC review and 
documented in SMC 
meeting minutes. 
 
DTLs will be based on SMC 
meeting minutes  
8.2 
MODIFICATIONS FROM THE APPROVED STATISTICAL ANALYSIS PLAN 
This is the first version of the final primary Statistical Analysis Plan (SAP) for the study. 
9 
REFERENCES 
Crowley, R. B. (1982). A Confidence Interval for the Median Survival Time. Biometrics, 29-41. 
Greenwood, M. (1926). The natural duration of cancer. Reports on Public Health and Medical 
Subjects, 1-26. 
Schemper, M., & Smith, T. L. (1926). A note on quantifying follow-up in studies of failure time. 
Contemporary Clinical Trials, 343-346. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 27 of 49  
CONFIDENTIAL 
 
10 
APPENDIX 
10.1 
SCHEDULE OF ASSESSMENTS 
The Schedules of Assessments are presented in Table 10-1 and Table 10-2. Sections in the footnotes are all referring to protocol 
sections.  
Table 10-1 
Schedule of Assessments (Dose Escalation for Dose Levels 1, 2, and 3) 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic/medical 
history 
X 
 
 
 
 
 
 
 
 
 
Vital signs/weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
B symptoms6  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete physical 
examination7  
X 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination7  
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
X 
 
X 
 
 
X 
X 
 
 
Echocardiogram or 
MUGA 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG8  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review AEs9 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Review concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 28 of 49  
CONFIDENTIAL 
 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
Hematology10  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry11  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
parameters 
X 
X 
 
 
 
 
X 
X 
 
 
Urinalysis12  
X 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy test13  
X 
X 
 
 
 
 
X 
X 
 
 
Thyroid function14  
X 
 
 
 
 
 
X 
X 
 
 
IgA, IgG, and IgM 
level 15  
X 
 
 
 
 
 
X 
X 
X 
 
Viral serologies16  
X 
 
 
 
 
 
 
 
 
 
tislelizumab 
administration (30 to 
120 minutes infusion) 
 
 
 
X 
 
 
X 
 
 
 
Zanubrutinib 
administration in 
clinic17  
 
Orally every day 
 
 
 
Tumor assessment by 
CT scan18 
X 
Every 4 cycles 
X 
X19 
 
Bone marrow 
evaluation20  
X 
• 
End of Cycle 4 
• 
To confirm CR (at any time, Cycle 4 or later) 
 
 
 
Overall disease 
response 21 
 
Every 4 cycles 
 
X22 
 
CLL prognostic 
factors23  
X 
 
 
 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
CENTRAL LABORATORY STUDIES 
Anti-tislelizumab 
 
 
 
X 
 
 
 
X 
X 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 29 of 49  
CONFIDENTIAL 
 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy 
Follow-
up3 
Survival 
Follow-
up4 
Cycle 1 
(DLT Period: 21 days from D8 to D28) 
Cycle 2 
and 
Additional 
Cycles  
(21 days) 
Days Window 
-28 to -1 
D1 
D2 
D8 
D15 ± 1 
D22 ± 1 
D1 ± 3 
30 ± 3 Days After Last 
Dose (Telephone 
Contacts 60 & 90 ± 14 
Days After Last Dose) 
Every 3 
Months 
±7 Days 
Every 3 
Months 
±7 Days 
antibodies24  
Archival tumor 
tissues25  
X 
 
 
 
 
 
 
 
 
 
 
Fresh tumor tissues25  
X 
 
 
X 
 
 
 
 
X 
 
 
PK blood sampling26  
 
X 
X 
 
 
 
 
X 
 
 
 
Pulmonary function 
tests27  
X 
 
 
 
 
 
 
 
 
 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual acuity 
tests28 
X 
 
 
 
 
 
X29 
X29 
 
 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CLL = chronic lymphocytic leukemia; CR = complete 
response; CT = computed tomography; D = day; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EPG = electrophoresis; FISH = fluorescence in situ hybridization; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgVH – immunoglobin variable region heavy chain; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PCR = polymerase 
chain reaction; PD-1 = programmed cell death-1; PD-L1 = programmed death ligand-1; PD-L2 = programmed death ligand-2; PET = positron emission tomography; PK = 
pharmacokinetic; QTc = corrected QT wave; TSH = thyroid stimulating hormone; WBC = white blood cell. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified. 
1 Performed within 28 days prior to Day 1. Assessments that are performed as standard of care assessments may be used for screening.  
2 The maximum duration of treatment will be until disease progression.  
3 Safety follow-up performed within 30 days after the last dose of zanubrutinib (± 3 days). If the patient continues on single-agent tislelizumab, a second safety follow-up should be 
performed 30 days after last dose of tislelizumab. Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, 
associated with an AE or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of tislelizumab (see Section 7.4). Efficacy follow-up will apply only to 
subjects who discontinue study drug due to reasons other than disease progression. They will remain on study and should follow the guidance provided in Section 7.5. 
4 Once subjects progress or start the use of alternative anti-cancer therapy, subjects only need to establish survival status and are not required to come in for a visit. (see 
Section 7.6.) 
5 Vital sign time points for PK sampling will be obtained per Table 4-3. 
6 Unexplained weight loss > 10% over previous 6 months, fever (>38°C), and/or drenching night sweats. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 30 of 49  
CONFIDENTIAL 
 
7 Complete physical exam includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical relevance (i.e., 
cardiovascular, respiratory, lymph nodes, liver, and spleen) and those systems associated with clinical signs/symptoms. 
8 Perform a 12-lead ECG in triplicate at screening and at the treatment completion/early termination visit. ECG time points for PK sampling will be obtained as per Table 4-3. 
Additional ECGs may be required if there is a prolongation of QT or QTc, see Section 7.2.3.  
9   AEs will be recorded from the time of the first dose and all SAEs will be collected after informed consent has been signed. Telephone contacts with patients should be conducted 
to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of 
tislelizumab. All AEs and SAEs, regardless of relationship to study drug, will be recorded until up to 90 days after the last dose of study drug.  Beyond the safety follow up 
period, all drug-related SAEs will be recorded by investigator until patient death, or lost to follow up, whichever occurs first. 
10 Hematology, including hemoglobin, reticulocyte count, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes) and platelet count. In the event of 
neutropenia (absolute neutrophil count < 1.0 × 109/L) or thrombocytopenia (platelets count < 50 ×109/L), assessments will be performed as frequent as the physician feels 
needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed with dosing; in 
these cases, a separate pre-treatment sample must still be taken. 
11 Clinical chemistry includes sodium, potassium, chloride, bicarbonate (total CO2), glucose, urea, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequent as 
the physician feels needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed 
with dosing; in these cases, a separate pre-treatment sample must still be taken. 
12Collect urine dipstick, as well as urine microscopy, if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24-hour urine test for total protein and a random urine test for 
total protein and creatinine will be obtained and evaluated on the first occasion; subsequent need for 24-hour collection will be determined by the investigator. Refer to 
Section 7.2.1. 
13 All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Laboratory-based highly sensitive pregnancy 
tests (urine or serum) will be performed at specified subsequent visits and continued (local laboratory is acceptable) every 4 weeks for at least 90 days after the last dose of study 
drug. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
14 T3, T4, TSH; at screening, then every other cycle starting from Cycle 2, and at the mandatory safety follow-up visit. Additional T3, T4 and TSH may be performed at the 
discretion of the investigator. 
15 If a paraprotein is present, testing will be repeated on all subsequent immunoglobulin assessments. IgA, IgG and IgM tests should be performed for all subjects at screening and 
only for those with significant abnormal findings at subsquent visits. EPG testing was removed with Amendment #4. 
16 Viral serologies include hepatitis B (HBsAg and total HB core antibody [anti-HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), HCV antibody (as well as 
HCV RNA by PCR if the subject is HCV antibody positive), and HIV. 
17 Administer 1 dose of zanubrutinib in the clinic (for the first dose only), review and dispense diary. If subjects discontinue tislelizumab but continue taking zanubrutinib, subjects 
are allowed to reduce visits after 1 year to every 2 months. 
18 Tumor assessments must be performed at screening, and then in conjunction with overall disease response assessments within 7 days of the end of every 4 cycles, and at disease 
progression. Assessments by PET-CT scan with IV contrast of neck, chest, abdomen, and pelvis and any other disease sites for non-Hodgkin lymphoma classifications that are 
reliably FDG-avid (includes MCL, FL, DLBCL, transformed FL, Richter’s transformation, and CNS lymphomas) must be performed at Screening, Cycles 4, 8, and 12, and at 
suspected PD or CR. After Cycle 12, standalone CT scans will be performed every 4 cycles. Screening findings will determine whether patients are followed with PET-CT-
based or CT-based assessments on study. (Refer to Section 7.2.4.)  
19 Tumor assessment including imaging scan required at a minimum of every 6 months, otherwise assessment via physical exam is acceptable. 
20 A bone marrow examination must be performed at screening for all subjects and within 7 days of the end of Cycle 4 for subjects with baseline marrow disease. 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 CR), a bone marrow 
aspirate and biopsy will be obtained to confirm the CR. Additional bone marrow examinations may be performed at the investigator’s discretion. Peripheral blood and/or bone 
marrow aspirate/biopsy with flow cytometry assessment(s) for minimal residual disease should be done 3 months after evidence of CR in all of the response parameters 
(i.e., hematology, CT scan). 
21 Overall disease response assessment will utilize components and guidelines specified per disease type in Appendix 4. They should accompany tumor assessments by imaging 
(CT, PET, etc.) as applicable. 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 31 of 49  
CONFIDENTIAL 
 
22 For subjects that enter efficacy follow-up, response assessments should be conducted every 3 months to identify potential progression. These response assessments may utilize 
physical examination rather than imaging provided an assessment utilizing imaging is conducted at least every 6 months. 
23 Subjects with CLL should have a blood sample sent at screening for interphase FISH for chromosomal abnormalities including 17p-, 11q-, 13q- and +12. Other analysis 
including IgVH and P53 mutational status is optional.  
24 Blood for anti-tislelizumab antibodies should be collected within 2 hours before start of Day 8 infusion on Cycle 1, Day 1 on Cycles 2, 4, 6, and every 4 cycles starting with 
Cycle 8 (Day 1), and also collected at the mandatory safety follow-up visit. In subjects who discontinue study therapy before 6 months, every effort should be made to analyze 
anti-tislelizumab antibodies approximately 6 months after the first dose. Corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are 
collected to assess the neutralizing capacity of ADA. Analysis will be performed by a central laboratory. 
25 Subjects with an accessible tumor lesion must agree to a fresh tumor biopsy at screening and another before drug administration on Cycle 1 Day 8 (unless deemed clinically 
unsafe), ideally taken from the same tumor lesion, for the biomarker analysis (up to the first 12 qualified subjects). Subjects with DLBCL must have archival tumor tissues or 
agree to a fresh tumor biopsy for the confirmation of the DLBCL subtype. 
 
. Optional biopsy will also be taken at the safety follow up visit for the subjects who have confirmed disease 
progression during the study from accessible tumor sites to obtain samples to explore resistance mechanism.  
26 Serial PK blood samples will be collected at the time points specified in Table 4-3. Procedures for collection of samples are described in the lab manual. In addition, 
corresponding tislelizumab PK samples will be collected at the same time when the ADA samples are collected to assess the neutralizing capacity of ADA. 
27  Patients who are suspected or known to have serious respiratory concurrent illness or who exhibit significant respiratory symptoms unrelated to underlying cancer will also take 
a pulmonary function test, which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the Screening period to assist the determination 
of suitability for enrollment into the study (Refer to Section 7.1.2.  
28 Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of study drug initiation may be used rather than repeating tests. Eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeat assessments approximately every 15 weeks (± 7 days). 
29 The ophthalmologic assessments including eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) should only be performed once at either 
the EOT or during safety follow up, within 30 days of study treatment end. 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 32 of 49  
CONFIDENTIAL 
 
Table 10-2 
Schedule of Assessments (Dose Expansion) 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy  
Follow-up4 
Survival 
Follow-up5 
Cycle 1 
(21 days) 
Cycle 2 Through Last Cycle 
(21 days) 
Days Window 
-28 to -1 
D1 
D8 
D1 ± 3 
30 ± 3 Days After 
Last Dose 
(Telephone 
Contacts 60 & 90 ± 
14 Days After Last 
Dose) 
Every 3 Months 
±7 Days 
Every 3 
Months 
±7 Days 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographic/medical history 
X 
 
 
 
 
 
 
Vital signs/weight6 
X 
X 
X 
X 
X 
X 
 
B symptoms7  
X 
X 
 
X 
X 
X 
 
Complete physical examination8  
X 
 
 
 
 
 
 
Targeted physical examination8  
 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
X 
X 
 
 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
12-lead ECG9  
X 
X 
 
X 
X 
 
 
Review AEs and concomitant 
medications10 
X 
X 
X 
X 
X 
 
 
Hematology11  
X 
X 
X 
X 
X 
X 
 
Clinical chemistry12  
X 
X 
X 
X 
X 
X 
 
Coagulation parameters 
X 
X 
 
X 
X 
 
 
Urinalysis13  
X 
X 
X 
X 
X 
 
 
Pregnancy test14  
X 
X 
 
X 
 
 
 
Thyroid function15  
X 
 
 
X 
X 
 
 
IgA, IgG, IgM level16  
X 
 
 
X 
X 
X 
 
Viral serologies17 
X 
 
 
 
 
 
 
Tislelizumab administration (30 to 60 
minutes infusion)18 
 
X 
 
X 
 
 
 
Zanubrutinib administration19  
 
Orally every day 
 
 
 
Tumor assessment by CT scan20  
X 
Every 4 cycles 
X 
X21 
 
MRI with gadolinium or CT with 
contrast of brain22 
X 
End of Cycles 2, 4, 6, 8, 10, 12, 14, and 16 
 
 
 
Lumbar puncture and/or Ommaya 
X 
End of Cycles 2, 4, 6, 8, 10, 12, 14, and 16 
X 
 
 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 33 of 49  
CONFIDENTIAL 
 
 
Screening1 
Treatment Period2 
Safety Follow-up3 
Efficacy  
Follow-up4 
Survival 
Follow-up5 
Cycle 1 
(21 days) 
Cycle 2 Through Last Cycle 
(21 days) 
Days Window 
-28 to -1 
D1 
D8 
D1 ± 3 
30 ± 3 Days After 
Last Dose 
(Telephone 
Contacts 60 & 90 ± 
14 Days After Last 
Dose) 
Every 3 Months 
±7 Days 
Every 3 
Months 
±7 Days 
tap23 
PK during lumbar puncture or 
Ommaya tap (optional)23 
 
End of Cycles 2, 6 and 12 
 
 
 
Ultrasound of testicles24 
X 
Repeat at suspected CR or CRu defined in 
Appendix 4 for SCNSL 
 
 
 
Mammogram of bilateral breast24 
X 
Repeat at CR or CRu defined in 
Appendix 4 for SCNSL 
 
 
 
 
 
 
 
 
 
Ocular assessment for CNS lymphoma 
cohort (PCNSL and SCNSL) 25 
X 
End of Cycles 4, 8, 12, and 16 for those 
with abnormality at Screening, and at 
suspected CR or CRu defined in 
Appendix 4  
 
 
 
Bone marrow evaluation26  
X 
• 
End of Cycle 4  
• 
To confirm CR (at any time, 
Cycle 4 or later) 
 
 
 
Overall disease response27 
 
Every 4 cycles 
 
X28 
 
Survival status 
 
 
 
 
 
 
X 
Anti-tislelizumab antibodies29  
 
X 
 
X30 
X 
 
 
Archival tumor tissues31  
X 
 
 
 
 
 
 
Fresh tumor tissues31  
X 
 
 
 
X 
 
 
PK blood sampling32  
 
X 
 
X 
 
 
 
Pulmonary function tests33 
X 
 
 
 
 
 
 
Optical coherence tomography (or 
equivalent diagnostic test) and visual 
acuity tests34, 35  
X 
 
 
X 
X 
 
 
ADA = anti-drug antibody; D = day; AE = adverse event; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CLL = chronic lymphocytic leukemia; CR = 
complete response; CRu = complete response unconfirmed; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IgVH – immunoglobin variable region heavy chain; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; MUGA = multigated acquisition 
scan; PCNSL  = primary central nervous system (CNS) lymphoma; PCR = polymerase chain reaction; PD-1 = Programmed cell death-1; PD-L1 = Programmed Death Ligand-1; 


BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 34 of 49  
CONFIDENTIAL 
 
PD-L2 = Programmed Death Ligand-2; PET = positron emission tomography; PK = pharmacokinetic; QTc = corrected QT wave; RNA = ribonucleic acid; SCNSL = secondary 
CNS lymphoma; TSH = thyroid stimulating hormone; WBC = white blood cell. 
Assessments scheduled on study drug administration days should be performed predose, unless otherwise specified. 
1 Performed within 28 days prior to Day 1. Assessments that are performed as standard of care assessments may be used for screening.  
2 The maximum duration of treatment will be until disease progression.  
3 Performed within 30 days after the last dose of zanubrutinib (± 3 days).  If the patient continues on single-agent tislelizumab, a second safety follow-up should be performed 30 
days after last dose of tislelizumab. Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE 
or is a new anticancer therapy) at 60, and 90 days (±14 days) after the last dose of tislelizumab. 
4 Efficacy follow-up will apply only to subjects who discontinue study drug due to reasons other than disease progression. They will remain on study and should follow the 
guidance provided in Section 7.5. 
5 Once subjects progress or start the use of alternative anti-cancer therapy, subjects only need to establish survival status and are not required to come in for a visit (telephone call, 
medical records, etc.). 
6 Vital sign time points for PK sampling will be obtained per Table 4-4. 
7 Unexplained weight loss > 10% over previous 6 months, fever (>38°C), and/or drenching night sweats. 
8 Complete physical exam includes all systems described in the body of the protocol. Targeted physical exams should be limited to systems of clinical relevance (i.e. 
cardiovascular, respiratory, lymph nodes, liver, and spleen) and those systems associated with clinical signs/symptoms. 
9 Perform a 12-lead ECG in triplicate at screening and at the treatment completion/early termination visit. ECG time points for PK sampling will be obtained as per Table 4-4. 
Additional ECGs may be required if there is a prolongation of QT or QTc, see Section 7.2.3. 
10 AEs will be recorded from the time of the first dose and all SAEs will be collected after informed consent has been signed but prior to administration of the study drug.  
Telephone contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate, ie, associated with an AE or is a new anticancer therapy) at 60, 
and 90 days (±14 days) after the last dose of tislelizumab. All AEs and SAEs, regardless of relationship to study drug, will be recorded until up to 90 days after the last dose of 
study drug.  Beyond the safety follow up period, all drug-related SAEs will be recorded by investigator until patient death, or lost to follow up, whichever occurs first 
11 Hematology, including hemoglobin, reticulocyte count, WBC count, absolute differential count (neutrophils, eosinophils, lymphocytes) and platelet count. In the event of 
neutropenia (absolute neutrophil count < 1.0 × 109/L) or thrombocytopenia (platelets count < 50 ×109/L), assessments will be performed as frequent as the physician feels 
needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed with dosing; in 
these cases, a separate pre-treatment sample must still be taken 
12 Clinical chemistry includes sodium, potassium, chloride, bicarbonate (total CO2), glucose, urea, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase and uric acid. In the event of ≥ Grade 3 clinical chemistry toxicity, these assessments will be conducted as frequent as 
the physician feels needed until toxicity resolves to ≤ Grade 2. Results of blood tests taken within 24 hours may be used to allow the investigator to make the decision to proceed 
with dosing; in these cases, a separate pre-treatment sample must still be taken 
13 Collect urine dipstick, as well as urine microscopy, if dipstick is abnormal. If urine protein is ≥2+ by dipstick, a 24-hour urine test for total protein and a random urine test for 
total protein and creatinine will be obtained and evaluated on the first occasion; subsequent need for 24-hour collection will be determined by the investigator. 
14 All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening. Laboratory-based highly sensitive pregnancy 
tests (urine or serum) will be performed at specified subsequent visits and continued every 4 weeks (locally is acceptable) for at least 90 days after the last dose of study drug. If 
a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
15 T3, T4, TSH; at screening, then every other cycle starting from Cycle 2, and at the mandatory safety follow-up visit. Additional T3, T4 and TSH may be performed at the 
discretion of the investigator. 
16 IgA, IgG and IgM tests should be performed for all subjects at screening and only for those with significant abnormal findings at subsquent visits.  
17 Viral serologies include hepatitis B (HBsAg and total HB core antibody [anti-HBc] as well as HBV DNA by PCR if the subject is HBcAb positive), Hepatitis C virus (HCV) 
antibody (as well as HCV RNA by PCR if the subject is HCV antibody positive), and HIV. 
18 For Cohort 4A, subjects will not receive the combination dosing of zanubrutinib and tislelizumab until Cycle 5.  
19 Administer 1 dose of zanubrutinib in the clinic (for the first dose only), review and dispense diary. If subjects discontinue tislelizumab but continue taking zanubrutinib, subjects 
are allowed to reduce visits after 1 year to every 2 months. 




BeiGene USA, Inc 
     BGB-3111_BGB-A317_001 
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 36 of 49  
CONFIDENTIAL 
 
33  Patients who are suspected or known to have serious respiratory concurrent illness or who exhibit significant respiratory symptoms unrelated to underlying cancer will also take 
a pulmonary function test, which may include, but is not limited to, spirometry and assessment of diffusion capacity done during the Screening period to assist the determination 
of suitability for enrollment into the study. (Refer to Section 7.1.2.) 
34 Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to obtaining written 
informed consent and within 28 days of study drug initiation may be used rather than repeating tests. Eye exam, visual acuity test, and optical coherence tomography (or 
equivalent diagnostic test) will be assessed at the Screening Visit. Subjects will undergo repeat assessments approximately every 15 weeks (± 7 days). For subjects with PCNSL 
or SCNSL (Cohorts 4A and 4B), eye examinations performed for response evaluation do not need to be duplicated if they fall within the acceptable scheduling window for the 
eye exam, visual acuity test, and optical coherence tomography. 
35 The ophthalmologic assessments including eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) should only be performed once at either 
the EOT or during safety follow up, within 30 days of study treatment end. (Refer to Section 7.2.7.) 
 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 37 of 49  
CONFIDENTIAL 
 
10.1.1 
A Brief summary of efficacy assessments’ frequencies 
On-treatment 
Efficacy  
follow-
Dose escalation 
   Tumor by CT 
Every 4 cycles (12 weeks) 
Every 3 
months 
   Bone marrow evaluation 
Every 4 cycles (12 weeks) 
   Overall disease response 
Every 4 cycles (12 weeks) 
Every 3 
months 
Dose expansion 
   Tumor by CT 
Every 4 cycles (12 weeks) 
Every 3 
months 
   Disease specific assessments 
           MRI with gadolinium/ CT 
with contrast 
Every 2 cycles  
(6  weeks till end of cycle 16 [48 wks]) 
           Lumbar puncture and/or
Ommaya tap  
Every 2 cycles  
(6  weeks till end of cycle 16 [48 wks])  
           Ultrasound of testicles 
Repeat at suspected CR/Cru for SCNSL? 
           Mammogram of bilateral
breast 
Repeat at suspected CR/Cru for SCNSL? 
           Ocular assessment for CNS 
lymphoma cohort  
Every 4 cycles till cycle 16 [48 weeks] 
for those with abnormality at screening, 
and at suspected  CR/CRu 
   Bone marrow evaluation 
Every 4 cycles (12 weeks) 
   Overall disease response 
Every 4 cycles (12 weeks) 
Every 3 
months 
OS 
Every 3 months 
Every 3 
months 
 
 
 
 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 38 of 49  
CONFIDENTIAL 
 
10.2 
RESPONSE CRITERIA 
Per Protocol Appendix 4. Note: increases and decreases are relative to baseline unless otherwise 
indicated. 
10.2.1 
CHRONIC LYMPHOCYTIC LEUKEMIA  
Response* 
Group A 
Group B 
Bone 
Marrow‡ 
Lymphadenopathy† 
Physical 
Exam 
(Liver, 
Spleen) 
Blood 
lymphocytes 
Peripheral Blood 
 
CR 
None > 1.5 cm 
Normal 
< 4 x 109/L 
Platelets > 100 x 
109/L 
Hemoglobin > 
11.0 g/dL 
ANC > 1.5 x 109/L 
Normocellular, 
< 30% 
lymphocytes 
No B-
lymphoid 
nodules, 
hypocellular 
marrow 
defines CRi* 
CRi 
None > 1.5 cm 
Normal 
< 4 x 109/L 
Persistent anemia, 
thrombocytopenia, 
or neutropenia 
related to drug 
toxicity 
PR 
Decrease ≥ 50% in 
lymphadenopathy 
Decrease ≥ 
50% in 
spleen or 
liver 
enlargement  
< 5 x 109/L 
OR 
Decrease ≥ 50%  
Platelets > 100 x 
109/L or ≥ 50% 
improvement over 
baseline 
OR 
Hemoglobin 
> 11.0 g/dL or 
>50% 
improvement over 
baseline 
OR 
ANC > 1.5 x 109/L 
or > 50% 
improvement over 
baseline 
50% reduction 
in marrow 
infiltrate 
PRL 
Decrease ≥ 50% in 
lymphadenopathy 
Decrease ≥ 
50% in 
spleen or 
liver 
enlargement  
Decrease < 50% 
or increase from 
baseline 
Platelets > 100 x 
109/L or 50% 
improvement over 
baseline 
OR 
Hemoglobin 
> 11.0 g/dL or 
50% improvement 
over baseline 
OR 
ANC > 1.5 x 109/L 
or > 50% 
improvement over 
baseline 
50% reduction 
in marrow 
infiltrate, or B-
lymphoid 
nodules 
SD 
Absence of PD and failure to achieve at least a PR 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 39 of 49  
CONFIDENTIAL 
 
PD** 
Increase ≥ 50% in 
lymphadenopathy 
from nadir 
OR 
new lesion 
Increase ≥ 
50% in 
splenomegaly 
OR 
Increase ≥ 
50% in 
hepatomegaly 
 Not assessed 
Platelets decrease 
≥ 50% from 
baseline secondary 
to CLL 
OR 
Hemoglobin 
decrease of > 2 
g/dL from baseline 
secondary to CLL 
 
Abbreviations: ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; CR = complete remission 
(response); CRi = CR with incomplete bone marrow recovery; PD = progressive disease; PR = partial remission 
(response); PRL = partial remission (response) with lymphocytosis; SD = stable disease. 
Group A criteria define the tumor load, group B criteria define the function of the hematopoietic system (or 
marrow). 
*CR: all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR: at 
least 2 of the criteria of group A (lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytes) plus 1 of the 
criteria of group B (platelets, hemoglobin, or ANC) have to be met; PRL: presence of lymphocytosis, plus ≥ 50% 
reduction in lymphadenopathy and/or in spleen or liver enlargement, plus 1 of the criteria for platelets, hemoglobin, 
or ANC have to be met; SD: is absence of PD and failure to achieve at least a PR; PD: at least 1 of the above PD 
criteria has to be met.  
**Note: Isolated elevation of treatment-related lymphocytosis by itself will not be considered PD unless patient 
becomes symptomatic as a result from this per Cheson 2012. 
a. 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal 
b. Without need for exogenous growth factors 
c. 
If the sum products of ≤ 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected 
before therapy and no increase in any lymph node or new enlarged lymph nodes 
† Sum of the products of multiple lymph nodes (as evaluated by CT scans, or by physical examination) 
‡ These parameters are irrelevant for some response categories 
References: 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic 
lymphocytic leukemia. J Clin Oncol 2012;30:2820-2. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-5. 
 
Group A criteria define the tumor load, group B criteria define the function of the hematopoietic system (or 
marrow). 
* CR (complete remission): all of the criteria have to be met, and subjects have to lack disease-related constitutional 
symptoms; PR (partial remission): at least 1 of the criteria of group A plus 1 of the criteria of group B have to be 
met (Persistent lymphocytosis should not interfere with the time of designation of a PR, which should be based more 
on the other measurable aspects of the disease than on lymphocytosis.) ; SD is absence of progressive disease (PD) 
and failure to achieve at least a PR; PD: at least 1 of the above criteria of group A or group B has to be met. 
† Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical 
examination in general practice). 
‡ These parameters are irrelevant for some response categories. 
CRi (CR with incomplete bone marrow recovery): Fulfills all requirements for CR except has persistent neutropenia, 
anemia, or thrombocytopenia thought to be unrelated to the disease and likely related to drug toxicity. These 
subjects must have a normal bone marrow aspirate and biopsy with no evidence of clonal infiltrates. 
Nodular PR: Persistent bone marrow nodules on bone marrow biopsy in subjects achieving a CR or PR. Lymphoid 
aggregates should be evaluated with immunohistochemistry to determine whether they are comprised of CLL cells, 
lymphocytes other than CLL cells, or T cells. 






BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 42 of 49  
CONFIDENTIAL 
 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = 
longest transvers diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; 
PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = 
sum of the product of the perpendicular diameters for multiple lesions. 
a 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan.  However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to six 
of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters.  nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs).  GI involvement, cutaneous lesions, or those noted on palpation.  Nonmeasured 
lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.  In 
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow).  FDG uptake may be greater than the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic 
uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
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. 
non-Hodgkin lymphoma 
 
 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 43 of 49  
CONFIDENTIAL 
 
10.2.3 
HAIRY CELL LEUKEMIA (HCL) 
Response Criteria 
• Complete response (CR) is defined as the absence of hairy cells from the 
peripheral blood and bone marrow along with resolution of organomegaly and 
cytopenia. In CR immunohistochemistry reveals no clustering (≥ 3 cells) of 
CD20-positive or DBA.44-positive cells. 
• Partial response (PR) is defined as a normalization of cytopenia along with a 
minimum 50% improvement in both organomegaly and bone marrow infiltration 
with no circulating hairy cells. 
Consensus resolution: proposed criteria for evaluation of response to treatment in hairy cell 
leukemia (Author anonymous). Leukemia. 1987;1:405. 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 44 of 49  
CONFIDENTIAL 
 
10.2.4 
CNS LYMPHOMAS (PCNSL and SCNSL) Response Criteria 
Radiographic Response Assessment 
Radiographic criteria will be assessed using gadolinium-enhanced magnetic resonance imaging 
(MRI) of brain (contrast-enhanced CT may be substituted in patients in whom MRI is medically 
contraindicated), in accordance with the criteria developed in the International Workshop to 
Standardize Baseline Evaluation and Response Criteria in Primary CNS Lymphoma.22 Thorough 
evaluation to determine full extent of disease in subjects with PCNSL or SCNSL is critical and 
includes whole body PET/diagnostic CT scan with contrast (refer to Table 4-2). Whole body 
PET/diagnostic CT will be required at screening, and if positive, at specified timepoints during 
study treatment, to evaluate for presence of extra-CNS disease in PCNSL and primary site 
disease (i.e., breast or testes) in SCNSL. Response criteria will be assessed in accordance with 
the Lugano Classification (Cheson et al, 2014). 
Ocular Response Assessment 
A detailed ophthalmologic examination with dilated fundus examination and slit-lamp 
examination should be done to exclude vitreous, retinal, or optic nerve involvement. Fluorescein 
angiography may be helpful to confirm lymphomatous involvement of the retina. Color 
photography of the posterior pole of the eye should be obtained in those patients with ocular 
involvement to follow and document response to therapy. 
CSF Cytology Assessment 
Cerebrospinal fluid will be obtained by lumbar puncture and/or Ommaya tap, and will include 
cytology, total cell count, protein level, and glucose level. Total protein has been identified as an 
important prognostic factor and should be analyzed in all patients. Ideally, CSF protein levels 
should be assessed on lumbar puncture samples because ventricular CSF has a lower normal 
value. Lumbar puncture though should only be performed in subjects who are not at risk of 
herniation. Cerebrospinal fluid analyses are required after screening only if these studies were 
initially positive at screening or if clinically indicated by new signs/symptoms, or to confirm CR 
or CRu.  
 
Response 
Whole Body 
Imaging 
Brain Imaging 
Corticosteroid 
Doseb 
Eye Examinationc 
CSF 
Cytologyd 
CR 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on CR status 
No contrast 
enhancement 
None 
Normal 
Negative 
CRu 
No contrast 
enhancement 
Any 
Normal 
Negative 
 
Minimal 
abnormality 
Any 
Minor RPE 
abnormality 
Negative 
PRe 
Refer to 
50% decrease in 
Irrelevant 
Minor RPE 
Negative 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 45 of 49  
CONFIDENTIAL 
 
Lugano 
criteria 
provided 
above for 
NHL response 
on PR status 
enhancing tumor 
abnormality or 
normal 
No contrast 
enhancement 
Irrelevant 
Decrease in vitreous 
cells or retinal 
infiltrate 
Persistent or 
suspicious 
SD 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on No 
Response or 
SD status 
Does not meet conditions specified in responses or PD; defined as less than a 
PR but is not PD 
PDf 
Refer to 
Lugano 
criteria 
provided 
above for 
NHL response 
on PD status 
25% increase in 
lesion 
Irrelevant 
Recurrent or new 
ocular disease 
Recurrent 
or positive 
Any new site of 
disease: central 
nervous system or 
systemic 
 
 
 
CR: complete response; CRu: unconfirmed complete response; NHL = non-Hodgkin lymphoma; RPE: retinal pigment 
epithelium; PR: partial response; SD: stable disease; PD: progressive disease 
1. a 
Repeat testicular ultrasound for male subjects or bilateral breast mammogram for female or male subjects 
are required at suspected CR or CRu for SCNSL only. 
2. b 
At the time a CR is determined, the patient should have discontinued use of all corticosteroids for ≥ 2 
weeks (rare exceptions may be made for those receiving corticosteroids for another diagnosis). 
3. c 
All CRs should be confirmed by repeat imaging; CR in the eyes should be confirmed by repeat evaluation. 
4. d 
In the setting of primary leptomeningeal disease, PR is not recognized; all patients should be categorized as 
CR, CRu, SD, or PD. 
5. e 
For subjects with PCNSL or SCNSL, repeat lumbar puncture and Ommaya tap are both required at 
suspected CR or Cru or if clinically indicated by new symptoms or signs. 
f 
For classification of PD, confirmation of any of the listed conditions would qualify as having met PD criteria. 
 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 46 of 49  
CONFIDENTIAL 
 
10.3 
DEFINITION OF DLT 
Note that per protocol section 4.1.1, a DLT is a toxicity or adverse event (AE) occurring during 
the DLT assessment period (21 days from Cycle 1 Day 8 to Cycle 1 Day 28), which cannot be 
primarily attributed to a cause other than zanubrutinib and/or tislelizumab (such as disease 
progression, underlying illness, concurrent illness, or concomitant medication) and meets 1 of 
the following criteria: 
1) Nonhematologic Grade 4 (or Grade 3 lasting > 3 days) toxicity excluding:  
a. Laboratory abnormalities deemed by investigators as being not clinically 
important 
b. Grade 3 tumor flare  
c. Grade 3 infusion-related event that resolves to Grade 1 within 21 days  
d. Grade 3 nausea or vomiting  
e. Grade 3 hypertension  
2) Grade 4 neutropenia lasting > 7 days, not attributable to active leukemia or lymphoma 
3) Grade 4 thrombocytopenia lasting > 7 days, not attributable to active leukemia or 
lymphoma 
4) Any toxicity that requires drug hold of 1 or both investigational agents for more than 
2 weeks   


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 47 of 49  
CONFIDENTIAL 
 
10.4 
MISSING DATA IMPUTATION RULE  
In general, missing or partial dates will not be imputed.  The following rules will apply for the 
specific analysis and summary purposes mentioned below only.   
10.4.1 
Prior/Concomitant Medications/Procedures 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant.  The following rules will be applied to 
impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
•         If both month and day are missing, then set to January 01 
•         If only day is missing, then set to the first of the month 
If end date of a medication is partially missing, impute as follows: 
•         If both month and day are missing, then set to December 31 
•         If only day is missing, then set to last day of the month 
If start date or end date of a medication is completely missing, do not impute. 
10.4.2 
Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates.  
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent.  When in doubt, the adverse event 
will be considered treatment-emergent by default.  The following rules will be applied to impute 
partial dates for adverse events: 
If start date of an adverse event is partially missing, impute as follows: 
• 
If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
• 
If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
• 
If day is missing and month and year = month and year of treatment start date, then set to 
treatment start date 
• 
If day is missing and month and year ≠ month and year of treatment start date, then set to 
first day of the month 
• 
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: 


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 48 of 49  
CONFIDENTIAL 
 
• 
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. 
10.4.3 
Deaths 
In case only the day of a death date is missing, the death will be assumed to be on the 1st date of 
the month if the last date of subject known to be alive is earlier that the 1st date of the month, 
otherwise the death date will be assumed to be on 1 day after the last date of subject known to be 
alive.   
10.4.4 
Date of diagnosis or date of progression to most recent prior therapy 
When the date of diagnosis or date of progression to most recent prior therapy is partially 
missing, the date will be imputed to calculate time from diagnosis and time from most recent 
progression.  The following rules will be applied to impute partial dates: 
If start date of a medication is partially missing, impute as follows: 
•         If both month and day are missing, then set to January 01 
•         If only day is missing, then set to the first of the month 
  


BeiGene USA, Inc 
   BGB-3111_BGB-A317_001  
(Statistical Analysis Plan) 
 
Version 1.0: 25Nov2020 
Page 49 of 49  
CONFIDENTIAL 
 
10.5 
CLINICAL LABORATORY ASSESSMENTS 
Clinical 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Immunoglobulin 
Assessment and 
Thyroid Testing 
Cerebrospinal 
fluidb 
Alkaline 
phosphatase 
ALT 
AST 
Albumin 
Bicarbonate 
(Total CO2) 
Calcium 
Chloride 
Creatinine 
Glucose 
LDH 
Magnesium 
Phosphorus 
Total protein 
Potassium 
Sodium 
Total and direct 
bilirubin 
Urea 
Uric acid 
Hemoglobin 
Reticulocyte 
count 
Platelet counts 
WBC count 
with differential 
Neutrophil 
count 
Bands 
(optional) 
Lymphocyte 
count 
Eosinophil 
count 
 
Prothrombin time 
Partial 
thromboplastin 
time 
International 
normalized ratio 
pH  
Specific gravity 
Glucose 
Protein 
Ketones 
Blood  
24-hour proteina 
Random urine 
protein to 
creatinine ratioa 
IgA  
IgG 
IgM 
T3 
T4 
TSH 
Cell count 
Total protein 
Glucose 
Cytology