A Phase II, Single-Site, Open-Label Study of Zanubrutinib in Patients With IgG4-Related Disease
Phase: PHASE2
Conditions: IgG4 Related Disease
Sponsor: Matthew C. Baker

 
 
1. 
Protocol 
 
A Phase II, Single-Site, Open-Label Study of Zanubrutinib in Patients with IgG4-Related 
Disease 
 
Coordinating Center 
Stanford Rheumatology 
300 Pasteur Drive, East Pavilion, Floor 3, Room H302 
 
Palo Alto, CA 94304 
P: 650-498-5630 
F: 650-723-9656 
 
Protocol Director 
Matthew Baker, M.D., M.S. 
300 Pasteur Drive, East Pavilion, Floor 3, Room H302 
 
Palo Alto, CA 94304 
650-498-5630 
mbake13@stanford.edu 
 
Sub-Investigator 
Robert Fairchild, M.D., Ph.D. 
300 Pasteur Drive, East Pavilion, Floor 3, Room H302 
Palo Alto, CA 94304 
650-498-5630 
rfairchi@stanford.edu 
 
Study Coordinator 
 
 
Palo Alto, CA 94304 
P: 
 
F: 
 
 
 
 
Version 6/Version Date: 14-MAR-2025 
 
 
 

 
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2. 
Synopsis 
 
Name of Investigational Product: 
Zanubrutinib 
Title of Study: 
A Phase II, Single-Site, Open-Label Study 
of Zanubrutinib in Patients with IgG4-
Related Disease 
Number of Planned Subjects: 
10 
Phase of Development: 
II 
Length of Study: 
All consented subjects will enter a screening 
period of up to 35 days.  Eligible subjects 
with symptomatic IgG4-related disease 
affecting the submandibular and/or lacrimal 
glands with prior inadequate response to, or 
intolerance of, glucocorticoids, or who 
experience recurrent symptoms after 
previous treatment with glucocorticoids, will 
receive study drug (zanubrutinib) over a 
period of 24 weeks.  Patients will return 8 
weeks later for a final safety visit. 
Primary Objective: 
To demonstrate that zanubrutinib treatment 
reduces the volume of the submandibular 
and/or lacrimal glands on PET/MRI at week 
24 compared to baseline. 
Secondary Objectives: 
To determine the effect of zanubrutinib on 
change in FDG avidity of the 
submandibular, parotid, and/or lacrimal 
glands on PET, changes in submandibular, 
parotid, and/or lacrimal gland architecture 
on MRI, changes in serum IgG4 level, 
plasmablast count, and regulatory B cell 
count, change in IgG4-RD responder index, 
changes in physician and patient global, 
FACIT-F fatigue score, visual analog scales 
for ocular and salivary symptoms, changes 
in laboratory values, and safety parameters 
including adverse events. 
Study Design: 
This will be a single-site, open-label study in 
patients with symptomatic IgG4-related 
disease affecting the submandibular and/or 
lacrimal glands with prior inadequate 
response to, or intolerance of, 
glucocorticoids, or who experience recurrent 
symptoms after previous treatment with 
glucocorticoids.  All patients will receive 
zanubrutinib orally at a dose of 80mg BID 
for 24 weeks. 

 
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Main Criteria for Inclusion: 
• Are men or women aged 18 to 85, 
inclusive, at the time of initial 
screening 
• Meet the 2019 ACR/EULAR 
Classification Criteria for IgG4-
Related Disease 
• Have involvement of either the 
lacrimal gland(s) and/or the 
submandibular gland(s) 
• Have active symptoms from their 
enlarged submandibular or lacrimal 
gland  
• Have a prior inadequate response to, 
or intolerance of, glucocorticoids, or 
who experience recurrent symptoms 
after previous treatment with 
glucocorticoids 
• All women must test negative for 
pregnancy and agree to use a reliable 
method of birth control 
• No current treatment with 
immunosuppressive medications 
other than prednisone ≤40mg daily 
(or other glucocorticoid equivalent) 
with stable dosing for ≥28 days 
(glucocorticoids are permitted as 
above, but glucocorticoid use is not 
required to be eligible for the study) 
Main Criteria for Exclusion: 
• Unstable prescribed dose of 
glucocorticoids within 28 days prior 
to baseline 
• Any treatment with a synthetic 
DMARD including but not limited to 
hydroxychloroquine, methotrexate, 
leflunomide, or sulfasalazine within 
28 days prior to baseline 
• Any treatment with a cytotoxic or 
immunosuppressive drug including 
but not limited to cyclophosphamide, 
mycophenolic acid, azathioprine, 
cyclosporine, sirolimus, or 
tacrolimus within 28 days prior to 
baseline 
• Any treatment with a BTK inhibitor 
within 6 months before baseline 

 
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• Any treatment with a JAK inhibitor 
within 28 days prior to baseline 
• Use of biologic agents including 
infliximab, abatacept, or tocilizumab 
within 56 days prior to baseline 
• Use of a B cell depleting therapy 
(such as rituximab) within 12 months 
prior to baseline 
• A history of, or current, 
inflammatory or autoimmune disease 
(that could affect the interpretation of 
safety or efficacy outcomes) other 
than IgG4-related disease 
• Evidence of active tuberculosis, HIV, 
or hepatitis B or C infection 
• History of cancer other than non-
melanoma skin cancer, cervical 
dysplasia or carcinoma in situ (cured 
>1 year), prostate cancer (cured >5 
years), or colon cancer (cured >5 
years) 
Investigational Product, Dosage, and Mode of 
Administration: 
Zanubrutinib will be given orally at a dose 
of 80mg twice daily. 
Comparator, Dose, and Mode of 
Administration: 
No comparator will be used. 
Planned Duration of Treatment: 
Zanubrutinib will be given over a 24-week 
period, starting at Baseline (Day 1). 
Criteria for Evaluation: 
Efficacy will be assessed through the change 
in submandibular and/or lacrimal gland 
volume and FDG avidity by PET/MRI  
Evaluation Methods:  
Imaging of the head and neck will be 
performed using positron emission magnetic 
resonance imaging at the PET/MRI suite at 
the Lucas Imaging Center at Stanford 
University.   
 
For positron emission tomography (PET) 
imaging, participants will be injected 
intravenously (IV) with 5 mCi (+/- 20%) or 
185 MBq (+/- 20%) of 18F 
Fluorodeoxyglucose (18F FDG).  
Submandibular gland, lacrimal gland, 
parotid gland, and lymph node SUVmax will 
be assessed [2].  
 

 
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3. 
Table of Contents 
 
A Phase II, Single-Site, Open-Label Study of Zanubrutinib in Patients with IgG4-Related 
Disease 
1. 
PROTOCOL .......................................................................................................................................................................... 1 
2. 
SYNOPSIS ............................................................................................................................................................................. 2 
3. 
TABLE OF CONTENTS ....................................................................................................................................................... 5 
4. 
ABBREVIATIONS AND DEFINITIONS ........................................................................................................................ 10 
5. 
INTRODUCTION .............................................................................................................................................................. 16 
5.1. 
ZANUBRUTINIB BACKGROUND......................................................................................................................................................... 16 
5.2. 
IGG4-RELATED DISEASE BACKGROUND ........................................................................................................................................ 16 
5.3. 
KNOWN AND POTENTIAL RISKS AND BENEFITS OF ZANUBRUTINIB ......................................................................................... 16 
5.3.1. 
Known and Potential Risks of Zanubrutinib ..................................................................................................................... 17 
5.3.1.1 
Known Risks of Zanubrutinib ................................................................................................................................................... 17 
5.3.1.2 
Potential Risks of Zanubrutinib ............................................................................................................................................... 17 
5.3.2. 
Reproductive and Developmental Toxicity ....................................................................................................................... 18 
5.3.3. 
Known and Potential Benefits of Zanubrutinib .............................................................................................................. 19 
5.4. 
RATIONALE AND JUSTIFICATION FOR THE STUDY ........................................................................................................................ 19 
6. 
OBJECTIVES ...................................................................................................................................................................... 21 
6.1. 
PRIMARY OBJECTIVE ......................................................................................................................................................................... 21 
6.2. 
SECONDARY OBJECTIVE .................................................................................................................................................................... 21 
7. 
INVESTIGATIONAL PLAN ............................................................................................................................................. 23 
7.1. 
SUMMARY OF STUDY DESIGN ........................................................................................................................................................... 23 
7.2. 
DISCUSSION OF DESIGN AND CONTROL .......................................................................................................................................... 24 
8. 
STUDY POPULATION ..................................................................................................................................................... 25 
8.1. 
CRITERIA FOR ENROLLMENT ........................................................................................................................................................... 25 
8.1.1. 
Inclusion Criteria .......................................................................................................................................................................... 25 
8.1.2. 
Exclusion Criteria ......................................................................................................................................................................... 26 
8.1.3. 
Rationale for Exclusion of Certain Study Candidates ................................................................................................... 29 
8.1.4. 
Females of Childbearing Potential and Contraception ............................................................................................... 29 
8.2.  
DISCONTINUATION ............................................................................................................................................................................ 30 
8.2.1. 
Discontinuation of Subjects ...................................................................................................................................................... 30 
8.2.1.1. Subjects Inadvertently Enrolled ........................................................................................................................................................ 30 
8.2.1.2. Discontinuations from Investigational Product or from the Study .................................................................................... 30 
8.2.1.3. Subjects Lost to Follow-up .................................................................................................................................................................. 31 
8.2.2. 
Discontinuation of the Study ................................................................................................................................................... 31 
9. 
TREATMENT .................................................................................................................................................................... 32 
9.1. 
TREATMENT MATERIALS AND SUPPLIES ....................................................................................................................................... 32 
9.1.1. 
Packaging and Labeling ............................................................................................................................................................ 32 
9.1.2. 
Handling and Storage ................................................................................................................................................................. 32 
9.1.3. 
Compliance and Accountability ............................................................................................................................................. 32 
9.1.4. 
Disposal and Destruction .......................................................................................................................................................... 33 
9.2. 
TREATMENT ADMINISTRATION ....................................................................................................................................................... 33 
9.3. 
RATIONALE FOR SELECTION OF DOSE ............................................................................................................................................ 33 
9.4. 
SPECIFIC RESTRICTIONS/REQUIREMENTS .................................................................................................................................... 33 
9.5. 
DOSE MODIFICATION FOR TOXICITY .............................................................................................................................................. 34 
9.6. 
OVERDOSE ........................................................................................................................................................................................... 34 

 
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9.6.1. 
Minor Surgical Procedures ....................................................................................................................................................... 34 
9.6.2. 
Elective Major Surgical Procedures ..................................................................................................................................... 34 
9.6.3. 
Emergency Major Surgery Procedures ............................................................................................................................... 34 
9.7. 
CONTINUED ACCESS TO INVESTIGATIONAL PRODUCT ................................................................................................................. 34 
9.8. 
BLINDING ............................................................................................................................................................................................ 35 
9.9. 
CONCOMITANT THERAPY ................................................................................................................................................................. 35 
9.9.1. 
Glucocorticoid Taper ................................................................................................................................................................... 35 
9.9.2. 
Effects of Zanubrutinib on Exposure of Other Concomitant Medications ........................................................... 35 
9.9.3. 
Permitted Medications for Treatment of IgG4-Related Disease .............................................................................. 36 
9.9.4. 
Rescue Medications ...................................................................................................................................................................... 36 
9.9.5. 
Prohibited Medications .............................................................................................................................................................. 36 
10. 
INVESTIGATIONAL AGENT ..................................................................................................................................... 37 
10.1. 
ZANUBRUTINIB ................................................................................................................................................................................... 37 
10.1.1. 
Summary of Nonclinical Studies ...................................................................................................................................... 37 
10.1.1.1. 
Pharmacokinetics .......................................................................................................................................................................... 37 
10.1.1.2. 
Absorption, Distribution, Metabolism, and Excretion ................................................................................................... 38 
10.1.1.3. 
Single-Dose Toxicology ............................................................................................................................................................... 39 
10.1.1.4. 
Repeat-Dose Toxicology ............................................................................................................................................................. 39 
10.1.1.5. 
Summary of Nonclinical Safety ................................................................................................................................................ 39 
10.1.1.6. 
Efficacy ............................................................................................................................................................................................... 40 
10.1.2. 
Summary of Clinical Studies .............................................................................................................................................. 40 
10.1.2.1. 
Pharmacokinetics, Pharmacodynamics, and Product Metabolism in Humans ................................................... 41 
10.1.2.2. 
Safety .................................................................................................................................................................................................. 41 
10.1.2.3.1. 
Study BGB-3111-103 ........................................................................................................................................................... 41 
10.1.2.3.2. 
Study BGB-3111-104 ........................................................................................................................................................... 42 
10.1.2.3.3. 
Study BGB-3111-105 ........................................................................................................................................................... 42 
10.1.2.3.4. 
Study BGB-3111-106 ........................................................................................................................................................... 43 
10.1.2.3.5. 
Study BGB-3111-107 ........................................................................................................................................................... 43 
10.1.2.3.6. 
Study BGB-3111-108 ........................................................................................................................................................... 44 
10.1.2.3.7. 
Study BGB-3111-AU-003 ................................................................................................................................................... 44 
10.1.2.3.8. 
Study BGB-3111-1002 ......................................................................................................................................................... 45 
10.1.2.3.9. 
Study BGB-3111-GA101-Study_001 .............................................................................................................................. 46 
10.1.2.3.10. 
Study BGB-3111-205 ......................................................................................................................................................... 46 
10.1.2.3.11. 
Study BGB-3111-206 ......................................................................................................................................................... 46 
10.1.2.3.12. 
Study BGB-3111-207 ......................................................................................................................................................... 47 
10.1.2.3.13. 
Study BGB-3111-210 ......................................................................................................................................................... 47 
10.1.2.3.14. 
Study BGB-3111-212 ......................................................................................................................................................... 47 
10.1.2.3.15. 
Study BGB-3111-213 ......................................................................................................................................................... 48 
10.1.2.3.16. 
Study BGB-3111-302 ......................................................................................................................................................... 48 
10.1.2.3.17. 
Study BGB-3111-304 ......................................................................................................................................................... 48 
10.1.2.3.18. 
Study BGB-3111-A317-Study_001 .............................................................................................................................. 49 
10.1.2.3. 
Serious Adverse Events and Serious Adverse Events with a Fatal Outcome ....................................................... 49 
10.1.2.4. 
Expected Adverse Events ........................................................................................................................................................... 49 
10.1.2.5. 
Adverse Events Considered Possibly Related to Zanubrutinib .................................................................................. 50 
10.1.2.6. 
Efficacy ............................................................................................................................................................................................... 51 
11. 
SAMPLE COLLECTION AND SAFETY DATA COLLECTION .............................................................................. 54 
11.1. 
LABORATORY SAMPLES .................................................................................................................................................................... 54 
11.2. 
SAMPLES FOR RESEARCH .................................................................................................................................................................. 54 
11.2.1. 
Exploratory Samples (Peripheral Blood Mononuclear Cells and Plasma) ................................................... 54 
11.3. 
OTHER EXPLORATORY EVALUATIONS ............................................................................................................................................ 54 
11.3.1. 
Patient-Reported Outcomes ............................................................................................................................................... 54 
11.3.1.1. 
Patient’s Global Assessment of Disease Activity .............................................................................................................. 54 
11.3.1.2. 
Patient’s Global Assessment of Fatigue ................................................................................................................................ 54 
11.3.1.3. 
Patient’s Global Assessment of Ocular Symptoms........................................................................................................... 55 
11.3.1.4. 
Patient’s Global Assessment of Salivary Symptoms........................................................................................................ 55 
11.3.1.5. 
RAND Short Form-36 ................................................................................................................................................................... 55 

 
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11.3.1.6. 
FACIT-F .............................................................................................................................................................................................. 55 
11.3.2. 
Physician Assessments .......................................................................................................................................................... 55 
11.3.2.1. 
Physician’s Global Assessment of Disease .......................................................................................................................... 55 
11.3.2.2. 
IgG4-Related Disease Responder Index ............................................................................................................................... 56 
11.3.3. 
Other Study Procedures ....................................................................................................................................................... 56 
11.3.3.1. 
Positron Emission and Magnetic Resonance Imaging of the Head and Neck ...................................................... 56 
11.3.3.2. 
Salivary Gland Ultrasonography ............................................................................................................................................. 57 
11.4. 
SAFETY EVALUATIONS ...................................................................................................................................................................... 57 
11.4.1. 
Adverse Events ......................................................................................................................................................................... 57 
11.4.1.1 
Definitions and Reporting .......................................................................................................................................................... 58 
11.4.1.2 
Assessment of Severity ............................................................................................................................................................... 58 
11.4.1.3 
Assessment of Causality ............................................................................................................................................................. 59 
11.4.1.4 
Follow-up of Adverse Events and Serious Adverse Events ......................................................................................... 60 
11.4.2. 
Laboratory Test Abnormalities ........................................................................................................................................ 60 
11.4.3. 
Lack of Efficacy ........................................................................................................................................................................ 61 
11.4.4. 
Serious Adverse Events ......................................................................................................................................................... 61 
11.4.4.1. 
Serious Adverse Event Definitions ......................................................................................................................................... 61 
11.4.4.2. 
Suspected Unexpected Serious Adverse Reactions ......................................................................................................... 62 
11.4.4.3. 
Serious Adverse Events Reporting ......................................................................................................................................... 62 
11.4.5. 
Sponsor Investigator Reporting Responsibilities to BeiGene .............................................................................. 62 
11.4.6. 
Other Safety Measures .......................................................................................................................................................... 63 
11.4.6.1. 
Physical Examination ................................................................................................................................................................... 63 
11.4.6.2. 
Vital Signs ......................................................................................................................................................................................... 63 
11.4.6.3. 
Body Weight and Height ............................................................................................................................................................. 64 
11.4.6.4. 
Electrocardiograms ...................................................................................................................................................................... 64 
11.4.7. 
Safety Monitoring ................................................................................................................................................................... 64 
11.4.8. 
Stopping Criteria for Subjects ........................................................................................................................................... 64 
11.4.9. 
Stopping Criteria for the Study ........................................................................................................................................ 65 
11.5. 
APPROPRIATENESS AND CONSISTENCY OF MEASUREMENTS ..................................................................................................... 65 
11.6. 
COMPLIANCE ....................................................................................................................................................................................... 65 
12. 
SAMPLE SIZE AND DATA ANALYSES ................................................................................................................... 67 
12.1. 
DETERMINATION OF SAMPLE SIZE ................................................................................................................................................. 67 
12.2. 
DATA ANALYSIS PLANS..................................................................................................................................................................... 67 
12.2.1. 
General Considerations ........................................................................................................................................................ 67 
12.2.2. 
Study Participant Disposition ........................................................................................................................................... 67 
12.2.3. 
Study Participant Characteristics ................................................................................................................................... 67 
12.2.4. 
Safety Analyses ........................................................................................................................................................................ 67 
12.2.4.1. 
Clinical Evaluation of Safety ...................................................................................................................................................... 67 
12.2.4.2. 
Statistical Evaluation of Safety ................................................................................................................................................. 68 
12.3. 
INTERIM ANALYSES ........................................................................................................................................................................... 68 
13. 
DATA MANAGEMENT METHODS .......................................................................................................................... 69 
13.1. 
DATA QUALITY ASSURANCE............................................................................................................................................................. 69 
13.2. 
DATA CAPTURE SYSTEMS ................................................................................................................................................................. 69 
13.2.1. 
Source Data and Case Report Form ............................................................................................................................... 69 
14. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ............................... 70 
14.1. 
INFORMED CONSENT ......................................................................................................................................................................... 70 
14.2. 
ETHICAL REVIEW ............................................................................................................................................................................... 70 
14.3. 
REGULATORY CONSIDERATIONS ..................................................................................................................................................... 70 
14.3.1. 
Investigator Information .................................................................................................................................................... 70 
14.3.2. 
Protocol Signatures ............................................................................................................................................................... 70 
14.3.3. 
Final Report Signature ......................................................................................................................................................... 70 
14.3.4. 
Data and Safety Monitoring Plan .................................................................................................................................... 71 
15. 
STUDY SCHEDULE ..................................................................................................................................................... 72 

 
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REFERENCES ............................................................................................................................................................... 73 
 
 
 
 
 
 

 
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4. 
Abbreviations and Definitions 
 
Ab 
Antibody 
ACR 
American College of Rheumatology 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADL 
Activities of daily living 
AE 
Adverse event: Any untoward medical occurrence 
in a patient or clinical investigation subject 
administered a pharmaceutical product that does 
not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
(investigational) product, whether or not related to 
the medicinal (investigational) product. 
AIP 
Autoimmune pancreatitis 
AL 
Aggressive lymphoma 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear autoantibody 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
Audit 
A systematic and independent examination of the 
trial-related activities and documents to determine 
whether the evaluated trial-related activities were 
conducted, and the data were recorded, analyzed, 
and accurately reported according to the protocol, 
sponsor’s standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
AUC 
Area under the concentration versus time curve 
BGB-3111 
Zanubrutinib 
BID 
Twice daily 
BTK 
Bruton’s tyrosine kinase 
BTKi 
Bruton’s tyrosine kinase inhibitor 
BSA 
Body surface area 
CBC 
Complete blood count 
CIB 
Clinical investigation brochure 
CK 
Creatinine kinase 
CLL 
Chronic lymphocytic leukemia 
Clinical research physician 
Individual responsible for the medical conduct of 
the study. Responsibilities of the clinical research 
physician may be performed by a physician, 
clinical research scientist, global safety physician 
or other medical officer. 

 
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CNS 
Central nervous system 
Complaint 
A complaint is any written, electronic, or oral 
communication that alleges deficiencies related to 
the identity, quality, purity, durability, reliability, 
safety or effectiveness, or performance of a drug or 
drug delivery system. 
Compliance 
Adherence to all the trial-related requirements, 
good clinical practice (GCP) requirements, 
and the applicable regulatory requirements. 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMARDs 
Disease modifying anti-rheumatic drugs 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
End of trial 
End of trial is the date of the last visit or last 
scheduled procedure shown in the Study 
Schedule for the last subject. 
Enroll 
The act of assigning a subject to a treatment. 
Subjects who are enrolled in the trial are those 
who have been assigned to a treatment. 
Enter 
Subjects entered into a trial are those who sign the 
informed consent form directly or through their 
legally acceptable representatives. 
ERB 
Ethics Review Board 
EULAR 
European League Against Rheumatism 
FACIT 
Functional assessment of chronic illness therapy 
FL 
Follicular lymphoma 
GCP 
Good clinical practice: A standard for the design, 
conduct, performance, monitoring, auditing, 
recording, analyses, and reporting of clinical trials 
that provides assurance that the data and reported 
results are credible and accurate, and that the rights, 
integrity, and confidentiality of trial subjects are 
protected. 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBV 
Hepatitis B virus  
HCV Ab 
Hepatitis C antibody 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 

 
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HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure: A compilation of the 
clinical and nonclinical data on the investigational 
product(s) which is relevant to the study of the 
investigational product(s) in 
human subjects. 
ICF 
Informed consent form 
Ig 
Immunoglobulin 
IgG 
Immunoglobulin G 
IgG4 
Immunoglobulin G subclass 4 
IgG4-RD 
IgG4-related disease 
IL 
Interleukin 
Informed consent 
A process by which a subject voluntarily confirms 
his or her willingness to participate in a particular 
trial, after having been informed of all aspects of 
the trial that are relevant to the subject's decision to 
participate. Informed consent is documented by 
means of a written, signed and dated informed 
consent form. 
Investigational product 
A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a 
clinical trial, including products already on the 
market when used or assembled (formulated or 
packaged) in a way different from the authorized 
form, or marketed products used for an 
unauthorized indication, or marketed products used 
to gain further information about the authorized 
form 
Investigator 
A person responsible for the conduct of the clinical 
trial at a trial site. If a trial is conducted by a team 
of individuals at a trial site, the investigator is the 
responsible leader of the team and may be called 
the principal investigator. 
IP 
Investigational product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
LASIK 
Laser-assisted in situ keratomileusis 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal  
MCL 
Mantle cell lymphoma 
MTD 
Maximal tolerated dose 
MZL 
Marginal zone lymphoma 
NOAEL 
No-observed-adverse-effect level 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OS 
Overall survival  

 
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PK 
Pharmacokinetic 
PLT 
Platelet 
PR 
Partial response 
PRO 
Patient-reported outcome 
QD 
Once daily 
Q2W 
Every 2 weeks 
RBC 
Red blood cells 
Re-screen 
To screen a subject who was previously declared a 
screen failure for the same study 
RF 
Rheumatoid factor 
R/R 
Relapsed or refractory 
RR 
Response rate 
SAE 
Serious adverse event: any untoward medical 
occurrence that at any dose results in death, is life 
threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect. 
SC 
Subcutaneous 
Screen 
The act of determining if an individual meets 
minimum requirements to become part of a pool of 
potential candidates for participation in a clinical 
trial. In this study, screening involves invasive or 
diagnostic procedures. For this type of screening, 
informed consent for these screening procedures 
and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study. 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SJC 
Swollen joints count 
SS 
Sjogren’s syndrome 
SS-A 
Sjogren’s syndrome antigen A. Also known as anti-
Ro; autoantibody associated with Sjogren’s 
syndrome 
SS-B 
Sjogren’s syndrome antigen B. Also known as anti-
La; autoantibody associated with Sjogren’s 
syndrome 
TB 
Tuberculosis 
TEAEs 
Treatment emergent adverse events 
TJC 
Tender joints count 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
U/S 
Ultrasound 
v 
Version 

 
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VAS 
Visual analog scale 
WBC 
White blood cell 
 

 
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A Phase II, Single-Site, Open-Label Study of Zanubrutinib in Patients with IgG4-Related 
Disease 
 
5. 
Introduction 
 
5.1. 
Zanubrutinib Background  
Zanubrutinib (also known as BGB-3111) is a novel, irreversible, second-generation Bruton’s 
tyrosine kinase (BTK) inhibitor with great potency and selectivity.  Inhibition of BTK has emerged 
as a promising strategy for targeting B-cell malignancies and autoimmune disease.  Ibrutinib (PCI-
32765) is a first-in-class, orally active inhibitor of BTK that covalently binds to the cysteine Cys-
481 of BTK, inhibiting its autophosphorylation at Tyr-223, resulting in irreversible inactivation of 
the kinase. Only 9 other kinases in the human genome, including ITK, EGFR, and JAK3, among 
others, contain this similar cysteine residue.  In both biochemical and cellular assays, zanubrutinib 
has demonstrated potent BTK inhibition activity.  Zanubrutinib is more selective than ibrutinib 
against off-target kinases, including EGFR, JAK3, HER2, TEC, ITK, and others. Furthermore, 
zanubrutinib has favorable PK properties with excellent oral bioavailability and rapid clearance in 
rodents and dogs.  Zanubrutinib has also demonstrated better antitumor activity than ibrutinib in 
human MCL and DLBCL xenograft models.  Unlike ibrutinib, zanubrutinib has not been shown to 
interfere with the anti-CD20 antibody-induced ADCC effect.   
 
5.2. 
IgG4-Related Disease Background 
IgG4-related disease (IgG4-RD) is a systemic, immune-mediated disease that manifests as 
inflammatory, fibrotic, tumor-like lesions that can form throughout the body [1].  It was first 
described in Japan in 2001, when patients with sclerosing pancreatitis were found to have elevated 
serum levels of IgG4 [2].  It was subsequently discovered that many patients presenting with 
enlarged, fibrotic tissues elsewhere in the body, including most commonly the submandibular 
glands, lacrimal glands, and lymph nodes, all shared a common tissue histopathology.  It is now 
understood that the characteristic pathologic findings of IgG4-RD include a lymphoplasmacytic 
infiltrate comprised of IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis [3].  In 
addition, the majority (~80%) of IgG4-RD patients have elevated serum IgG4 [4, 5] and elevated 
peripheral blood plasmablasts [6].  Clinically, IgG4-RD has a large spectrum of severity depending 
on the organs or tissues involved, ranging from sicca symptoms and discomfort from enlarged 
glands to potentially life-threatening aortitis, pancreatitis, pachymeningitis, or retroperitoneal 
fibrosis.  Patients typically respond well to glucocorticoid treatment, but the majority will flare 
within one year if additional immunosuppressive medications are not initiated [7].  This, in addition 
to the significant side effects from glucocorticoids [8] and the contraindication to their use in some 
patients, highlights the importance of developing alternative approaches.  There is a significant 
unmet need for safe, effective therapies to treat and maintain remission in patients with IgG4-RD.   
 
5.3. 
Known and Potential Risks and Benefits of Zanubrutinib 
Through the date of 16 September 2018, approximately 1200 patients have received zanubrutinib in 
B-cell malignancies either as monotherapy or in combination with another agent.  Safety and 
efficacy data are derived from this experience. 
 

 
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5.3.1. Known and Potential Risks of Zanubrutinib 
 
5.3.1.1 Known Risks of Zanubrutinib 
Hemorrhage 
 
Serious and fatal hemorrhagic events have occurred in patients with hematological malignancies 
treated with zanubrutinib monotherapy. All hemorrhagic events were reported in 46.3% of patients 
with hematological malignancies in the combined database of 671 patients who were treated with 
zanubrutinib monotherapy, with the majority (44.1%) consisting of Grade 1 and 2 events. 
Petechiae, purpura, and contusion were reported in 28.2% of the patients, and all of the petechiae, 
purpura, and contusion events were Grades 1 and 2, except for one. Grade 3 or higher bleeding 
events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been 
reported in 2.2% of these patients. 
 
The mechanism for the bleeding events is not well understood. 
 
Zanubrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or 
anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the 
benefit-risk of withholding zanubrutinib for 3-7 days pre and post-surgery depending upon the 
type of surgery and the risk of bleeding. 
 
5.3.1.2 Potential Risks of Zanubrutinib 
Infections 
 
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred in patients with 
hematological malignancies treated with zanubrutinib monotherapy. Infections have occurred in 
66.6% of patients with hematological malignancies in the combined database of 671 patients who 
were treated with zanubrutinib monotherapy. Grade 3 or higher infections occurred in 21.3% of 
these patients. The most common Grade 3 or higher infection was pneumonia.  Infections due to 
hepatitis B virus (HBV) reactivation have occurred. 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. 
 
Consider prophylaxis according to standard of care in patients who are at increased risk for 
infections. Monitor patients for signs and symptoms of infection and treat appropriately. 
 
Cytopenias 
 
Cytopenias including neutropenia, thrombocytopenia, and anemia based on laboratory 
measurements were reported in 41.1%, 39.3%, and 23.4%, respectively, in patients with 
hematologic malignancies in the combined database of 671 patients who were treated with 
zanubrutinib monotherapy. Grade 3 or 4 events occurred in 19.8%, 8.5%, and 6.5% of these 
patients with neutropenia, thrombocytopenia, and anemia, respectively. 

 
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Monitor complete blood counts during treatment. 
 
Second Primary Malignancies 
 
Second primary malignancies, including non-skin carcinoma have occurred in 7.9% of patients 
with hematological malignancies in the combined database of 671 patients who were treated with 
zanubrutinib monotherapy. The most frequent second primary malignancy was skin cancer (basal 
cell carcinoma, 3.6%, and squamous cell carcinoma of skin, 1.9%).  
 
Advise patients to use sun protection. 
 
Atrial Fibrillation and Flutter 
 
Atrial fibrillation and atrial flutter have occurred in 1.8% of patients with hematological 
malignancies in the combined database of 671 patients who were treated with zanubrutinib 
monotherapy, particularly in patients with cardiac risk factors, hypertension, and acute infections.  
 
Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate. 
 
Toxic Epidermal Necrolysis 
 
One case (0.1%) of toxic epidermal necrolysis was reported in a patient receiving zanubrutinib 
treatment along with febuxostat which is known to be associated with toxic epidermal necrolysis 
and severe hypersensitivity reaction in the combined database of 671 patients.  
 
Severe skin reactions will be closely monitored. 
 
Death 
 
Of the 44 fatal events (in 40 patients) reported as of 16 September 2018 in the zanubrutinib 
monotherapy studies, 9 fatal events were assessed by the investigator as related to study drug 
(pneumonia [in 3 patients], arthritis bacterial, toxic epidermal necrolysis, death, cerebral 
haemorrhage, platelet count decreased, and 1 event with an unreported term from a blinded study). 
 
In the zanubrutinib combination studies (BGB-3111-GA101, BGB-3111-213, and BGB-3111- 
A317-Study_001), 9 fatal events (renal impairment, skin squamous cell carcinoma metastatic, 
dyspnoea, pleural effusion, abdominal pain and completed suicide [same patient], abdominal pain, 
multiple organ dysfunction syndrome, and sepsis), in 8 patients, had been reported as of 16 
September 2018; none of these fatal events were assessed by the investigator as related to 
zanubrutinib or either study treatment (zanubrutinib or tislelizumab in Study BGB-3111-A317-
Study_001). 
 
5.3.2. Reproductive and Developmental Toxicity 
The risk of fertility impairment was considered to be low as zanubrutinib had no impact on fertility 
or early embryonic development to implantation in male or female rats at doses up to 300 mg/kg or 

 
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histopathological changes in reproductive organs in rats or dogs in up to 91-day repeat-dose studies. 
 
No apparent treatment-related maternal or embryo-fetal toxicities were noted at doses up to 150 
mg/kg/day in both rats and rabbits; no apparent teratogenicity was noted in the rabbit fetus at any 
dose levels; and the only teratogenicity included one 3-chambered heart (0.3%), one 2-chambered 
heart (0.3%), and five 3-chambered hearts (1.5%) noted in rat fetuses at doses of 30, 75, and 150 
mg/kg/day, respectively. 
 
No pre- and post-natal developmental toxicity was noted in the maternal or offspring rats, with the 
exception that an increased incidence (26% to 42%) and severity of multiple ophthalmic lesions 
were noted in the treated animals as compared to the concurrent control group (26%). 
 
5.3.3. Known and Potential Benefits of Zanubrutinib 
Nothing is known about the potential benefits of zanubrutinib therapy for IgG4-RD, although a 
scientific rationale does exist for hypothesizing that this drug may improve the signs and symptoms 
of this disease. 
 
5.4. 
Rationale and Justification for the Study  
The pathogenesis of IgG4-RD is incompletely understood, but based on elevations in serum IgG4 
and plasmablast levels, as well as the significant improvement seen with B cell depleting and 
inhibiting therapies [9, 10], B cells are believed to play an important role [11].  Follicular helper T 
cells [12, 13] and CD4+ cytotoxic T cells [14] are also expanded in patients with IgG4-RD, and 
their numbers correlate with plasmablast levels, suggesting they may be involved in disease 
pathogenesis.  It remains unknown whether these T cells promote B cell activation, or conversely, 
whether B cells may act as antigen presenting cells to the T cells.  In addition, several groups have 
identified potential autoantibodies in IgG4-RD [15, 16], which may provide further support for 
therapies directed at the B cell compartment.  Ultimately, given the success of drugs like rituximab, 
targeting B cells with novel agents that are safer and more easily titrated holds great promise. 
 
Bruton’s tyrosine kinase (BTK) activity, downstream of B cell receptor (BCR) signaling, 
contributes to B cell survival through activation of NF-kB [17-19].  In humans, BTK deficiency 
results in the B cell immunodeficiency syndrome X-linked agammaglobulinemia (XLA) [20].  In 
mice, overexpression of BTK in B cells results in spontaneous germinal center formation, plasma 
cell differentiation, and the production of autoantibodies, similar to human autoimmune diseases 
such as systemic lupus erythematosus and Sjogren’s syndrome [21].  Furthermore, BTK 
overexpressing B cells are resistant to apoptosis and to elimination when self-reactive.  In IgG4-RD 
patients, BTK gene expression is elevated in lacrimal glands compared to healthy controls [22].  
 
The evidence suggests BTK plays a critical role in the development and propagation of a number of 
autoimmune diseases, and this likely includes IgG4-RD.  Currently, there is a paucity of disease 
modifying treatments for IgG4-RD.  The patient population that will be treated in this study has 
symptomatic enlargement of the submandibular and/or lacrimal glands and has failed a course of 
glucocorticoids (or was intolerant to glucocorticoid use).  These patients require treatment for their 
symptoms (pain/pressue, dryness, headaches, disfigurement) and to potentially help prevent the 
disease from spreading to additional sites in the body.  The standard of care treatments, including 
moderate to high doses of glucocorticoids, DMARDs such as azathioprine, and rituximab all have 

 
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potential toxicities and side effects.  Given the critical role of BTK in B cell activation and survival 
of autoreactive B cells, BTK inhibition is a compelling and rational strategy for the treatment of 
IgG4-RD, and may provide a much needed alternative therapy for these patients. 
 

 
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6. 
Objectives 
 
6.1. 
Primary Objective 
The primary objective of this study is to demonstrate that zanubrutinib treatment reduces the 
volume of the submandibular and/or lacrimal glands on PET/MRI at Week 24 compared to 
Baseline. 
 
6.2. 
Secondary Objective 
The secondary objectives of this study are to determine the effect of zanubrutinib on: 
• Change in FDG avidity (SUVmax) [23] of submandibular and/or lacrimal glands on PET 
from Baseline to Week 24 
• Change in metabolic lesion volume (MLV) of submandibular and/or lacrimal glands on PET 
from Baseline to Week 24 
• Change in total lesion glycolysis (TLG) of submandibular and/or lacrimal glands on PET 
from Baseline to Week 24 
• Change in submandibular glands on MRI (parenchymal architecture scored 0 to 4 and 
sialography scored 0 to 4) from Baseline to Week 24 
• Change in parotid glands on MRI (parenchymal architecture scored 0 to 4 and sialography 
scored 0 to 4) from Baseline to Week 24 
• Change in lacrimal glands on MRI (parenchymal architecture scored 0 to 4 and sialography 
scored 0 to 4) from Baseline to Week 24 
• Change in the volume of the parotid glands on PET/MRI from Baseline to Week 24  
• Change in the volume of the submandibular glands on PET/MRI from Baseline to Week 12 
• Change in the volume of the lacrimal glands on PET/MRI from Baseline to Week 12 
• Change in the volume of the parotid glands on PET/MRI from Baseline to Week 12 
• Change in FDG avidity (SUVmax) of submandibular and/or lacrimal glands on PET from 
Baseline to Week 12 
• Change in metabolic lesion volume (MLV) of submandibular and/or lacrimal glands on PET 
from Baseline to Week 12 
• Change in total lesion glycolysis (TLG) of submandibular and/or lacrimal glands on PET 
from Baseline to Week 12 
• Change in submandibular glands on MRI (parenchymal architecture scored 0 to 4 and 
sialography scored 0 to 4) from Baseline to Week 12 
• Change in parotid glands on MRI (parenchymal architecture scored 0 to 4 and sialography 
scored 0 to 4) from Baseline to Week 12 
• Change in lacrimal glands on MRI (parenchymal architecture scored 0 to 4 and sialography 
scored 0 to 4) from Baseline to Week 12 
• Change in serum IgG4 level from Baseline to Week 24 
• Change in serum IgG4 level from Baseline to Week 12 
• Change in plasmablast count from Baseline to Week 24 
• Change in plasmablast count from Baseline to Week 12 
• Change in absolute regulatory B cell count from Baseline to Week 24 
• Change in absolute regulatory B cell count from Baseline to Week 12 

 
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• Change in the IgG4-RD Responder Index [24-26] from Baseline to Week 24 
• Change in the IgG4-RD Responder Index from Baseline to Week 12 
• Proportion of patients with no disease flares between Week 12 and Week 24 
• Change in total salivary grey scale ultrasound score (TUS) from Baseline to Week 24 
• Change in total salivary grey scale ultrasound score (TUS) from Baseline to Week 12 
• Change in highest score among the salivary glands for the grey scale ultrasound score 
(HSUS) from Baseline to Week 24 
• Change in highest score among the salivary glands for the grey scale ultrasound score 
(HSUS) from Baseline to Week 12 
• Change in glandular inflammation total ultrasound score (iTUS) from Baseline to Week 24 
• Change in glandular inflammation total ultrasound score (iTUS) from Baseline to Week 12 
• Change in highest score among the salivary glands for the glandular inflammation 
ultrasound score (iHSUS) from Baseline to Week 24 
• Change in highest score among the salivary glands for the glandular inflammation 
ultrasound score (iHSUS) from Baseline to Week 12 
• Change in physician global assessment of disease from Baseline to Week 24 
• Change in physician global assessment of disease from Baseline to Week 12 
• Change in patient global assessment of disease from Baseline to Week 24 
• Change in patient global assessment of disease from Baseline to Week 12 
• Change in VAS for ocular symptoms from Baseline to Week 24 
• Change in VAS for ocular symptoms from Baseline to Week 12 
• Change in VAS for salivary symptoms from Baseline to Week 24 
• Change in VAS for salivary symptoms from Baseline to Week 12 
• Change in FACIT-F fatigue score from Baseline to Week 24 
• Change in FACIT-F fatigue score from Baseline to Week 12 
• Change in RAND Short Form-36 from Baseline to Week 24 
• Change in RAND Short Form-36 from Baseline to Week 12 
• Change in labs: C3, C4, total IgG, IgE, IgG1, ESR, and CRP from Baseline to Week 24 
• Change in labs: C3, C4, total IgG, IgE, IgG1, ESR, and CRP from Baseline to Week 12 
• Safety parameters including adverse events and abnormal laboratory results 
 
 

 
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7. 
Investigational Plan 
 
7.1. 
Summary of Study Design 
This study is a single-site, open-label study in subjects with histopathologically confirmed, 
symptomatic IgG4-related disease affecting the submandibular and/or lacrimal glands with prior 
inadequate response to, or intolerance of, glucocorticoids, or who experience recurrent symptoms 
after previous treatment with glucocorticoids, being conducted at the Stanford University 
rheumatology clinic.  Ten subjects will be included in the study.  All eligible subjects will receive 
zanubrutinib 80mg BID over a period of 24 weeks and will be followed up for an additional 8 
weeks after the last dose.  Patients are not required to be taking glucocorticoids, but those patients 
on prednisone ≤40mg daily (or other glucocorticoid equivalent) will undergo a scheduled taper over 
the first 8 weeks (see Table 2 for prednisone taper schedule).   
 
After the Screening visits, consenting patients will be seen in clinic on day 1 (Baseline) and return 
to clinic on Weeks 2, 4, 8, 12, 16, 20, 24, and 32.  For the complete schedule of events, see Section 
15: Study Schedule. 
 
At Screening (up to 35 days before baseline), a complete medical history, physical exam, vital 
signs, clinical laboratory tests [comprehensive metabolic panel, complete blood count, IgG 
subclasses (including IgG4), ANA, RF, anti-Ro, anti-La, serum pregnancy test for females, HIV 
serologies, hepatitis B serologies, hepatitis C serologies, quantiFERON test for tuberculosis], chest 
x-ray, and electrocardiogram will be conducted.   
 
At all subsequent visits, at a minimum, a complete physical exam, vital signs, focused history, and 
clinical laboratory tests (comprehensive metabolic panel, complete blood count, and urine 
pregnancy test for females) will be conducted.  
 
At Baseline, Week 4, Week 12, and Week 24 additional labs including total IgG, IgG subclasses 
(including IgG4), B cell phenotyping (including plasmablast number), complement levels (C3, C4), 
ESR, and CRP will be collected.   
 
At, or just prior to, Baseline, Week 12, and Week 24, PET/MRI and salivary gland ultrasound will 
be performed.   
 
At Week 12 and Week 24 an electrocardiogram will be obtained. 
 
At each visit, patients will record their global assessment of disease as well as visual analog scales 
for ocular and salivary symptoms and the FACIT-F for fatigue and RAND SF-36, and the physician 
will calculate the IgG4-RD Responder Index score as well as physician global assessment of 
disease. 
 
In addition, safety will be assessed for all patients. 
 

 
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Figure 1 
Study design 
 
7.2. 
Discussion of Design and Control 
IgG4-RD was selected as a relevant patient population based on the mechanism of action of 
zanubrutinib and the current understanding of the pathogenesis of the disease.  An open-label 
design was chosen based on practical considerations regarding the number of patients that could be 
recruited.  Although open-label studies are subject to bias, objective primary endpoints were 
intentionally chosen to minimize this concern.   
 
 
 

 
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8. 
Study Population 
 
8.1. 
Criteria for Enrollment 
Eligibility of subjects for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG). 
 
Posteroanterior (PA) and lateral chest x-rays will be completed at screening, unless obtained within 
90 days prior to initial screening and the x-rays and/or report are available for investigator 
review. Variations on the chest x-ray view requirements will only be permitted if the parameters 
are within local guidelines of care for standard tuberculosis (TB) screening. 
 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions/medical/surgical history will be documented at screening. 
 
Screening may occur up to 35 days before baseline. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once in certain situations.  For example, the following subjects may be eligible for re-
screening: 
1. Subjects who had a transient condition(s) which no longer applies or for which the 
 
condition has been medically managed so that there is no longer a safety concern for trial 
 
participation.  
2. Subjects whose previous prohibited treatments have since been discontinued and 
 
subsequently meet the specified time frame described in the inclusion/exclusion criteria. 
3. Subjects who have become eligible to enroll in the study as the result of a protocol 
Amendment. 
 
If re-screening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new subject identification number. Chest x-rays and/or TB testing (including 
an interferon-gamma release assay) do not need to be repeated if completed within 90 days of the 
re-consent date, at the discretion of the investigator.  Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, are not 
permitted. 
 
8.1.1. Inclusion Criteria 
Subjects are eligible for enrollment in the study only if they meet all of the following criteria: 
• Have given written informed consent 
• Are men or women aged 18 to 85, inclusive, at the time of initial screening 
• All women (regardless of childbearing potential) must test negative for pregnancy at the 
time of screening (see Section 8.1.4. for more information about women of childbearing 
potential). Women must also agree to use a reliable method of birth control from screening 
until 12 weeks following last dose of study drug (adequate contraceptive measures include: 
intrauterine devices, hormonal contraceptives, complete sexual abstinence, or vasectomized 
partner), unless they are not of child-bearing potential as defined by meeting either of the 
following: 

 
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o Are at least 6 weeks after bilateral oophorectomy, tubal ligation, or hysterectomy 
o Are postmenopausal, as defined by having had spontaneous amenorrhea for at least 
12 months and a follicle-stimulating hormone level >40 mIU/mL at screening 
• Meet the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease 
• Have involvement of either the lacrimal gland(s) and/or the submandibular gland(s) 
• Have symptoms from their enlarged submandibular and/or lacrimal glands including pain, 
dryness, headache, or vision changes 
• Have had a prior inadequate response to, or intolerance of, glucocorticoids, or who 
experience recurrent symptoms after previous treatment with glucocorticoids 
o Inadequate response is defined as treatment with glucocorticoids with minimal or no 
improvement in symptoms, or an initial response with relapse upon stopping 
glucocorticoids 
o Intolerance of glucocorticoids is based on the investigator’s discretion but includes 
events such as mood disturbances (severe lability and/or psychosis), poorly 
controlled diabetes, osteoporosis, and avascular necrosis. 
• Are not receiving current treatment with immunosuppressive medications other than 
prednisone ≤40mg daily (or other glucocorticoid equivalent) with stable dosing for ≥28 days 
(glucocorticoids are permitted as above, but glucocorticoid use is not required to be eligible 
for the study) 
• Are willing to undergo a scheduled glucocorticoid taper (including reducing to prednisone 
≤40mg daily before Day -28) if they are on glucocorticoids per Table 2 in Section 9.7.1 
• Have venous access sufficient to allow for blood sampling, as per the protocol 
• Are reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures 
 
8.1.2. Exclusion Criteria 
Subjects will be excluded from study enrollment if they meet any of the following criteria: 
• Have previously been treated with a BTK inhibitor within 6 months before Baseline 
• Have synthetic disease-modifying antirheumatic drug (DMARD) or immunosuppressive use 
as follows: 
o Treatment with synthetic DMARDs including but not limited to 
hydroxychloroquine, methotrexate, leflunomide, or sulfasalazine within 28 days 
prior to baseline or planned treatment during the study 
o Treatment with cytotoxic or immunosuppressive drugs including but not limited to 
cyclophosphamide, mycophenolic acid, azathioprine, cyclosporine, sirolimus, or 
tacrolimus within 28 days prior to screening or planned treatment during the study 
o Treatment with a janus kinase (JAK) inhibitor (including but not limited to 
tofacitinib, baricitinib, upadacitinib, or filgotinib) within 28 days prior to baseline or 
planned treatment with a JAK inhibitor during the study 
• Have had treatment with biologic DMARDs as follows: 
o Treatment with etanercept, adalimumab, or anakinra within 28 days before baseline 
or planned treatment during the study 
o Treatment with infliximab, certolizumab pegol, golimumab, abatacept, or 
tocilizumab within 56 days before baseline or planned treatment during the study 
o Treatment with a B cell depleting agents including but not limited to rituximab, 
ocrelizumab, obinutuzumab, and obexelimab (XmAb5871) within 12 months before 

 
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baseline or planned treatment during the study 
o Treatment with a BAFF antagonist (such as belimumab or tabalumab) within 6 
months before baseline or planned treatment during the study 
o Treatment with an IL-17 antagonist (such as secukinumab, ixekizumab, brodalumab) 
within 6 months before baseline or planned treatment during the study 
o Treatment with other biologic agents may be allowed at the discretion of the 
protocol director 
• Are currently enrolled in a clinical trial involving an investigational product or off-label use 
of a drug, are concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study, or have received: 
o Any nonbiologic investigational product within 30 days or 5 half-lives (whichever is 
longer) of their baseline (Day 1) visit 
o Any biologic investigational product within 3 months or 5 half-lives (whichever is 
longer) of their baseline visit, or any leukocyte depleting agent within 12 months of 
baseline 
• Have a prescribed dose >40 mg/day of oral prednisone (or equivalent) within 28 days before 
baseline, or plan to increase >40 mg/day during the study. (Stable prescriptions ≤40 mg/day 
are allowed.)  Parenteral corticosteroids are not permitted within 28 days prior to baseline. 
• Have received a live (attenuated) vaccine within 28 days prior to baseline or intend to 
receive one during the study 
• Have clinically significant hematological abnormalities at screening, including: hemoglobin 
<9.0 g/dL, total platelet count <100,000 cells/uL, total white blood cell count <3000 
cells/uL, neutrophil count <1200 cells/uL, or lymphocyte count <800 cells/uL.  A repeat 
analysis is allowed per judgment of investigator before making a final determination of 
eligibility. The repeat laboratory test does not require a reconsent, as the result does not 
constitute a screen-fail until the clinically significant, out-of-range value is confirmed. 
• Have abnormal liver function tests at screening, including: aspartate transaminase >2 times 
the upper limit of normal, alanine transaminase >2 times the upper limit of normal, total 
bilirubin >2 times the upper limit of normal, unless patient has a known history of Gilbert 
syndrome.  A repeat analysis is allowed per judgment of the investigator before making a 
final determination of eligibility. The repeat laboratory test does not require a reconsent, as 
the result does not constitute a screen-fail until the clinically significant, out-of-range value 
is confirmed. 
• Have an estimated glomerular filtration rate at screening <30 mL/min/1.73 m2 by 
Modification of Diet in Renal Disease Study (MDRD) equation.  A repeat analysis is 
allowed per judgment of the investigator before making a final determination of eligibility. 
The repeat laboratory test does not require a reconsent, as the result does not constitute a 
screen-fail until the clinically significant, out-of-range value is confirmed. 
• Have an abnormality in the chest x-ray or 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study 
• Have human immunodeficiency virus infection/acquired immunodeficiency syndrome 
(AIDS) or positive human immunodeficiency virus antibodies at screening 
• Have evidence of active hepatitis C virus (HCV) infection.  The HCV panel includes HCV 
antibody as well as quantitative HCV RNA by PCR if the patient is HCV antibody positive.  
Patients positive for HCV antibody, but negative for HCV RNA, must undergo monthly 
HCV RNA screening. Patients with HCV RNA ≥ 15 IU/mL should stop study drug and 

 
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antiviral therapy should be initiated. Resumption of study drug in patients whose HCV 
reactivation resolves should be discussed with, and approved by, the medical monitor and 
physicians with expertise in managing HCV infection.  All patients with a history of 
hepatitis B and C viral infection and baseline negative PCR that develop elevations in liver 
function tests should be evaluated for viral hepatitis reactivation.  The medical monitor 
should be informed of any suspected HBV or HCV reactivation.  See Table 1 for a 
description of how the results for HCV testing at Screening relate to study eligibility. 
• Have evidence of active hepatitis B virus (HBV) infection.  The HBV panel includes 
HBsAg, HBcAb, and hepatitis B surface antibody (HBsAb).  Patients positive for HBsAg 
and/or with detectable levels of HBV DNA are not eligible for the study.  Patients who are 
HBcAb positive are also not eligible for the study.  Subjects who are only HBsAb positive 
at screening (with a history of immunization) are permitted to enroll.  All patients with a 
history of hepatitis B and C viral infection and baseline negative PCR that develop 
elevations in liver function tests should be evaluated for viral hepatitis reactivation.   
• Have evidence of TB as documented by chest-x ray, medical history, physical examination 
or a positive interferon-gamma release assay (ie QuantiFERON®-TB Gold).  If the 
interferon-gamma release assay is indeterminate, a retest is allowed, per investigator 
judgment.  If the retest is also indeterminate, the subject will be excluded from the study.  
Subjects with chest x-rays obtained within 90 days prior to initial screening may be exempt 
from a screening chest x-ray if deemed medically appropriate in the judgment of the 
investigator. The images and/or written report must be available for investigator review and 
filed with the subject’s records at the site. Image views must be as per above, unless in 
accordance with local standard of care for TB screening.  Subjects with a history of latent 
TB must have documented evidence of having completed a full course of prophylactic 
treatment, have no known history of reexposure, and no evidence of active TB on chest x-
ray, medical history or physical examination. These subjects are exempt from interferon-
gamma release testing.  Subjects with any history of active TB, whether treated or untreated, 
are excluded. 
• Have any history of cancer except for skin basal or squamous cell carcinoma, cervical 
dysplasia or carcinoma in situ that has been treated and is considered cured >1 year prior to 
baseline, prostate cancer considered cured for >5 years with a normal prostate specific 
antigen, or colon cancer considered cured >5 years. 
• Have a history of arrhythmia or underlying cardiac disease that could predispose to 
development of arrhythmia (including cardiomyopathy and/or coronary artery disease) 
• Have a blood dyscrasia or are at increased risk of bleeding 
• Have planned surgical procedures during the study 
• Use of known strong or moderate CYP3A inducers or inhibitors within 3 days of Baseline 
• Have known hypersensitivity or allergy to the study drug 
• Have a history of, or current, inflammatory or autoimmune disease (that could affect the 
interpretation of safety or efficacy outcomes) other than IgG4-RD 
• Are women who intend to become pregnant or breastfeed during any portion of the study  
• Have a psychiatric disorder rendering the subject incapable of providing informed consent 
• Have any condition that, in the opinion of the investigator, may compromise the safety of 
the subject in the study; confound the analysis of the data, render the subject unable to 
understand the nature, scope, and possible consequences of the study; or preclude the 
subject from following and completing the protocol 

 
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Table 1 
Active Hepatitis B or Hepatitis C Infection (Detected Positive by Polymerase 
Chain Reaction) 
 
 
8.1.3. Rationale for Exclusion of Certain Study Candidates 
Exclusion criteria were chosen to prevent conflict of interest in study participants and to exclude 
medical conditions, medication intolerance, and concomitant medication use that may constitute a 
risk for the subject and/or may confound the assessment of study endpoints. 
 
8.1.4. Females of Childbearing Potential and Contraception 
A woman is considered of childbearing potential (ie, fertile) after menarche and until becoming 
postmenopausal unless surgically sterilized. Surgical sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy.  
 
• Contraception methods include the following:  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
the inhibition of ovulation − Oral, intravaginal, or transdermal  
• Progestogen-only hormonal contraception associated with the inhibition of ovulation − Oral, 
injectable, implantable  
• An intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion  
• Vasectomized partner (provided that the vasectomized partner is the sole sexual partner of 
the woman of childbearing potential study participant and that the vasectomized partner has 
received medical assessment of surgical success)  
• Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment, starting the day before first dose of study 
drug, for the duration of the study, and for ≥ 90 days after the last dose of study drug).  
 
Total sexual abstinence should only be used as a contraceptive method if it is in line with the 
patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, 

 
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postovulation methods), declaration of abstinence for the duration of exposure to investigational 
medicinal product, and withdrawal are not acceptable methods of contraception.  
 
Of note, barrier contraception (including male and female condoms with or without spermicide) is 
not considered a highly effective method of contraception, and, if used, this method must be used in 
combination with another acceptable method listed above.  
 
If a woman of childbearing potential is using hormonal contraceptives such as birth control pills or 
devices, a second barrier method of contraception (eg, condoms) must also be used.  
 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single follicle-
stimulating hormone measurement is insufficient. 
 
8.2.  
Discontinuation 
The reason for, and date of, discontinuation will be collected for all subjects. All enrolled 
subjects who discontinue, regardless of whether or not they received investigational product, will 
have procedures performed as shown in the Study Schedule. 
 
8.2.1. Discontinuation of Subjects  
 
8.2.1.1. Subjects Inadvertently Enrolled 
The criteria for enrollment must be followed explicitly. If the investigator identifies a subject who 
did not meet enrollment criteria and who was inadvertently enrolled, the investigator will discuss 
with the DSMC and a decision will be made regarding continuation or removal. 
 
8.2.1.2. Discontinuations from Investigational Product or from the Study 
Subjects will be discontinued from study drug and/or from the study in the following 
circumstances: 
• Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
• Investigator decision: 
o The investigator decides that the subject should be discontinued from the study 
o If the subject, for any reason, requires protocol excluded treatment, discontinuation 
from the study drug should occur prior to introduction of the other agent (in some 
cases, the subject may continue in the study for the purpose of assessments without 
receiving further study drug) 
• Subject decision: 
o The subject requests to be discontinued from the study 
 
Following the investigator’s determination that clinically significant event criteria have been met 
and the investigator’s judgment of relatedness to the investigational product is documented, a 
decision will be made between the investigator and DSMC regarding subject discontinuation. 

 
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The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values present 
at the time of discontinuation and any applicable follow-up procedures will be documented. 
 
8.2.1.3. Subjects Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit and these should be 
documented. 
 
8.2.2. Discontinuation of the Study  
The study will be discontinued if the protocol director or sponsor judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
 
 
 

 
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9. 
Treatment 
 
9.1. 
Treatment Materials and Supplies 
9.1.1. Packaging and Labeling  
Zanubrutinib will be supplied to the investigator. Clinical trial materials are manufactured in 
accordance with current Good Manufacturing Practices and labeled according to regulatory 
requirements. All study medication will be stored, inventoried, reconciled, and destroyed according 
to applicable regulations.   
 
Zanubrutinib 80mg capsules will be provided in a child-resistant, high-density polyethylene bottle 
with induction seal and bottle label.  The contents of the label will be in accordance with all 
applicable local regulatory requirements.  Zanubrutinib 80mg capsules are formulated as hard 
gelatin capsules with the same appearance.  
 
Zanubrutinib drug product contains BGB-3111 active pharmaceutical ingredient, microcrystalline 
cellulose (VIVAPUR 102) as a filler, croscarmellose sodium (VIVASOL) as a disintegrant, sodium 
lauryl sulfate (Killiphor®SLS Fine) as a wetting agent, colloidal silica (AEROSIL200) as a glidant, 
and magnesium stearate (Ligamed MF-2-V) as a lubricant, all of which are standard compendial 
excipients (USP/Ph. Eur) and provided by qualified suppliers. 
 
9.1.2. Handling and Storage  
The study drug will be dispatched to a study center only after receipt of the required documents in 
accordance with applicable regulatory requirements and the sponsor’s procedures. The investigator 
or pharmacist/designated personnel is responsible for maintaining the drug supply inventory and 
acknowledging receipt of all study drug shipments. All study drug must be stored in a secure area, 
with access limited to the investigator and authorized study center personnel and kept under 
physical conditions that are consistent with study drug-specific requirements. The study drug must 
be kept at the temperature condition as specified on the labels.  
 
Study drug bottles must be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).  Study drug 
must be dispensed or administered according to procedures described herein. Only patients enrolled 
in the study may receive study drug, in accordance with all applicable regulatory requirements. 
Only sponsor authorized study center personnel may supply or administer study drug.  
 
9.1.3. Compliance and Accountability  
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or guardian.  
 
The investigator and/or study personnel will keep accurate records of the quantities of study drug 
dispensed and used by each patient. This information must be captured in the source document at 
each patient visit. The investigator is responsible for study drug accountability, reconciliation, and 
record maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study center personnel must maintain study drug accountability records throughout the 
course of the study. This person will document the amount of study drug received from the sponsor, 
the amount supplied, and/or the amount administered to and returned by patients, if applicable.  

 
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9.1.4. Disposal and Destruction  
After completion of the study and after final drug inventory reconciliation by the monitor, the study 
site, upon sponsor’s election, will destroy or return all unused study drug supplies to sponsor. The 
inventoried supplies can be destroyed on site or at the depot according to institutional policies after 
receiving prior written sponsor approval. 
 
9.2. 
Treatment Administration 
All subjects will be administered zanubrutinib 80mg orally twice daily (BID) over a period of 24 
weeks starting on Baseline Day 1.   
 
Zanubrutinib tablets are to be taken with or without food approximately 12 hours apart.  
Gastrointestinal tolerability may be better if given with food.   
 
Patients may also be on glucocorticoids, which are not to exceed 40mg/day of prednisone (or its 
equivalent), and which will be tapered over a maximum of 10 weeks as per Table 2 in Section 9.7.1.   
 
The investigator or designee is responsible for: 
• Explaining the correct use of the investigational agent to the subject 
• Verifying that instructions are followed properly 
• Maintaining accurate records of investigational product dispensing and collection 
 
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.  
 
All clinical trial material provided to the investigator will be stored in a secure place and allocated 
and dispensed by appropriately trained persons. The allocation and dispensing of the investigational 
products will be fully documented. Detailed records of the amounts of the investigational product 
received, dispensed and remaining at the end of the study will be maintained. 
 
9.3. 
Rationale for Selection of Dose 
The dose level and regimen planned for this study was selected based on analyses of BTK 
occupancy, PK/PD, safety, and efficacy from the Phase 1 BGB-3111-AU-003 study [27].  The dose 
of 80mg BID was considered optimal based on high BTK inhibition, low rates of adverse events, 
and potential for efficacy in this patient population. 
 
9.4. 
Specific Restrictions/Requirements 
Before beginning the study, all subjects will complete written, informed consent and baseline tests. 
 
As the risk of zanubrutinib to the human fetus is unknown, all female subjects of child-bearing 
potential must agree to use a reliable method of birth control (ie, surgical sterilization, intrauterine 
devices, hormonal contraceptives, complete abstinence from sexual intercourse with men, or 
vasectomized partner) from screening to 12 weeks after last dose of study drug. Male subjects 
should use a reliable method of birth control (vasectomy, barrier contraception during intercourse 

 
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with female partners, or abstinence from sexual intercourse with women) from screening to 12 
weeks after last dose of study drug. 
 
9.5. 
Dose Modification for Toxicity 
A dose reduction of zanubrutinib from 80mg BID to 80mg QD will be permitted for management of 
toxicity at the discretion of the investigator.  Rationale for dose reduction may include, but is not 
limited to, laboratory abnormalities and mild side effects such as increased bruising/bleeding, rash, 
or diarrhea.  
 
The study treatment will be suspended if the subject develops a significant infection or AE.  If the 
infection or AE resolves, then the study treatment may be restarted at the next scheduled dose.  It is 
up to the discretion of the investigator whether zanubrutinib is restarted at 80mg BID or 80mg QD.   
 
9.6. 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose. 
AEs associated with an overdose or incorrect administration of study drug will be recorded on the 
AE eCRF. Any SAEs associated with an overdose or incorrect administration are required to be 
reported within 24 hours via the SAE reporting process. There is no specific antidote for an 
overdose of zanubrutinib. In the event of an overdose, patients should be closely monitored and 
given appropriate supportive treatment.  
 
9.6.1. Minor Surgical Procedures  
For minor procedures (eg, central venous catheter, arterial line placement) that are urgently needed 
and could result in bleeding, immediately stop study drug and consider transfusion with platelets 
just prior to procedure. Study drug should be held for 24 hours after procedure. If there is ongoing 
bleeding after the procedure, additional platelet transfusions can be administered and study drug 
held to 24 hours after bleeding stops. No drug hold or platelet transfusions are needed for routine 
venipunctures or peripheral IV placement.  
 
9.6.2. Elective Major Surgical Procedures  
For any elective surgery or invasive procedure requiring sutures or staples for closure, study drug 
should be discontinued and the subject should exit the study.  
 
9.6.3. Emergency Major Surgery Procedures  
For emergency procedures that could result in bleeding and require sutures or staples for closure, 
transfusion with platelets prior to the procedure should be given and study drug should be 
discontinued and the subject should exit the study. 
 
9.7. 
Continued Access to Investigational Product 
The investigational product should only be administered to study subjects as per protocol and will 
not be made available at the conclusion of this study. 
 

 
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9.8. 
Blinding 
This is an open-label study and neither the subject nor the investigator will be blinded. 
 
9.9. 
Concomitant Therapy 
The introduction of new prescriptions or over-the-counter drugs is to be avoided during the study, 
unless required to treat an AE. Any additional medication used during the course of the study must 
be documented. 
 
If the need for concomitant medication arises, inclusion or continuation of the subject will be at the 
discretion of the protocol director and investigator. 
 
Reductions in background synthetic DMARDs will be permitted for toxicity and safety issues and 
should be documented. 
 
9.9.1. Glucocorticoid Taper 
Glucocorticoids may be prescribed during the screening period with a dose of ≤40mg daily of 
prednisone (or other glucocorticoid equivalent).  Patients are not required to be taking 
glucocorticoids, but those who are should be on an approved starting dose listed in Table 2 (40mg, 
30mg, 20mg, 15mg, 10mg, or 5mg daily) and remain on that dose stably for ≥28 days before 
Baseline.   
 
The glucocorticoid dose will be tapered over a maximum of 8 weeks per the schedule in Table 2. 
 
Table 2 
Prednisone Taper Schedule 
 
Prednisone 8-Week Taper 
Week 
Starting Dose, mg/day 
0 
40 
30 
20 
15 
10 
5 
2 
20 
15 
10 
7.5 
5 
2.5 
3 
15 
10 
7.5 
5 
2.5 
0 
4 
10 
7.5 
5 
2.5 
0 
 
5 
7.5 
5 
2.5 
0 
 
 
6 
5 
2.5 
0 
 
 
 
7 
2.5 
0 
 
 
 
 
8 
0 
 
 
 
 
 
 
9.9.2. Effects of Zanubrutinib on Exposure of Other Concomitant Medications 
A clinical drug-drug interaction study (Study BGB-3111-108) indicated that zanubrutinib is a mild 
inducer of CYP3A4 and CYP2C19. Narrow therapeutic index drugs that are metabolized by 
CYP3A4 (alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), and CYP2C19 (eg, S-mephenytoin) should be used with caution, as 
zanubrutinib may decrease the plasma exposures of these drugs.  
 
Because ethinylestradiol (a key ingredient in a variety of combined oral contraceptives) is partly 
metabolized by CYP3A4, patients using hormonal contraceptives (eg, birth control pills or devices) 

 
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must use a barrier method of contraception (eg, condoms) as well (Section 5.2.2).  
 
Repeated dosing of zanubrutinib increased exposure of digoxin (P-gp substrate) with a mean 
increase of 11% for AUC0-t and 34% for Cmax. The coadministration of oral P-gp substrates with 
a narrow therapeutic index (eg, digoxin) should be used with caution as zanubrutinib may increase 
their concentrations. 
 
9.9.3. Permitted Medications for Treatment of IgG4-Related Disease 
Glucocorticoids are permitted (but not required) for IgG4-RD during the study, and should be 
maintained at a stable dose before Baseline and tapered during the first 8 weeks of the study per 
Table 2.  No other treatments specific for IgG4-RD are permitted during the study.   
 
9.9.4. Rescue Medications 
No rescue medications will be allowed during this study.  If a patient needs to adjust or add to their 
immunosuppressive regimen, they will stop the study drug and exit the study. 
 
9.9.5. Prohibited Medications 
• Any BTK inhibitor (other than zanubrutinib) 
• Synthetic DMARDs such as hydroxychloroquine, methotrexate, leflunomide, or 
sulfasalazine 
• Cytotoxic or immunosuppressive drugs including but not limited to cyclophosphamide, 
mycophenolic acid, azathioprine, cyclosporine, sirolimus, and tacrolimus 
• Any investigational or marketed biologic DMARDs, including but not limited to etanercept, 
infliximab, adalimumab, golimumab, certolizumab pegol, rituximab, ocrelizumab, 
obinutuzumab, obexelimab (XmAb5871), tocilizumab, anakinra, abatacept, secukinumab, 
ixekizumab, brodalumab, belimumab, or tabalumab. Other biologic treatments may be 
allowed with sponsor approval. 
• Any janus kinase (JAK) inhibitor including but not limited to tofacitinib, baricitinib, 
upadacitinib, or filgotinib 
• Parenteral glucocorticoids 
• Strong and moderate inducers of CYP3A including but not limited to avasimibe, 
carbamazepine, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, 
modafinil, and nafcillin. 
• Strong and moderate inhibitors of CYP3A including but not limited to clarithromycin, 
itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole, telaprevir, telithromycin, and 
voriconazole.  For a more complete list, please refer to https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers#table3-2. 
 
 
 

 
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10. 
Investigational Agent 
 
10.1. Zanubrutinib 
Zanubrutinib is a potent, specific, and irreversible BTK inhibitor that was designed to be more 
specific than ibrutinib; similar to ibrutinib, zanubrutinib potently inhibited BTK kinase in 
biochemical assays, with a 50% inhibitory concentration (IC50) of 0.3 nM, and in vitro cellular 
assays also show that zanubrutinib inhibited BTK signaling in mantle cell lymphoma (MCL) cell 
lines and cellular growth of several MCL cell lines.  
 
Zanubrutinib is more selective than ibrutinib for the inhibition of kinase activity of BTK versus 
EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC. Cellular assays also confirmed that 
zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR (> 6-
fold). Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib in inhibiting rituximab-
induced antibody‐dependent cell‐mediated cytotoxicity (ADCC). In a randomized clinical trial 
comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia, fewer 
adverse events were noted in the zanubrutinib arm. Adverse events > Grade 3 occurred in 58.4% of 
patients in the zanubrutinib arm and 63.3% of patients in the ibrutinib arm of the study. Four 
percent of zanubrutinib-treated patients discontinued therapy because of adverse events, and 1% 
had a Grade 5 event; 9.2% of ibrutinib-treated patients discontinued because of an adverse event, 
and 4.1% had Grade 5 events. For zanubrutinib and ibrutinib, respectively, the rates of all-grade 
atrial fibrillation/flutter were 2% and 15.3%, of minor bleeding were 48.5% and 59.2%, of major 
hemorrhage were 5.9% and 9.2%, and of diarrhea were 20.8% and 31.6%. Neutropenia was more 
common with zanubrutinib (29.7%) than with ibrutinib (13.3%). 
 
10.1.1. Summary of Nonclinical Studies 
 
10.1.1.1. 
Pharmacokinetics  
Pharmacokinetic parameters of zanubrutinib were determined for rats and dogs after intravenous 
(IV) and oral dosing. 
 
The kinetics were linear after oral administration over the dose range of 10, 30, and 100 mg/kg in 
female rats, and 2.5, 7.5, and 25 mg/kg in dogs. The linearity in male rats from 10 to 100 mg/kg 
was not as good, with the dose-normalized AUC at 30 mg/kg slightly higher (1.5 to 2.1-fold) 
than those at 10 mg/kg and 100 mg/kg. There was no significant difference in AUC0-inf of the 7th 
dose over the 1st dose for rats or dogs, suggesting no accumulation of zanubrutinib following 
multiple oral dosing in both rats and dogs. Although exposures in female rats were significantly 
higher than that in male rats (1.7 to 4.9-fold), this difference is not expected to be of clinical 
relevance as gender difference in elimination pathways in rats are much more pronounced 
compared with those in dogs or humans. 
 
Following single dose oral administration at 3 different dose levels in both rats and dogs, the 
bioavailability of zanubrutinib ranged from 9.3% to 41% in rats, and from 45% to 50% in dogs. 
Permeability studies in Caco-2 monolayers suggested a high permeability of zanubrutinib in 
human intestine. Zanubrutinib exhibited high plasma clearance (CL) in rats and medium plasma 
CL in dogs. Steady-state volume of distribution (Vdss) in both rats and dogs were low which is 

 
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typical for neutral/weakly basic compound such as zanubrutinib. Elimination half-life (T1/2) 
ranged from 1.2 to 2.6 hours in rats and 1.4 to 3.9 hours in dogs after single-dose oral 
administration. 
 
10.1.1.2. 
Absorption, Distribution, Metabolism, and Excretion  
The oral bioavailability of zanubrutinib was found to range from 9.3% to 41% in rats and from 
45% to 50% in dogs. Elimination half-lives ranged from 1.2 to 2.6 hours in rats and 1.4 to 
3.9 hours in dogs after oral administration. Clearance was high in rats (52.3 mL/min/kg) and 
moderate in dogs (23.6 mL/min/kg). The steady-state volume of distribution (Vdss) in rats and 
dogs was 1.4 L/kg and 1.7 L/kg, respectively. The kinetics was mostly linear over the dose range 
of 10 to 100 mg/kg in rats, and 2.5 to 25 mg/kg in dogs. There was no accumulation of 
zanubrutinib following multiple oral dosing in both species. Plasma protein binding (PPB) for 
zanubrutinib ranged from 93% to 97% in human, monkey, dog, rat, and mouse plasma. The red 
blood cell (RBC)/plasma ratio result showed that zanubrutinib had a partitioning preference in 
plasma in humans. 
 
Zanubrutinib was considered to be a moderate- to high-turnover compound in human, monkey, 
dog, rat, and mouse liver microsomes, with the lowest clearance rate observed in dog liver 
microsomes. Zanubrutinib was extensively metabolized in rats and humans and drug-related 
materials were excreted primarily in feces. A total of 20 metabolites were identified in humans 
after oral administration of 14C-BGB-3111. The major metabolic pathways in humans involved 
mono-oxidation, di-oxidation, acrylamide hydrolysis, hydrogenation, dehydrogenation, oxidative 
ring opening, N-glucuronidation, cysteine conjugation, O-sulfation, O-glucuronidation 
(following oxidation), and combinations thereof. A cytochrome P450 (CYP) phenotyping study 
using human liver microsomes with selective CYP inhibitors and recombinant CYP enzymes 
suggested that CYP3A was the major CYP isoform responsible for zanubrutinib metabolism. 
 
In the reversible CYP inhibition study, zanubrutinib exhibited IC50 values of 4.03, 5.69, and 
7.80 μM for CYP2C8, CYP2C9 and CYP2C19, respectively, IC50 > 10 μM for CYP2D6 and 
CYP3A, and IC50 > 100 μM for CYP1A2 and 2B6. Based on estimates of R1 values for 
reversible CYP inhibition following FDA guidance, zanubrutinib is predicted to cause clinically 
relevant inhibition of intestinal CYP3A and hepatic CYP2C8. Zanubrutinib is not a timedependent 
CYP inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or 
CYP3A. The human hepatocytes data suggest that zanubrutinib is not an inducer of CYP1A2, 
but zanubrutinib is predicted to cause clinically relevant induction of CYP3A4 and CYP2B6 
based on assessment of R3 values using the FDA’s basic static model of induction.   
 
In vitro drug transporter studies suggest that zanubrutinib is not the substrate of BCRP, 
OATP1B1, OATP1B3, OCT2, OAT1, or OAT3, except for showing marginal substrate potential 
on P-gp. Based on various estimates of the FDA’s ratios for inhibition of drug transporters, 
zanubrutinib is predicted to cause clinically relevant inhibition on the intestinal efflux 
transporters P-gp and BCRP, but not on the hepatic uptake transporters, OATP1B1 and 
OATP1B3, or the renal uptake transporters, OAT1, OAT3, and OCT2. 
 
Following a single oral dose of 30 mg/100 μCi/kg [Carbonyl-14C]zanubrutinib to rats, a total of 
98.08% (up to 168 hours) of the total radioactivity dosed was recovered in the urine and feces, 

 
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with the majority of radioactivity excreted via feces. Less than 0.1% of zanubrutinib parent drug 
was excreted in urine and bile, and less than 2% was excreted in feces in rats. 
 
10.1.1.3. 
Single-Dose Toxicology  
The single-dose toxicology studies were conducted in both rats and dogs. No mortality or severe 
toxicity was noted up to 1000 mg/kg i.e. the maximum tolerated dose (MTD) was > 1000 mg/kg 
in both species. 
 
10.1.1.4. 
Repeat-Dose Toxicology  
Repeat-dose studies have been performed in rats of durations of 28 days, 13 weeks, and 26 weeks.  
Further details of these studies can be found in the IB.  Based on the result of the 28-day study, the 
MTD was 500 mg/kg/day.  Based on the result of the 13-week study, the MTD was 300 mg/kg/day.  
Based on the results of the 26-week study, the No-Observed Adverse Effect Level (NOAEL) was 
300 mg/kg/day.   
 
Repeat-dose studies have also been performed in dogs of durations of 28 days, 13 weeks, and 39 
weeks.  Further details of these studies can be found in the IB.  Based on the result of the 28-day 
study, the MTD was greater than 100 mg/kg/day.  Based on the result of the 13-week study, the 
MTD was greater than 100 mg/kg/day.  Based on the results of the 39-week study, the No-Observed 
Adverse Effect Level (NOAEL) was 100 mg/kg/day.   
 
10.1.1.5. 
Summary of Nonclinical Safety  
The toxicity of zanubrutinib was well-characterized in rats and dogs in up to 6- and 9- month 
repeat-dose studies, respectively. Test article-related clinical pathology changes were slight in 
magnitude, including increased WBCs and decreased RBCs; reversible histopathology changes 
were mainly noted in rats, including pancreas, spleen, prostate gland, cecum, colon, rectum, skin 
(lip and/or nose), and uterus. None of these findings were adverse. 
 
Systemic exposure increased dose-proportionally without accumulation for as long as 6- or 9- 
months in duration in both species. The sex difference in systemic exposure was only noted in 
rats, which is not expected to be of clinical relevance, as it reflects differences in elimination 
pathways in rats for which gender differences are much more pronounced than in dogs and 
humans. 
 
No genotoxic potential was observed in a core battery of genotoxicity studies for zanubrutinib. 
No mutagenic potential was observed for a total of 29 impurities identified to date, following an 
assessment based on ICH M7 guidance. 
 
No treatment related gross lesions or histopathological changes were noted in male or female 
reproductive organs in rats and dogs in up to 6- or 9-month repeat-dose studies; no apparent 
general toxicity was noted in maternal or fetal rats and rabbits, and no teratogenicity was noted, 
with the exception that one 3-chambered heart (0.3%), one 2-chambered heart (0.3%), and five 
3-chambered hearts (1.5%) were noted in rat fetuses at doses of 30, 75, and 150 mg/kg/day, 
respectively. No pre- and post-natal developmental toxicity was noted in the maternal or 
offspring rats, with the exception that an increased incidence (26% to 42%) and severity of 
multiple ophthalmic lesions were noted in the treated animals as compared to the concurrent 

 
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control group (26%). 
 
No abnormal findings or changes in respiratory function or central nervous system function were 
observed in the rat single-dose study, nor were any abnormal findings or changes in 
cardiovascular function observed in the dog single-dose study or in the rat or dog repeat-dose 
studies of up to 6- or 9-months in duration. No QT interval prolongation was noted in the 
cardiovascular function study in conscious dogs nor in the 9-month repeat-dose toxicity studies 
in dogs. 
 
10.1.1.6. 
Efficacy  
Zanubrutinib is a potent, specific, and irreversible BTK inhibitor that was designed to be more 
specific than ibrutinib; similar to ibrutinib, zanubrutinib potently inhibited BTK kinase in 
biochemical assays, with a 50% inhibitory concentration (IC50) of 0.3 nM, and in vitro cellular 
assays also show that zanubrutinib inhibited BTK signaling in MCL cell lines and cellular 
growth of several MCL cell lines. 
 
In vivo studies showed that zanubrutinib induced dose-dependent antitumor effects against REC- 
1 MCL xenografts engrafted either subcutaneously or systemically in mice. Zanubrutinib was 
found to be more effective than ibrutinib in both models. In addition, zanubrutinib demonstrated 
better antitumor activity than ibrutinib in a TMD-8 DLBCL subcutaneous xenograft model. 
 
Zanubrutinib was more selective than ibrutinib for the inhibition of kinase activity of BTK vs. 
EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC. Cellular assays also confirmed 
that zanubrutinib is significantly less active than ibrutinib in inhibiting ITK (10-fold) and EGFR 
(> 6-fold). Zanubrutinib was shown to be at least 10-fold weaker than ibrutinib in inhibiting 
rituximab-induced antibody‐dependent cell‐mediated cytotoxicity (ADCC).   
 
A complete battery of Good Laboratory Practice (GLP)-compliant safety pharmacology studies 
was conducted with zanubrutinib. Zanubrutinib moderately inhibited hERG current in vitro, with 
an IC50 = 9.11 μM; however, no cardiovascular findings, including effects on QT or QTc, were 
observed in telemetry-instrumented conscious dogs at single doses of zanubrutinib up to 100 
mg/kg. In addition, no abnormal changes in electrocardiogram (ECG) or cardiovascular function 
were noted in repeat-dose toxicity studies in dogs at doses up to 100 mg/kg. No abnormal 
findings or changes in respiratory or central nervous system function were observed in single- or 
repeat-dose studies in rat. 
 
10.1.2. Summary of Clinical Studies 
As of 16 September 2018, a total of 5 Phase 1 clinical pharmacology studies have been 
conducted and completed: a food effect study (Study BGB-3111-103); a drug-drug interaction 
(DDI) study with a strong CYP3A inducer and inhibitor (Study BGB-3111-104); an absorption, 
metabolism, and excretion (AME) study (Study BGB-3111-105); a thorough QT (TQT) study 
(Study BGB-3111-106); and a cocktail DDI study to assess the effect of zanubrutinib on the PK 
of substrates of CYP3A (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), P-gp 
(digoxin), BCRP (rosuvastatin) (BGB-3111-108). An additional Phase 1 clinical 
pharmacology study (BGB-3111-107: a safety, tolerability, and pharmacokinetics study of 
zanubrutinib in subjects with varying degrees of hepatic impairment) is ongoing.   

 
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Additionally, 14 clinical studies investigating zanubrutinib in patients are ongoing. 
 
10.1.2.1. 
Pharmacokinetics, Pharmacodynamics, and Product Metabolism in Humans 
Zanubrutinib is rapidly absorbed and eliminated after oral administration in human subjects. The 
mean t1/2 was between 2 to 4 hours, and peak concentrations occurred around 2 hours postdose. 
The Cmax and the drug exposure (the AUC) increased in a nearly dose proportional manner from 
40 mg to 320 mg, both after the single-dose and repeat-dose administrations. 
 
Human absorption, metabolism, and excretion (AME) study indicated that zanubrutinib was 
primarily eliminated by hepatic metabolism and fecal excretion. An approximately 87.1% of the 
radiolabeled dose was excreted in feces with only 0.4% of the dose excreted in urine as parent 
drug, zanubrutinib. 
 
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 multipledosing, 
these results are also applicable for steady-state conditions. 
 
Coadministration of zanubrutinib with strong CYP3A inducer rifampin (600 mg once daily for 8 
days) decreased exposure of zanubrutinib by 13.5-fold for AUC0-∞, and 12.6-fold for Cmax, in 
healthy subjects. Coadministration of zanubrutinib with strong CYP3A inhibitor itraconazole 
(200 mg once daily for 4 days) increased exposure of zanubrutinib by 3.8-fold for AUC0-∞, and 
2.6-fold for Cmax. These results are consistent with the role for CYP3A isoenzymes as the 
principal metabolic pathway for zanubrutinib. Coadministration with food or PPI/other ARA did 
not appear to significantly impact the PK of zanubrutinib. 
 
Zanubrutinib has no effect on CYP2C9 enzyme and BCRP activity. Zanubrutinib is a mild 
CYP3A4 and CYP2C19 inducer per FDA guidelines). AUC0-t and Cmax values were 
approximately 47% and 30% lower, respectively, when midazolam was coadministered with 
zanubrutinib. AUC0-t and Cmax values were approximately 36% and 20% lower, respectively, 
when omeprazole was coadministered with zanubrutinib. 
 
10.1.2.2. 
Safety 
Zanabrutinib has been evaluated in 18 clinical pharmacology studies. These studies included 
healthy subjects and subjects with B cell malignancies. 
 
10.1.2.3.1. Study BGB-3111-103 
Overall, 40 treatment-emergent adverse events (TEAEs) were reported for 14 (77.8%) of the 18 
subjects. In the HF-fed state, 15 TEAEs were reported for 8/15 (53.3%) subjects, 12 TEAEs 
(6/16 [37.5%] subjects) in the LF-fed state, and 13 TEAEs (8/15 [53.3%] subjects) in the fasted 
state. 
 
No deaths or SAEs were reported. Three (16.7%) subjects had TEAEs that led to discontinuation 
of study. The TEAE of ECG QT prolonged led to discontinuation in 2 patients (both assessed by 
the investigator as not related to study drug), and the TEAE of pyelonephritis led to 

 
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discontinuation in 1 patient (assessed by the investigator as severe in intensity and related to 
study drug). 
 
There were 14 drug-related TEAEs reported for 10 (55.6%) subjects. 
 
In the fasted state, a severe TEAE (pyelonephritis) was reported for 1 (6.7%) subject. 
 
The most frequently reported TEAEs by Preferred Term (PT) (≥ 10% of subjects overall) were 
headache (4 [22.2%] subjects), lymphadenopathy (3 [16.7%] subjects), pharyngitis, catheter site 
pain, ECG QT prolonged, contusion, skin abrasion, and rhinorrhoea (2 [11.1%] subjects each). 
 
No unexpected safety issues were identified during the study. Oral doses of 320 mg zanubrutinib 
were safe and well-tolerated in subjects either with HF-fed, or LF-fed, or fasted state. 
 
10.1.2.3.2. Study BGB-3111-104 
Single doses of 320 mg and 20 mg zanubrutinib administered alone and coadministered with 
600 mg rifampin and 200 mg itraconazole, respectively, were safe and well tolerated in healthy 
subjects in this study. 
 
In both parts, no subject reported a TEAE higher than Grade 2 or an SAE, and no subject 
discontinued due to a TEAE. The majority of TEAEs were considered not related to the study 
drugs, were Grade 1 in severity, and resolved without treatment. 
 
No clinically significant changes or findings were noted in clinical laboratory evaluations, vital 
signs, physical examinations, or body weight in this study. No subject had a QTcF value 
> 450 msec or an increase from baseline in QTcF of > 60 msec during the study. 
 
10.1.2.3.3. Study BGB-3111-105 
A single oral dose of 320 mg of zanubrutinib containing ~200 μCi of [14C]-zanubrutinib was 
well tolerated during the study. 
 
Four (66.7%) subjects reported a total of 13 TEAEs during the study. All of the TEAEs were 
assessed as being mild in severity. Two (33.3%) subjects reported a total of 2 TEAEs that were 
considered to be possibly related to study drug. All of the remaining 11 TEAEs were considered 
to be unlikely related or not related to study drug. 
 
The most frequently reported TEAEs by System Organ Class (SOC) were Gastrointestinal (GI) 
disorders; 4 (66.7%) subjects reported a total of 9 TEAEs in this SOC. These TEAEs were 
assessed as being unlikely related or not related to study drug. The next most frequently reported 
TEAEs by SOC were Nervous system disorders; 2 (33.3%) subjects reported TEAEs of dizziness 
that were assessed by the investigator as being possibly related to study drug. These TEAEs 
resolved on the same day without concomitant medication. All other TEAEs in the study were 
assessed by the investigator as being either unlikely related to study drug or not related to study 
drug. 
 
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SAEs, or severe TEAEs reported and no subjects withdrew from the study because of a TEAE. 
 
10.1.2.3.4. Study BGB-3111-106 
Overall, zanubrutinib 160 mg and 480 mg oral doses were safely administered and well tolerated 
by the subjects in this study. 
 
In Part A of the study, 2 (25.0%) subjects reported a total of 5 TEAEs. In 1 subject receiving 
zanubrutinib 480 mg, individual TEAEs of diarrhoea, proteinuria, thrombocytopenia, and viral 
infection, each of mild or moderate severity, were reported. In 1 subject receiving placebo, a 
TEAE of mild blood creatinine increased was reported. All TEAEs were assessed as related to 
study drug by the investigator. 
 
In Part B of the study, 12 (37.5%) subjects reported a total of 24 TEAEs, distributed across all 
4 treatments (zanubrutinib 160 mg, zanubrutinib 480 mg, placebo, and moxifloxacin 400 mg). 
All TEAEs occurred in single instances. The TEAEs reported by SOC were Gastrointestinal 
disorders (4 subjects, 12.5%) (TEAEs of abdominal pain, diarrhoea, dry mouth, and dyspepsia), 
Metabolism and nutrition disorders (3 subjects, 9.4%) (hyperglycaemia, hypophosphataemia, and 
polydipsia), Musculoskeletal and connective tissue disorders (2 subjects, 6.3%) (back pain, 
musculoskeletal pain, and myalgia), Nervous system disorders (2 subjects, 6.3%) (headache and 
presyncope), Renal and urinary disorders (2 subjects, 6.3%) (dysuria, haematuria, and proteinuria), 
Blood and lymphatic disorders (1 subject, 3.1%, neutropenia), General disorders and administration 
site conditions (1 subject, 3.1%, fatigue), Infections and infestations (1 subject, 3.1%, urinary tract 
infection), Investigations (1 subject, 3.1%, alanine aminotransferase increased and aspartate 
aminotransferase increased), and Skin and subcutaneous tissue disorders (1 subject, 3.1%, 
dermatitis). All TEAEs were mild in intensity except for one TEAE of urinary tract infection 
assessed as moderate in intensity. All TEAEs were assessed as related to study drug by the 
investigator, except for TEAEs of dermatitis and presyncope which were assessed as not related to 
study drug by the investigator. 
 
There were no deaths, other SAEs, or severe TEAEs reported and no subjects withdrew from the 
study because of a TEAE. There were no dose-related AEs observed with the zanubrutinib 480 mg 
dose relative to the 160 mg dose and no individual AE was reported in more than 1 subject. 
 
10.1.2.3.5. Study BGB-3111-107 
Overall, the single 80 mg zanubrutinib dose was safely administered and well tolerated by the 
subjects in this study and all 20 subjects (6 with mild hepatic impairment, 6 with moderate hepatic 
impairment, and 8 healthy control subjects) completed the study. 
 
A total of 2 (10.0%) subjects reported a total of 2 TEAEs. Both events were reported in the Nervous 
system disorders SOC. One (5.0%) subject in the mild hepatic impairment group experienced 
dizziness that was assessed as not related to study drug by the investigator and 1 (5.0%) subject in 
the moderate hepatic impairment group experienced somnolence that was assesses as related to 
study drug by the investigator. There were no deaths or other SAEs reported and no subjects 
withdrew from the study because of a TEAE. 
 

 
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10.1.2.3.6. Study BGB-3111-108 
Seventeen of the 18 (94.4%) subjects were administered zanubrutinib and completed the study; 1 
(5.6%) subject withdrew from the study before receiving zanubrutinib. In general, the 160 mg twice 
daily doses of zanubrutinib were well tolerated during the study. 
 
TEAEs were grouped in 3 ways based on the design of the study. Any TEAEs occurring following 
the administration of any probe drug on Day 1 until the administration of zanubrutinib on Day 7 
were reported as a group. Any TEAEs occurring following the administration of zanubrutinib on 
Day 7 until the administration of warfarin or vitamin K or midazolam on Day 14 were assigned to a 
group (“zanubrutinib only”). Any TEAEs occurring at the administration of warfarin, vitamin K or 
midazolam on Day 14 through the Follow-up visit were assigned to a third group. 
 
A total of 6 (33.3%) subjects reported a total of 9 TEAEs during the study; all of mild (Grade 1) 
severity. Three (16.7%) subjects experienced TEAEs in the probe drugs only group and were 
therefore not related to zanubrutinib. In the zanubrutinib-only group, 2 (11.8%) subjects 
experienced a total of 3 TEAEs; all assessed by the investigator as related to zanubrutinib. In the 
final group (Day 14 through the Follow-up visit), 2 (11.8%) subjects experienced a total of 2 
TEAEs assessed by the investigator as related to zanubrutinib and 1 (5.9%) subject experienced a 
TEAE assessed by the investigator as not related to zanubrutinib. The event counts in this group 
include patients who may also have experienced separate TEAEs in the previous 2 groups. 
 
In the overall study population, the most frequently reported TEAEs by SOC were Nervous system 
disorders and Skin and subcutaneous tissue disorders (2 [11.1%] subjects each). The only TEAE 
reported in more than 1 subject was petechiae (2 subjects [11.1%] in the Day 14 through the 
Follow-up group; both assessed as related to zanubrutinib). Other individual TEAEs included 
abdominal discomfort, diarrhea, and dizziness assessed as related to zanubrutinib; and headache, 
vessel puncture site pain, periorbital hematoma, and pollakiuria assessed as not related to 
zanubrutinib. 
 
There were no deaths or other SAEs, or severe TEAEs reported and no subjects withdrew from 
the study because of a TEAE. 
 
10.1.2.3.7. Study BGB-3111-AU-003 
As of the data cutoff, 358/365 patients (98.1%) had experienced at least 1 TEAE while on study, 
including 122/123 patients (99.2%) with CLL/SLL, 78/78 (100%) with WM, 48/50 (96.0%) with 
MCL, 39/40 (97.5%) with DLBCL, 32/33 (97.0%) with FL, 18/18 (100%) with MZL, 10/12 
(83.3%) with hairy cell leukemia (HCL), and 9/9 (100%) with RT.   
 
As of the data cutoff, 248/365 patients (67.9%) had experienced at least 1 TEAE assessed by the 
investigator as related (related or with missing assessment of the causal relationship) to study 
treatment, including 94/123 patients (76.4%) with CLL/SLL, 56/78 (71.8%) with WM, 33/50 
(66.0%) with MCL, 18/40 (45.0%) with DLBCL, 24/33 (72.7%) with FL, 12/18 (66.7%) with 
MZL, 6/12 (50.0%) with HCL, and 4/9 (44.4%) with RT.   
 
As of the data cutoff, 152/365 patients (41.6%) had experienced an SAE, including 49/123 patients 
(39.8%) with CLL/SLL, 37/78 (47.4%) with WM, 19/50 (38.0%) with MCL, 21/40 (52.5%) with 

 
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DLBCL, 12/33 (36.4%) with FL, 7/18 (38.9%) with MZL, 2/12 (16.7%) with HCL, and 4/9 
(44.4%) with RT. The most common SAEs overall were pneumonia (6.3%), cellulitis (2.5%), and 
pyrexia (2.2%).   
 
Due to the issue with GCP deviations described above, analyses of safety in which the data from 
patients enrolled at Site 003 from Study BGB-3111-AU-003 were excluded. A total of 12 patients 
were enrolled at this site. BeiGene performed analyses of safety and efficacy for the IB Edition 5.0 
showing that a total of 21 SAEs were reported in 9 patients, of which 2 SAEs, febrile neutropenia 
and pleural effusion, were assessed as related to the study drug during the reporting period. All 
other SAEs were assessed as not related. There were no death or fatal reports identified.   
 
As of the data cutoff, 38 patients (10.4%) had discontinued due to an TEAE including 4/123 
patients (3.3%) with CLL/SLL, 8/78 (10.3%) with WM, 11/50 (22.0%) with MCL, 7/40 (17.5%) 
with DLBCL, 3/33 (9.1%) with FL, 1/18 (5.6%) with MZL, 1/12 (8.3%) with HCL, and 3/9 
(33.3%) with RT. The most frequently reported TEAEs leading to discontinuation were pneumonia 
(n = 4; 1.1%) and nausea, acute kidney injury, and pleural effusion (n = 2 each; 0.5%). All other 
TEAEs occurred in single instances.  
 
Nine (2.5%) patients experienced TEAEs leading to treatment discontinuation that were assessed by 
the investigator as related to study treatment. This includes 1 patient in the WM group with a TEAE 
of arthritis bacterial that had no attribution and was therefore conservatively counted as related.   
 
As of the data cutoff, there were 18 patients (4.9% overall) that experienced fatal TEAEs including 
5/78 (6.4%) with WM, 5/50 (10.0%) with MCL, 5/40 (12.5%) with DLBCL, 2/33 (6.1%) with FL, 
and 1/9 (11.1%) with RT. The most frequently reported TEAEs leading to death were pneumonia (n 
= 4; 1.1%) and septic shock (n = 2; 0.5%). All other TEAEs occurred in single instances. 
 
Two (0.5%) patients experienced fatal TEAEs that were assessed by the investigator as related to 
study treatment (1 patient in the FL group with a TEAE of pneumonia and 1 patient in the WM 
group with TEAE of arthritis bacterial that had no attribution and was therefore conservatively 
counted as related). 
 
10.1.2.3.8. Study BGB-3111-1002 
As of the data cutoff, 43/44 patients (97.7%) had experienced at least 1 TEAE on study.   
 
As of the data cutoff, 41/44 (93.2%) of all patients had experienced a TEAE assessed by the 
investigator as related to treatment: 9/9 (100%) with CLL/SLL, 2/2 (100%) with MCL, 2/2 (100%) 
with WM, 23/26 (88.5%) with FL, and 5/5 (100%) with MZL. 
 
As of the data cutoff, 8/44 patients (18.2%) had experienced an SAE. 
 
As of the data cutoff, 2 patients (4.5%) had discontinued due to a TEAE. 
 
As of the data cutoff, there had been one fatal TEAE reported in this study. Patient 102005 in the 
MZL disease group experienced a fatal, related event of toxic epidermal necrolysis. 
 

 
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10.1.2.3.9. Study BGB-3111-GA101-Study_001 
As of the data cutoff, 118/119 patients (99.2%) had experienced at least 1 TEAE on study. 
 
As of the data cutoff, 98/119 patients (82.4%) had experienced at least 1 TEAE assessed by the 
investigator as related to zanubrutinib, including 41/45 patients (91.1%) with CLL/SLL, 15/23 
(65.2%) with DLBCL, 27/36 (75.0%) patients with FL, 5/5 (100%) patients with MCL, 3/3 (100%) 
patients with MZL, and 7/7 (100%) with WM. 
 
As of the data cutoff, 54/119 patients (45.4%) had experienced an SAE. 
 
As of the data cutoff, 9 patients (7.6%) had discontinued either study drug due to an TEAE: 3 
(6.7%) patients with CLL/SLL, 2 (8.7%) patients with DLBCL, 3 (8.3%) patients with FL, and 1 
(14.3%) patient with WM. 
 
As of the data cutoff (16 September 2018), there had been 2 fatal TEAEs reported in the study: 
1 TEAE in an MCL patient (renal impairment) and 1 AE in a CLL/SLL patient (skin squamous 
cell carcinoma metastatic). Neither fatal event was assessed by the investigator as related to 
zanubrutinib. 
 
10.1.2.3.10. 
Study BGB-3111-205 
As of the data cutoff, all 91 patients (100%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 89/91 (97.8%) patients had experienced at least 1 TEAE assessed by the 
investigator as related (probably and possibly related, or with missing assessment of the causal 
relationship) to study treatment. 
 
As of the data cutoff, 28/91 patients (30.8%) had experienced an SAE. 
 
As of the data cutoff, 8 patients (8.8%) had discontinued due to TEAEs. 
 
As of the data cutoff, 3 patients (3.3%) experienced TEAEs that led to death. In 1 patient, 3 fatal 
events had been reported (cardiac failure, lung infection, and respiratory failure). The other 2 
patients experienced events of multiple organ dysfunction syndrome and cardiopulmonary failure, 
respectively. None of these fatal TEAEs were assessed by the investigator as related to study drug. 
 
10.1.2.3.11. 
Study BGB-3111-206 
As of the data cutoff, 83/86 patients (96.5%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 75/86 patients (87.2%) had experienced at least 1 TEAE assessed by the 
investigator as related (related, probably related, possibly related or with missing assessment of the 
causal relationship) to study treatment. 
 
As of the data cutoff, 18/86 patients (20.9%) had experienced an SAE. 
 
As of the data cutoff, 9/86 patients (10.5%) had discontinued due to a TEAE; of which 6 events 
were considered related to study treatment. 

 
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As of the data cutoff, 7 total fatal AEs (8.1%) had been reported in 7 patients. Four events (death 
[no other PT noted], pneumonia, cerebral hemorrhage, and platelet count decreased) were reported 
as related to study drug as assessed by the investigator. This count includes all fatal AEs even those 
considered non-treatment emergent because they occurred after the start of post-treatment 
anticancer therapy. 
 
10.1.2.3.12. 
Study BGB-3111-207 
As of the data cutoff, 36/41 patients (87.8%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 30/41 patients (73.2%) had experienced at least 1 TEAE assessed by the 
investigator as related (definitely, probably, or possibly) to study treatment. 
 
As of the data cutoff, 11/41 patients (26.8%) had experienced an SAE. 
 
As of the data cutoff, 5/41 patients (12.2%) had discontinued due to a TEAE; of which 1 event was 
considered related to study treatment. 
 
As of the data cutoff, 4 fatal events (9.8%) had been reported in 4 patients.  One event (pneumonia) 
was reported as related to study drug as assessed by the investigator. 
 
10.1.2.3.13. 
Study BGB-3111-210 
As of the data cutoff, 42/44 patients (95.5%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 38/44 patients (86.4%) had experienced at least 1 TEAE assessed by the 
investigator as related (definitely, probably, or possibly) to study treatment.  
 
As of the data cutoff, 15/44 patients (34.1%) had experienced an SAE. 
 
As of the data cutoff, 5/44 patients (11.4%) had discontinued due to a TEAE; of which 2 events 
were considered related to study treatment. 
 
As of the data cutoff, a total of 2 fatal events (4.5%) had been reported in this study. Neither event 
(death [no other PT noted] and Waldenstrom's macroglobulinaemia) were reported as related to 
study drug as assessed by the investigator. This count includes all fatal AEs even those considered 
non-treatment emergent because they occurred > 30 days after the last dose of study drug. 
 
10.1.2.3.14. 
Study BGB-3111-212 
As of the data cutoff, 7/11 patients (63.6%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 6/11 patients (54.5%) had experienced at least 1 TEAE assessed by the 
investigator as related to study treatment. 
 
As of the data cutoff, 2/11 patients (18.2%) had experienced an SAE. These serious TEAEs 
consisted of 1 event of pneumonia (assessed as not related to study treatment by the investigator) 
and 1 event of infusion related reaction (assessed as related to study treatment by the investigator). 

 
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As of the data cutoff, no patients had experienced TEAEs that led to treatment discontinuation or 
death. 
 
10.1.2.3.15. 
Study BGB-3111-213 
As of the data cutoff, 27/32 patients (84.4%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 19/32 patients (59.4%) had experienced at least 1 TEAE assessed by the 
investigator as related to study treatment (10/20 [50.0%] patients in the non-GCB DLBCL cohort, 
5/8 [62.5%] patients in the FL cohort, and 4/4 [100%] in the MZL cohort. 
 
As of the data cutoff, 7/32 patients (21.9%) had experienced an SAE. 
 
As of the data cutoff, 4/32 patients (12.5%) had discontinued due to a TEAE; none of the TEAEs 
were considered related to study treatment. 
 
As of the data cutoff, 3 patients (9.4%) had reported in a total of 4 fatal events.  None of the TEAEs 
were reported as related to study drug as assessed by the investigator. 
 
10.1.2.3.16. 
Study BGB-3111-302 
As of the data cutoff, 207/228 patients (90.8%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 163/228 patients (71.5%) taking either zanubrutinib or ibrutinib had 
experienced at least 1 TEAE assessed by the investigator as related to study treatment. 
 
As of the data cutoff, 57/228 patients (25.0%) taking either zanubrutinib or ibrutinib had 
experienced an SAE. 
 
As of the data cutoff, 13 patients (5.7%) taking either zanubrutinib or ibrutinib had discontinued 
due to a TEAE. Nine of these patients (3.9%) had TEAEs leading to treatment discontinuation 
assessed by the investigator as being treatment-related. 
 
As of the data cutoff, 5 (2.2%) fatal TEAEs had been reported in Study BGB-3111-302. One patient 
(0.4%) had a fatal TEAE assessed by the investigator as being treatment-related. 
 
10.1.2.3.17. 
Study BGB-3111-304 
As of the data cutoff, 91/113 patients (80.5%) had experienced at least 1 TEAE while on study. 
 
As of the data cutoff, 68/113 patients (60.2%) had experienced at least 1 TEAE assessed by the 
investigator as related to study treatment. 
 
As of the data cutoff, 22/113 patients (19.5%) had experienced an SAE. 
 
As of the data cutoff, 5/113 patients (4.4%) had discontinued due to a TEAE. One patient (0.9%) 
had a TEAE leading to treatment discontinuation assessed by the investigator as being treatment-
related.  

 
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As of the data cutoff, no fatal events had been reported in Study BGB-3111-304. 
 
10.1.2.3.18. 
Study BGB-3111-A317-Study_001 
As of the data cutoff, 40/43 of patients (93.0%) had experienced at least 1 TEAE on study. 
 
As of the data cutoff, 24/43 (55.8%) of all patients had experienced a TEAE assessed by the 
investigator as related to either study treatment: 4/5 (80.0%) with CLL, 2/2 (100%) with WM, and 
18/36 (50.0%) with NHL. 
 
As of the data cutoff, 30/43 patients (69.8%) had experienced an SAE, including 3/5 patients 
(60.0%) with CLL, 25/36 (69.4%) with NHL, and 2/2 (100%) with WM. 
 
Two subjects with WM who received zanubrutinib in combination with tislelizumab experienced 
serious hemolytic transfusion reaction. These events resulted in hospitalizations and required 
treatment with RBC transfusion and medical therapy, including steroids. 
 
As of the data cutoff, 13 patients (30.2%) had discontinued either study drug due to an TEAE, 
including 3 patients (60.0%) with CLL, 2 patients (100%) with WM, and 8 patients (22.2%) with 
NHL. Four (4) patients (9.3%) had TEAEs leading to treatment discontinuation assessed by the 
investigator as being treatment-related. 
 
As of the data cutoff, 3 patients (7.0%) had reported in a total of 3 fatal events.  None of the TEAEs 
were reported as related to study drug as assessed by the investigator. 
 
10.1.2.3. 
Serious Adverse Events and Serious Adverse Events with a Fatal Outcome 
Of the 44 fatal events (in 40 patients) reported as of 16 September 2018 in the zanubrutinib 
monotherapy studies, 9 fatal events were assessed by the investigator as related to study drug 
(pneumonia [in 3 patients], arthritis bacterial, toxic epidermal necrolysis, death, cerebral 
haemorrhage, platelet count decreased, and 1 event with an unreported term from a blinded 
study).  
 
In the zanubrutinib combination studies (BGB-3111-GA101, BGB-3111-213, and BGB-3111- 
A317-Study_001), 9 fatal events (renal impairment, skin squamous cell carcinoma metastatic, 
dyspnoea, pleural effusion, abdominal pain and completed suicide [same patient], abdominal 
pain, multiple organ dysfunction syndrome, and sepsis), in 8 patients, had been reported as of 
16 September 2018; none of these fatal events were assessed by the investigator as related to 
zanubrutinib or either study treatment (zanubrutinib or tislelizumab in Study 
BGB-3111-A317-Study_001). 
 
10.1.2.4. 
Expected Adverse Events 
A listing of expected adverse drug reactions, defined as adverse events experienced by patients 
receiving zanubrutinib monotherapy that the sponsor considers expected for the purpose of 
determining requirements for expedited reporting, is presented in Table 3. 
 
Table 3 
Expected Adverse Drug Reactions 
 

 
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10.1.2.5. 
Adverse Events Considered Possibly Related to Zanubrutinib 
A listing of AEs experienced by patients that the Sponsor considers possibly related to zanubrutinib 
and will be monitored in ongoing studies, is presented in Table 4. 
 
Table 4 
Adverse Events Considered Possibly Related to Zanubrutinib 
 

 
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10.1.2.6. 
Efficacy 
No information is available regarding efficacy in patients with IgG4-RD at this time.  As 
demonstrated by clinical data obtained to date, zanubrutinib is a highly selective and orally 
bioavailable BTK inhibitor that not only achieves high systemic exposure for complete BTK 
occupancy in the blood and lymph nodes; it also remains highly tolerable, despite its exposure and 
occupancy advantages.  Below is an overview of key efficacy data from treatment of patients with 
B cell malignancies. 
 
Study BGB-3111-206 is an ongoing single-arm, open-label, multicenter ongoing Phase 2 study 
conducted in China in patients with histologically documented mantle cell lymphoma (MCL) who 
have no response or relapse after ≥ 1 but < 5 prior lines of therapy, in which patients were treated 
with zanubrutinib at a dose of 160 mg orally twice a day.  As of the cutoff date of 27 March 2018, 
86 patients with MCL had been enrolled.  The objective response rate was 83.5% (71/85), with a 
complete response rate of 58.8% (50/85) and a partial response rate of 24.7% (21/85). Subgroup 
analysis revealed that the treatment benefit of zanubrutinib was generally consistent across all 

 
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subgroups analyzed. The responses achieved by zanubrutinib treatment appear durable although 
longer follow-up is needed (median DOR and PFS were not reached). 
 
Study BGB-3111-GA101-Study_001 is an ongoing global Phase 1b, open-label, multicenter study 
of the combination of zanubrutinib and obinutuzumab in patients with B-cell malignancies—
specifically, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), 
Waldenström macroglobulinemia (WM), follicular lymphoma (FL), mantle cell lymphoma (MCL), 
marginal zone lymphoma (MZL), and diffuse large B-cell lymphoma (DLBCL).  As of 01 June 
2017, 45 patients with CLL/SLL (20 patients treatment naïve (TN); 25 patients relapsed or 
refractory (R/R)), and 22 patients with R/R FL had been enrolled. Preliminary efficacy 
results for these patients are described below.  Objective response rates (complete response [CR] + 
partial response) were 89%, 92%, and 69% in TN CLL/SLL, R/R CLL/SLL, and R/R FL, 
respectively, with 5 CRs in TN CLL/SLL, 4 CRs in R/R CLL/SLL, and 5 CRs in FL. Four patients 
(1 R/R CLL; 3 FL) experienced disease progression; no instances of disease transformation 
occurred. 
 
Study BGB-3111-AU-003 is an ongoing global FIH, Phase 1, open-label, multiple-dose, dose-
escalation and dose-expansion study of zanubrutinib that was initiated in Australia in August 2014. 
As of the cutoff date of this IB (16 September 2018), 365 patients had been dosed in this clinical 
study. In Part 1, the primary objectives are to determine the safety and tolerability of zanubrutinib 
in patients with B-cell malignancies (CLL/SLL, NHL, and WM) and determine the RP2D and 
regimen of zanubrutinib when given continuously, orally. The secondary objectives are to 
characterize the PK of zanubrutinib after drug administration, determine the extent of BTK 
inhibition in peripheral blood mononuclear cells (PBMCs) after treatment with zanubrutinib, and 
describe the preliminary antitumor activity of zanubrutinib. In Part 2, the primary objective is to 
further assess the safety and tolerability of zanubrutinib administered orally either once or twice 
daily in patients with specified B-cell malignancies, while the secondary objectives are to assess 
the preliminary antitumor activity of zanubrutinib at RP2D(s) in patients with specific B-cell 
malignancies, further characterize the PK profile of zanubrutinib, and determine the extent of 
BTK inhibition in PBMCs after treatment with zanubrutinib.  Based on the safety, tolerability, PK, 
and PD (as measured by BTK occupancy in PBMCs) profiles of zanubrutinib observed in this 
study, the RP2D has been selected as 160 mg twice daily.  As of 24 July 2018, 48 patients with 
mantle cell lymphoma (MCL) had been enrolled.  The objective response rate was 88.9% (40/45), 
with a complete response rate of 26.7% (12/45) and a partial response rate of 62.2% (28/45). The 
overall duration of response was 16.2 months (95% CI 12.6, 28.2). As of the data cut off, 53.3% 
(24/45) of efficacy evaluable MCL patients remained on treatment. The estimated median 
progression-free survival for relapsed or refractory (R/R) patients was 18 months.  As of 24 July 
2018, 77 patients with Waldenström macroglobulinemia (WM) had been enrolled.  The objective 
response rate was 91.8% (67/73), with a major response rate of 82.2% (60/73): very good partial 
response (VGPR) in 41.1% (30/73) and partial response (PR) in 41.1% (30/73).  Median time to 
response was 85 days. Data show an increased depth of response over time. The estimated 
progression-free survival at 12 months was 89%.  In 32 patients with HGB < 10 g/dL at baseline, 
median HGB increased from a median of 8.85 g/dL (6.3 to 9.8) to 13.4 g/dL (7.7 to 17.0). Median 
IgM decreased from a median of 32.7 g/L (5.3 to 91.9) at baseline to 8.2 g/L (0.3 to 57.8).  As of 15 
December 2016, 68 patients with chronic lymphocytic leukemia (CLL) / small lymphocytic 
lymphoma (SLL) had been enrolled.  Of the 54 patients evaluable for response (> 12 weeks follow-

 
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up or discontinuation before 12 weeks), the objective response rate (ORR) was 96% (52/54), with 
partial response in 67% (36/54), partial response with lymphocytosis in 30% (16/54), stable disease 
in 1 R/R patient, and no assessment for 1 R/R patient because of AE. No instances of disease 
progression or Richter transformation were reported. Zanubrutinib is well tolerated and highly 
active in R/R and TN CLL/SLL. With only 7.2 months of median follow-up, only 1 toxicity-related 
discontinuation, and no progressive disease was seen thus far on study.  As of 18 May 2017, 75 
patients with non-Hodgkin lymphoma (NHL) had been enrolled, including 23 diffuse large B-cell 
lymphoma (DLBCL), 31 mantle cell lymphoma (MCL), 14 follicular lymphoma (FL), and 7 
marginal zone lymphoma (MZL) patients.  Of the 62 NHL patients evaluable for response (> 12 
weeks follow-up or discontinuation before 12 weeks), the ORR was 58.1% (36/62) overall, 60.9% 
(28/46) in the aggressive lymphoma (AL) group (DLBCL and MCL), and 50.0% (8/16) in the 
indolent lymphoma (IL) group (FL and MZL). Most responses were partial responses: 45.2% 
(28/62) overall, 45.7% (21/46) in AL, and 43.8% (7/16) in IL. Stable disease was seen in 13/62 
(21.0%) overall. Nine patients progressed by the first response assessment (all DLBCL patients), 
and 4 AL patients discontinued before assessment. 
 
 

 
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11. 
Sample Collection and Safety Data Collection 
 
11.1. Laboratory Samples 
Blood and urine samples will be collected to determine whether subjects meet inclusion/exclusion 
criteria and to monitor subject health.  Routine clinical laboratory tests will be analyzed by the 
Stanford University Hospital central laboratory. 
 
Investigators must document their review of each laboratory safety report. 
 
Tests will be run and confirmed promptly whenever scientifically appropriate. 
 
11.2. Samples for Research 
 
11.2.1. Exploratory Samples (Peripheral Blood Mononuclear Cells and Plasma) 
Blood will be collected at Baseline, Week 12, and Week 24 and processed for peripheral blood 
mononuclear cells (PBMCs) and plasma.  This will be stored for future investigations into how 
specific biomarkers, cytokine levels, and immune cell phenotypes correlate with treatment 
response.  The exploratory samples will be coded with the subject number and stored for up to a 
maximum of 25 years after the last subject visit for the study. 
 
11.3. Other Exploratory Evaluations 
The following have been selected to explore the clinical effects of zanubrutinib in subjects with 
IgG4-RD. 
 
11.3.1. Patient-Reported Outcomes 
All patient-reported outcomes (PROs) should be collected from the subject before other study visit 
assessments, to the extent possible. 
 
11.3.1.1. 
Patient’s Global Assessment of Disease Activity 
This assessment will be taken at selected visits as outlined in the Study Schedule.  The subject will 
be asked to give an overall assessment of their IgG4-RD over the last week. She/he will be asked to 
place a single vertical mark on a 100-mm horizontal visual analog scale (VAS).  The leftmost end 
of the scale is equivalent to “no IgG4-RD symptoms,” whereas the rightmost end of the scale is 
equivalent to “extremely severe IgG4-RD symptoms.” The question will be: “How severe has your 
IgG4-RD been over the past week?  Please place a vertical mark on the line to indicate the severity 
of the disease.” Results are expressed in millimeters measured between the left end of the scale and 
the crossing point of the vertical line, as placed by the subject. Measurements will be verified by the 
sponsor or sponsor’s designee. This applies for all VAS scales used in the trial. 
 
11.3.1.2. 
Patient’s Global Assessment of Fatigue 
The subject will assess his or her fatigue from IgG4-RD at selected visits as outlined in the Study 
Schedule. The subject will be asked to assess his or her current level of fatigue using a VAS as 
described in Section 10.3.1.1. The leftmost end of the scale is equivalent to “no fatigue,” whereas 
the rightmost end of the scale is equivalent to “worst imaginable fatigue.” The question will be: 

 
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“Please indicate how severe your fatigue has been over the past week by placing a vertical mark on 
the line.” 
 
11.3.1.3. 
Patient’s Global Assessment of Ocular Symptoms 
The subject will assess his or her ocular symptoms from IgG4-RD at selected visits as outlined in 
the Study Schedule.  The subject will be asked 3 questions to assess his or her current level of 
ocular symptoms using a VAS as described in Section 11.3.1.1.  The 3 questions will include 1.) 
“Please indicate how severe your current eye dryness from IgG4-RD has been over the past week 
by placing a vertical mark on the line”, 2.) “Please indicate how severe your current eye swelling 
from IgG4-RD has been over the past week by placing a vertical mark on the line”, 3.) “Please 
indicate how severe your current eye pain or pressure from IgG4-RD has been over the past week 
by placing a vertical mark on the line.”  The leftmost end of the scale is equivalent to no eye 
symptoms, whereas the rightmost end of the scale is equivalent to the worst imaginable eye 
symptoms.   
 
11.3.1.4. 
Patient’s Global Assessment of Salivary Symptoms 
The subject will assess his or her salivary symptoms at selected visits as outlined in the Study 
Schedule.  The subject will be asked 2 questions to assess his or her current level of salivary 
symptoms using a VAS as described in Section 11.3.1.1.  The 2 questions will include 1.) “Please 
indicate how severe the dryness of your mouth from IgG4-RD has been over the past week by 
placing a vertical mark on the line”, 2.) “Please indicate how severe your current salivary gland 
swelling from IgG4-RD has been over the past week by placing a vertical mark on the line.”  The 
leftmost end of the scale is equivalent to no salivary symptoms, whereas the rightmost end of the 
scale is equivalent to the worst imaginable salivary symptoms.   
 
11.3.1.5. 
RAND Short Form-36 
This assessment will be taken at selected visits as outlined in the Study Schedule.  The RAND 
Corporation SF-36 is a 36-item, patient-completed measure designed to be a short, multipurpose 
assessment of health in the areas of physical functioning, role-physical, role-emotional, bodily pain, 
vitality, social functioning, mental health, and general health.  The two overarching domains of 
mental well-being and physical well-being are captured by the Physical and Mental Component 
Summary scores, respectively.  The summary scores range from 0 to 100, with higher scores 
indicating better levels of function and/or better health.  Items are answered on Likert scales of 
varying lengths.  The recall period is the preceding 4 weeks. 
 
11.3.1.6. 
FACIT-F 
This assessment will be taken at selected visits as outlined in the Study Schedule.  The FACIT 
measurement system was first developed in 1987 to assess fatigue levels and quality of life in 
patients with chronic illness.  The recall period is 7 days.  There are 13 questions, each worth 0-4 
points.  The overall score is obtained by adding up the points from each question.  Higher overall 
score means less fatigue.  Respondent burden is 5-10 minutes. 
 
11.3.2. Physician Assessments 
 
11.3.2.1. 
Physician’s Global Assessment of Disease 
This assessment will be taken at selected study visits according to the Study Schedule. The 

 
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investigator will give an overall assessment of the subject’s disease activity using a VAS as 
described in Section 10.3.1.1. The leftmost end of the scale is equivalent to “no IgG4-RD activity,” 
whereas the rightmost end of the scale is equivalent to “extremely active IgG4-RD.” The question 
will be: “Please indicate the subject’s current IgG4-RD activity at this visit (independent of the 
subject’s self-assessment) by placing a vertical mark on the line.” 
 
11.3.2.2. 
IgG4-Related Disease Responder Index 
This assessment will be taken at selected study visits according to the Study Schedule.  The IgG4-
RD RI is designed to detect changes in disease activity in each affected organ system in a 
composite scoring system.  At specified visits, the investigator will assess the status by assigning a 
0-3 score after the organ/site listed with: 0 = absence of active disease in that site;  1 = improved but 
persistent activity in that site; 2 = new or recurrent disease activity in that site while off treatment, 
or unchanged from previous visit; 3 = worse or new despite treatment.  Any urgent disease at a site 
or IgG4-RD related damage in the organ-site will be recorded in the IgG4-RD RI form.  Urgent 
disease is defined as IgG4-RD activity within an organ system that requires therapy immediately to 
prevent the development of potentially permanent organ damage.  Damage is defined as the 
occurrence of permanent tissue injury or organ dysfunction that results from active or previously 
active IgG4-RD.  Damage in this context does not refer to treatment-induced injury.  PET/MRI will 
be employed for disease assessment of the salivary and lacrimal glands at Baseline, Week 12, and 
Week 24. 
 
11.3.3. Other Study Procedures 
 
11.3.3.1. 
Positron Emission and Magnetic Resonance Imaging of the Head and Neck 
Imaging of the head and neck will be performed using positron emission magnetic resonance 
imaging at the PET/MRI suite at the Lucas Imaging Center at Stanford University.  The total 
volume of the bilateral lacrimal glands and bilateral salivary glands (submandibular and parotid 
glands) will be calculated. 
 
In addition, MRI of the salivary glands and lacrimal glands in IgG4-RD patients demonstrates 
inhomogeneity of the parenchyma on both T1- and T2-weighted sequences.  The following grading 
system will be used [28]: grade 0, homogeneous intensity distribution, no abnormal fat signals 
detected, normal parotid glands; grade 1, sparse distribution of streaks-like fat signals; grade 2, 
diffusive distributed, honeycomb-like fat signals; grade 3, diffusive patchy fat signal, less than 50% 
of total area of whole parotid glands, nodular appearance of residual glands; grade 4: massive 
homogeneously distributed fat signal on T1-weighted images, more than 50% of whole parotid 
glands, barely see any normal gland structure.  A similar grading system will be used to assess the 
lacrimal glands. 
 
MR sialography [28, 29] will be scored as follows: stage 0 = normal. Stage 1 = punctate, in which 
diffuse, spherical areas of high-signal intensity, 1 mm or less in diameter and uniform in size, are 
distributed evenly throughout the gland. Stage 2 = globular: in this stage of disease, the spherical 
areas of high signal intensity increase to 1 to 2 mm in diameter. Stage 3 = cavity: with further 
disease progression, the areas of high intensity coalesce and enlarge further, more than 2 mm in 
diameter. Stage 4 = destructive, in which there is marked dilation of the main duct with an irregular 
diameter, as well as irregular branching. 

 
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For positron emission tomography (PET) imaging, participants will be injected intravenously (IV) 
with 370 MBq of 18F-Fluorodeoxyglucose (18F-FDG).  Parotid gland, submandibular gland, 
lacrimal gland, and lymph node SUVmax will be assessed using MIM PACS (MIM Software, 
Cleveland OH) [23].  The maximum standard uptake value (SUVmax), metabolic lesion volume 
(MLV), and total lesion glycolysis (TLG) will be measured.  The SUVmax is calculated as (decay-
corrected activity/tissue volume) divided by (injected dose/body weight).  For MLV, a threshold of 
SUVmax 2.5 will be used to define contour margins around FDG target lesions and boundaries will 
be drawn to include all areas of metabolically disease.  TLG is defined as the product of SUVmean 
and MLV.  The metabolic parameters, SUV (max and mean), MLV, and TLG as calculated and 
displayed by the MIM software package will be recorded [23, 30-33].   
 
11.3.3.2. 
Salivary Gland Ultrasonography  
Salivary gland ultrasound reveals characteristic abnormalities in the echo structure of the salivary 
glandular parenchyma and vascularity.  Salivary gland ultrasound will be conducted by the same 
ultrasonographer for all patients using a standard GE Logiq E machine.  OMERACT grey scale 
ultrasound salivary scoring and OMERACT glandular inflammation scores will be used to assess 
structural changes and inflammatory changes respectively [34, 35].  Both scoring systems are 
semiquantitative, ranging from 0-3 assessed for each gland.   Scoring systems will be applied to 
each parotid and submandibular gland at each time point.  The highest score among the salivary 
glands and the total summed scores across all four glands will assessed for both grey scale and 
glandular inflammation. 
 
11.4. Safety Evaluations 
Investigators are responsible for monitoring the safety of subjects who have entered this study and 
for alerting the Protocol Director or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject. 
 
The investigator is responsible for the appropriate medical care of subjects during the study. 
Planned safety assessments and measures are detailed in Section 11.4.3, but additional assessments 
and safety tests may be performed at the investigator’s discretion.  Further follow-up beyond 8 
weeks after the last dose may be implemented as clinically indicated. 
 
The investigator remains responsible for following, through an appropriate health care option, AEs 
that are serious, considered related to study treatment or the study, or that caused the subject to 
discontinue before completing the study. The subject should be followed until the event is resolved 
or explained. Frequency of follow-up evaluation is left to the discretion of the investigator. 
 
In addition to records of observations made at specific times, unexpected signs and symptoms and 
concomitant medications will be recorded in the clinical trial records throughout the study. 
 
11.4.1. Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the definition 
of an AE or SAE as provided in this protocol. In addition, a separate Data Safety Monitoring 
Committee (DSMC) will be formed to monitor the safety (including lack of efficacy) of the study 
on a periodic basis.   

 
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Study site personnel will record the occurrence and nature of each subject’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study. 
 
Cases of pregnancy that occur during maternal or paternal exposures to the investigational product 
should be reported. Data on fetal outcome and breastfeeding are collected for regulatory reporting 
and drug safety evaluation. 
 
After the informed consent is signed, site personnel will record any change in the subject’s 
condition and the occurrence and nature of any AEs. All AEs related to protocol procedures are to 
be reported to the DSMC and Stanford IRB. 
 
Any clinically significant findings from ECGs, laboratory test results, vital sign measurements, 
other procedures, etc, should be reported as AEs to the DMSC and Stanford IRB.  In addition, all 
AEs occurring after the subject receives the first dose of the investigational product must be 
reported as well. 
 
11.4.1.1 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not.  
 
Examples of AEs include the following:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse outcome  
• New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE)  
 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory results, and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the sponsor. In these instances, all patient identifiers will be blinded on the copies of the medical 
records before submission to the sponsor. When a new infection is reported, the site of infection and 
the diagnostic test used to make the diagnosis will be recorded.  
 
If a subject’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly document this and report to the DMSC and Stanford IRB the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment. 
 
11.4.1.2 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0.  

 
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Toxicities that are not specified in the NCI-CTCAE v5.0 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 (eg, 
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. 
 
11.4.1.3 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence of 
each AE or SAE, using best clinical judgement. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the 
AE or SAE to the study drug should be considered and investigated. The investigator should consult 
the IB 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 
assesses causality for every SAE before transmission of the SAE report to the sponsor because the 
causality assessment is one of the criteria used when determining regulatory reporting requirements. 
The investigator may change his/her opinion of causality in light of follow-up information and 
amend the SAE report accordingly.  
 
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 “a reasonable possibility” that the AE may have 
been caused by the study drug (ie, there are facts, evidence, or arguments to suggest possible 
causation). A number of factors should be considered in making this assessment, including the 
following:  
• 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 criteria are met, 
otherwise the event should be assessed as not related:  
• 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 

 
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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 patient’s clinical condition or other 
concomitant AEs).  
 
11.4.1.4 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition.  
 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  
 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent. 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, 
radiographic imaging, 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 patient 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 should be reported to the sponsor according to the SAE instructions 
provided by the sponsor 
 
11.4.2. Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen during the study. The definition of clinically significant is left to the 
judgment of the investigator; in general, these are laboratory test abnormalities that are associated 
with clinical signs or symptoms, require active medical intervention, or lead to dose interruption or 
discontinuation, require close observation, more frequent follow-up assessments, or further 
diagnostic investigation.  
 
Lymphocytosis is considered an expected manifestation of treatment with zanubrutinib and 
therefore may not be an AE; clinical correlates should be present if reporting lymphocytosis as an 
AE. Patients who develop marked and persistent lymphocytosis should have an analysis (ie, flow 
cytometry) to rule out an underlying hematologic malignancy disorder.  
 
For information on procedures for the monitoring and prevention of hepatitis B and hepatitis C see 

 
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Section 8.1.2 and Table 1. 
 
11.4.3. 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).  
 
11.4.4. Serious Adverse Events 
 
11.4.4.1. 
Serious Adverse Event Definitions 
 
An SAE is any untoward medical occurrence that, at any dose:  
• Results in death  
• Is life-threatening  
 
Note: the term “life-threatening” in the definition of “serious” refers to an AE in which the patient 
was at risk of death at the time of the AE. It does not refer to an AE, which hypothetically might 
have caused death, if it was more severe.  
• Requires hospitalization or prolongation of existing hospitalization  
 
Note: In general, hospitalization signifies that the patient was admitted (usually involving at least an 
overnight stay) to the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting.  
• Results in disability/incapacity  
 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle), which may interfere or prevent everyday life functions, but do not 
constitute a substantial disruption.  
• Is a congenital anomaly/birth defect  
• Is considered a significant medical AE by the investigator based on medical judgment (eg, 
may jeopardize the patient or may require medical/surgical intervention to prevent one of 
the outcomes listed above)  
 
The following are NOT considered SAEs:  
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline  
• Hospitalization for social/convenience considerations  
• Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience  
 
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study, necessitating a change in the date or extent of the planned 
surgery. 
 

 
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11.4.4.2. 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information) and meets the definition 
of a serious adverse drug reaction, the specificity or severity of which is not consistent with those 
noted in the IB.  These should be documented and reported to the DSMC and Stanford IRB within 
24 hours. 
 
11.4.4.3. 
Serious Adverse Events Reporting 
 
Study site personnel must alert the DSMC and Stanford IRB of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method (see Table 5). If alerts are 
issued via telephone, they are to be immediately followed with official notification on study-
specific SAE forms. This 24-hour notification requirement refers to the initial SAE information and 
all follow-up SAE information. 
 
Table 5 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
 
 
SAE collection begins after the subject has signed informed consent and has received 
investigational product. If a subject experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will NOT be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure. 
 
SAEs occurring up to and including the subject’s last study visit will be collected, regardless of the 
investigator’s opinion of causation, in the clinical data collection database and the 
pharmacovigilance system at the sponsor. 
 
The investigator does not need to actively monitor subjects for AEs once the trial has ended. 
However, if an investigator becomes aware of an SAE occurring to a subject after the subject’s 
participation in the trial has ended, the investigator should report the SAE to the sponsor, regardless 
of the investigator’s opinion of causation, and the SAEs will be entered in the pharmacovigilance 
system at the sponsor. 
 
11.4.5. Sponsor Investigator Reporting Responsibilities to BeiGene 
 
Investigator Sponsor will report all Serious Adverse Events (as defined in the Protocol) to the 
applicable regulatory authorities and the appropriate ethics committee as required by the Protocol 
and applicable law and/or regulation within the requisite applicable timeframes. Investigator will 
conduct follow-up activities with respect to Adverse Events as required by the Protocol and 

 
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applicable law and/or regulation. Investigator Sponsor will report Serious Adverse Events (as such 
term is defined in the Protocol) requiring expedited reporting to applicable regulatory authorities 
via an CIOMS I report form or MedWatch 3500a report form, as applicable, or other locally 
required form and concurrently provide a copy of such report to BeiGene.  
 
For expedited reports, Investigator Sponsor will send the report to BeiGene no later than seven (7) 
days for initial or follow-up life-threatening and death reports, and fifteen (15) days for all other 
initial or follow-up serious and unexpected suspected adverse reactions (SUSARs), from the time of 
receipt of the SAE by Investigator.  
 
For non-expedited SAE reports (i.e., unrelated to Study Drug or listed/expected event), Investigator 
Sponsor will send a quarterly line listing to BeiGene within 10 days after the start of each quarter 
(e.g., April 10th for Quarter 1 data due each year). 
 
11.4.6. Other Safety Measures 
 
11.4.6.1. 
Physical Examination 
Complete physical examinations and symptom-directed physical examinations will be conducted as 
specified in the Study Schedule and as clinically indicated. A complete physical examination should 
include evaluation of the following regions/systems: 
• General appearance 
• Head, ears, eyes, nose, throat 
• Lymph nodes 
• Cardiovascular 
• Respiratory 
• Abdominal 
• Extremities (tender/swollen joint counts to be documented separately) 
• Neurologic 
 
On visit days where a complete physical examination is not required as detailed in the Study 
Schedule, the investigator may conduct a symptom-directed physical examination as clinically 
indicated. 
 
11.4.6.2. 
Vital Signs 
Blood pressure and heart rate will be measured as specified in the Study Schedule and as clinically 
indicated. 
 
Blood pressure and heart rate should be measured after at least 5 minutes of sitting. 
 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. If the subject feels unable to stand, sitting or supine vital signs should 
be recorded. 
 
Additional vital signs may be measured during each study visit if warranted by the investigator. 
Body temperature will be measured as specified in the Study Schedule and as clinically indicated. 
 

 
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11.4.6.3. 
Body Weight and Height 
Body weight will be recorded as specified in the Study Schedule and as clinically indicated.  Height 
will be measured only at screening, with the subject’s shoes removed. 
 
11.4.6.4. 
Electrocardiograms 
For each subject, a 12-lead ECG will be collected at the Screening, Week 12, and Week 24 visits.  
Subjects should be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection. ECGs may be obtained at additional times, when deemed 
clinically necessary. Collection of additional ECGs at a particular time point is allowed to ensure 
high quality records. All ECGs recorded should be stored at the investigational site. 
 
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the site 
as soon after the time of ECG collection as possible, and ideally while the subject is still present, to 
determine whether the subject meets entry criteria at the relevant visit(s) and for immediate subject 
management, should any clinically relevant findings be identified.  
 
If a clinically significant finding is identified after enrollment, the investigator should determine if 
the subject can continue in the study. The investigator or qualified designee is responsible for 
determining if any change in subject management is needed and must document his/her review of 
the ECG printed at the time of collection. Any clinically significant finding should be reported as an 
AE. 
 
11.4.7. Safety Monitoring 
The investigator will monitor safety data throughout the course of the study. 
 
The investigator will review SAEs within 24 hours and periodically review: 
• Trends in safety data 
• Laboratory test results 
• AEs including injection site reactions, hypersensitivity/allergic reactions, infections, and/or 
cytopenias 
 
SAEs will be reported to the DSMC and Stanford IRB within 24 hours. 
 
11.4.8. Stopping Criteria for Subjects 
Subjects may be removed from the study at any time if it is deemed to be in the patient’s best 
interest by the investigator.  If a patient meets any of the stopping criteria listed below, the patient 
will complete the Early Termination assessments followed by a Safety Follow-up Visit 8 weeks 
later. 
 
Stopping criteria: 
• Development of life-threatening IgG4-related disease manifestations during treatment with 
zanubrutinib 
• Development of a grade 3 TEAE 
• Development of hepatic dysfunction defined as: 
o Aspartate transaminase (AST) >8 times the upper limit of normal 
o Alanine transaminase (ALT) >8 times the upper limit of normal 

 
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o AST or ALT >5 times the upper limit of normal for more than 2 weeks 
o AST or ALT >3 times the upper limit of normal and total bilirubin >2 times the 
upper limit of normal or INR >1.5 times the upper limit of normal 
o AST or ALT >3 times the upper limit of normal with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (>5%) 
o Total bilirubin >5 times the upper limit of normal 
• Development of a serious allergic reaction to zanubrutinib including anaphylaxis 
• Development of human immunodeficiency (HIV)/acquire immune deficiency syndrome 
(AIDS) during the study 
• Development of hepatitis B or hepatitis C infection during the study 
• Development of a new arrhythmia, including atrial fibrillation, during the study 
• Serious bleeding that requires surgical intervention or hospitalization 
• Pregnancy 
• Any medical condition that, in the opinion of the investigator, puts the subject’s life at risk 
by continuing zanubrutinib  
• If the investigator believes discontinuation of zanubrutinib is in the patient’s best interest 
• Violation of the protocol, if the investigator believes it would significantly compromise data 
interpretation or patient safety 
 
11.4.9. Stopping Criteria for the Study 
An independent Data and Safety Monitoring Committee (DSMC) will be formed, consisting of two 
experienced rheumatology clinicians at Stanford University.  The DSMC will audit study-related 
activities to determine whether the study has been conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may 
include review of the following types of documents participating in the study: regulatory binders, 
case report forms, eligibility checklists, and source documents.  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 
The DSMC will convene once 5 subjects have completed Week 12, and all safety data will be 
reviewed.  If the DSMC agrees there are no safety concerns, the study will continue.  The DSMC 
will convene again once all 10 subjects have completed Week 12 to review safety data.  The DSMC 
may recommend the trial be terminated if major safety concerns related to zanubrutinib occur. 
 
11.5. Appropriateness and Consistency of Measurements 
The clinical safety parameters and laboratory measurements in this study are routine elements of 
clinical health assessment and Phase 2 drug development. The efficacy measurements are used both 
in clinical practice and in clinical trials for IgG4-RD. 
 
11.6. Compliance 
Every attempt will be made to select subjects who have the ability to understand and comply with 

 
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instructions. Noncompliant subjects may be discontinued from the study. The time and day of drug 
administration will be recorded. Drug accountability records will be maintained by the study site. 
 
 
 

 
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12. 
Sample Size and Data Analyses 
 
12.1. Determination of Sample Size 
A sample size of 10 was calculated based on practical considerations and enrollment feasibility.  
Based on prior B cell directed therapies, in which 97% of patients responded to rituximab [9] and 
93% responded to XmAb5871 (a humanized anti-CD19 antibody with an Fc engineered for 
increased affinity to FcγRIIb) [10], we anticipate seeing meaningful benefit with only 10 subjects.   
 
12.2. Data Analysis Plans 
 
12.2.1. General Considerations 
The primary endpoint comparing Baseline and Week 24 changes in submandibular and/or lacrimal 
gland size on MRI will be conducted using the Wilcoxon signed-rank test.  The primary analysis set 
for efficacy analyses will be the Full Analysis Set (FAS), which includes all randomized subjects 
who received at least one dose of study drug.  For the secondary endpoints such as change in 
imaging at 12 weeks and change in subjective disease activity metrics the Wilcoxon signed-rank 
test will be used.  Laboratory results will be treated as continuous variables and analyzed with the 
Wilcoxon signed-rank test.  Adverse events and abnormal labs will be counted and described.  With 
regard to missing data, all subjects will have baseline data, or they will not be entered into the 
study.  The study duration is intentionally short, without excessive visits or testing, to minimize 
dropout.  In addition, given the small n, we will remain in close contact with each subject for the 
duration of the study to ensure compliance and completion of the study. 
 
12.2.2. Study Participant Disposition 
All subjects who discontinue from the study will be identified, and the extent of their participation 
in the study will be reported. If known, a reason for their discontinuation will be given. 
 
12.2.3. Study Participant Characteristics 
The subject’s age, sex, weight, body mass index, height, race/subrace, or other demographic 
characteristics will be recorded. 
 
12.2.4. Safety Analyses 
 
12.2.4.1. 
Clinical Evaluation of Safety 
All investigational product and protocol procedure AEs will be listed; if the frequency of events 
allows, safety data will be summarized using descriptive methodology. 
 
The incidence of symptoms for each treatment will be presented by severity and by association with 
investigational product as perceived by the investigator. Symptoms reported to occur before study 
treatment administration will be distinguished from those reported as new or increased in severity 
after study treatment is initiated. Each symptom will be classified by the most suitable term from 
the medical regulatory dictionary. 
 
The number of investigational product-related SAEs will be reported. 
 

 
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12.2.4.2. 
Statistical Evaluation of Safety 
Safety parameters that will be assessed include safety laboratory parameters and vital signs. The 
parameters will be listed and summarized using standard descriptive statistics. Additional analysis 
will be performed if warranted upon review of the data. 
 
12.3. Interim Analyses 
There are no planned interim analyses given the small number of subjects (n = 10) and short 
duration of the study (24 weeks). 
 
 
 

 
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13. 
Data Management Methods 
 
13.1. Data Quality Assurance 
To ensure accurate, complete, and reliable data, the investigators will do the following: 
• Train all study personnel including study coordinators.  This training will give instruction on 
the protocol, the completion of the CRFs, and study procedures. 
• Review and evaluate CRF data to detect errors in data collection. 
 
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ethics review boards with direct access to the 
original source documents. 
 
13.2. Data Capture Systems 
 
13.2.1. Source Data and Case Report Form 
The Protocol Director and team will prepare and maintain adequate and accurate participant case 
histories with observations and data pertinent to the study.  Study specific Case Report Forms 
(CRFs) will document treatment outcomes for data analysis.   Case report forms will be developed 
as paper forms and will be kept in a locked office, only accessible to the research team. 
 
 
 

 
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14. 
Informed Consent, Ethical Review, and Regulatory Considerations 
 
14.1. Informed Consent 
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the trial. 
 
The ICF will be used to explain the potential risks and benefits of study participation to the subject 
in simple terms before the subject is entered into the study, and to document that the subject is 
satisfied with his or her understanding of the potential risks and benefits of participating in the 
study and desires to participate in the study. 
 
The investigator is ultimately responsible for ensuring that informed consent is given by each 
subject before the study is started. This includes obtaining the appropriate signatures and dates on 
the ICF prior to the performance of any protocol procedures and prior to the administration of the 
investigational product. 
 
As used in this protocol, the term “informed consent” includes consent given by subjects. 
 
14.2. Ethical Review 
The protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB.  Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.   
 
14.3. Regulatory Considerations 
This study will be conducted in accordance with: 
• Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• ICH GCP Guideline 
• Applicable laws and regulations 
 
14.3.1. Investigator Information 
Contact information for the investigator and study coordinator will be provided to all subjects. 
 
14.3.2. Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best of 
his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
 
14.3.3. Final Report Signature 
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical study 

 
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report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
 
14.3.4. Data and Safety Monitoring Plan 
An independent Data and Safety Monitoring Committee (DSMC) will be formed, consisting of two 
experienced rheumatology clinicians at Stanford University.  The DSMC will audit study-related 
activities to determine whether the study has been conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may 
include review of the following types of documents participating in the study: regulatory binders, 
case report forms, eligibility checklists, and source documents.  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
 

 
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15. 
Study Schedule 
 
Screening 
Day -35 to 0 
Baseline 
Day 1 
Weeks 2, 
8, 16, 20 
Week 
4 
Week 
12 
Week 
24 
Week 
32 
ET 
Unscheduled 
visit 
Written IC 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE 
X 
 
 
 
 
 
 
X 
 
Limited PE 
 
X 
X 
X 
X 
X 
X 
 
X 
IgG4-RD Responder Index 
 
X 
X 
X 
X 
X 
X 
X 
 
Physician/Patient global 
 
X 
X 
X 
X 
X 
X 
X 
 
Patient VAS symptoms 
 
X 
X 
X 
X 
X 
X 
X 
 
FACIT-F 
 
X 
 
X 
X 
X 
X 
X 
 
RAND Short-Form 36 
 
X 
 
X 
X 
X 
X 
X 
 
Routine clinical labs: 
 
 
 
 
 
 
 
 
 
     Metabolic panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     CBC w/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     Urine pregnancy 
 
X 
X 
X 
X 
X 
X 
X 
X 
     Urinalysis, urine prot/creat 
 
X 
 
X 
X 
X 
 
 
 
IgG4-RD labs: 
 
 
 
 
 
 
 
 
 
     IgG subclasses 
X 
X 
 
X 
X 
X 
X 
X 
 
     B cell phenotyping 
 
X 
 
 
X 
X 
 
 
 
     IgG, IgA, IgM, IgE 
 
X 
 
X 
X 
X 
 
 
 
     C3, C4 
 
X 
 
 
X 
X 
 
 
 
     ESR, CRP 
 
X 
 
X 
X 
X 
 
 
 
Safety labs: 
 
 
 
 
 
 
 
 
 
     Serum pregnancy 
X 
 
 
 
 
 
 
 
 
     HIV-1/2 serology 
X 
 
 
 
 
 
 
 
 
     Hepatitis B serologies 
X 
 
 
 
 
 
 
 
 
     Hepatitis C Ab 
X 
 
 
 
 
 
 
 
 
     QuantiFERON TB 
X 
 
 
 
 
 
 
 
 
Screening tests: 
 
 
 
 
 
 
 
 
 
     EKG 
X 
 
 
 
X 
X 
 
 
 
     Chest x-ray 
X 
 
 
 
 
 
 
 
 
     ANA, RF 
X 
 
 
 
 
 
 
 
 
     Anti-Ro, Anti-La 
X 
 
 
 
 
 
 
 
 
IgG4-RD tests: 
 
 
 
 
 
 
 
 
 
     PET/MRI neck/face 
 
X 
 
 
X 
X 
 
 
 
     Salivary gland ultrasound 
 
X 
 
 
X 
X 
 
 
 
Research labs: 
 
 
 
 
 
 
 
 
 
     Serum and PBMCs 
 
X 
 
 
X 
X 
 
 
 
Review AEs and meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
 
 
X 
 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
 
 

 
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16. 
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Mahajan, V.S., et al., IgG4-related disease. Annu Rev Pathol, 2014. 9: p. 315-47. 
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