Clinical trial NCT03206970
Conditions: Refractory Mantle Cell Lymphoma Relapsed Mantle Cell Lymphoma
Sponsor: BeiGene
Start date: 2017-03-02; Completion date: 2020-09-08
Enrollment: 86 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study was to evaluate the efficacy of zanubrutinib in participants with centrally confirmed relapsed or refractory MCL.

Detailed description:

Arms: arm 1: Zanubrutinib (160 milligrams) administered orally twice daily
Interventions: intervention 1: Zanubrutinib
Intervention descriptions: intervention 1: Administered as specified in the treatment arm.

Protocol documents:
Prot_001.pdf: 
BGB-3111-206 (NCT03206970)
A Single-Arm, Open-Label, Multicenter Phase 2 Study to 
Evaluate Efficacy and Safety of BGB-3111, a Bruton's Tyrosine 
Kinase (BTK) Inhibitor, in Subjects With Refractory or Relapsed 
Mantle Cell Lymphoma (MCL)
Document Type: Study Protocol
Document Date: 06 September 2018




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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
 
 
Page:3 of 104 
 
Version 4.0, 6 September 2018 
PROTOCOL AMENDMENT (VERSION 4.0)  
Protocol BGB-3111-206 is amended primarily for the following reason: 
1. To update tumor assessment schedule 
Throughout are administrative updates, editorial changes, and/or style and formatting revisions made with the 
purpose of improving clarity and consistency throughout the document 
Major changes to the protocol are as follows: 
Synopsis, Section 4.1, Section 7.3 and Table 2: Revise text to clarify that, for patients with avid PET diseases 
at screening, PET and contrast CT should be repeated every 12 weeks for the first 96 weeks, and every 24 weeks 
thereafter until disease progression (PD) or end of study, whichever comes first. For subjects with non-avid PET 
diseases at screening, only contrast CT should be performed every 12 weeks for the first 96 weeks, and every 24 
weeks thereafter until PD or end of study, whichever comes first.  
Page 4




BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
 
 
Page:5 of 104 
 
Version 4.0, 6 September 2018 
2. Men and women, 18-75 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 
0-2.  
4. Measurable disease by computed tomography/magnetic resonance 
imaging (computerized tomography/magnetic resonance imaging 
(MRI). Measurable disease is defined as at least 1 lymph node > 1.5 
cm in longest diameter and measurable in 2 perpendicular 
dimensions.  
5. Received at least one but less than five prior regimens for MCL 
(1 ≤ the number of prior regimens < 5). 
6. Documented failure to achieve any response, [stable disease (SD) or 
progressive disease during treatment] or documented progressive 
disease after response to the most recent treatment regimen. 
7. Neutrophils ≥ 1 × 109/L independent of growth factor support within 
7 days of study entry 
8. Platelets ≥ 75 × 109/L independent of growth factor support or 
transfusion (Platelets ≥ 50 × 109/L with bone marrow involvement) 
within 7 days of study entry 
9. Creatinine clearance of ≥ 30 mL/min (as estimated by the 
Cockcroft-Gault equation or estimated glomerular filtration rate 
[eGFR] from the Modification of Diet in Renal Disease [MDRD]). 
10. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 x ULN. 
11. Total bilirubin ≤ 2 × ULN (unless documented Gilbert’s syndrome). 
12. International normalized ratio (INR) ≤ 1.5 and activated partial 
thromboplastin time (APTT) ≤ 1.5 × ULN. If a factor inhibitor is 
present with prolongation of the INR or APTT, a patient may be 
enrolled after consultation with the medical monitor. 
13. Subjects may be enrolled who relapse at least 6 months after 
autologous stem cell transplant. To be eligible after transplant, 
subjects should have no active related infections.  
14. Females of childbearing potential must agree to use highly effective 
forms of birth control throughout the course of the study and at least 
up to 90 days after last dose of study drug. Highly effective forms of 
birth control include abstinence, hysterectomy, bilateral 
oophorectomy with no menstrual bleeding for 6 months, intrauterine 
contraception, hormonal methods such as contraceptive injection, oral 
contraceptive, etc. Males must have undergone sterilization–
vasectomy, or utilize a barrier method while the female partner 
utilizes the effective forms of birth control noted above.  
15. Life expectancy of > 4 months. 
16. Able to provide written informed consent and can understand and 
comply with the requirements of the study. 
Exclusion criteria:  
1. Current or history of central nervous system (CNS) lymphoma. 
2. Prior exposure to a BTK inhibitor before enrollment. 
3. Prior corticosteroids in excess of prednisone 10 mg/day or its 
equivalent with antineoplastic intent within 7 days of the start of 
study drug. Prior chemotherapy, targeted therapy, or radiation therapy 
Page 6


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
 
 
Page:6 of 104 
 
Version 4.0, 6 September 2018 
within 3 weeks, antineoplastic therapy with Chinese herbal medicine 
or antibody based therapies within 4 weeks of the start of study drug. 
4. Major surgery within 4 weeks of screening. 
5. Toxicity must recover to ≤ Grade 1 from prior chemotherapy (except 
for alopecia, absolute neutrophil count (ANC) and platelet count). 
Please refer to Inclusion Criteria 7 and 8 for ANC and platelet count, 
respectively). 
6. History of other active malignancies within 2 years of study entry, 
with exception of (1) adequately treated in-situ carcinoma of cervix; 
(2) localized basal cell or squamous cell carcinoma of skin; (3) 
previous malignancy controlled and treated locally (surgery or other 
modality) with curative intent. 
7. Currently clinically significant active cardiovascular disease such as 
uncontrolled arrhythmia, uncontrolled hypertension, congestive heart 
failure, any Class 3 or 4 cardiac disease as defined by the New York 
Heart Association (NYHA) Functional Classification (Appendix 7), 
or history of myocardial infarction within 6 months of screening. 
Echocardiogram (ECHO) must demonstrate left ventricular ejection 
fraction (LVEF) less than 50% (AHA, 2016). 
8. QTcF > 450 msecs or other significant ECG abnormalities including 
second degree atrioventricular (AV) block Type II, or third degree 
AV block.  
9. Unable to swallow capsules or disease significantly affecting 
gastrointestinal function such as malabsorption syndrome, resection 
of the stomach or small bowel, symptomatic inflammatory bowel 
disease, or partial or complete bowel obstruction. 
10. Active infection including infections requiring oral or intravenous 
antimicrobial therapy. 
11. Known infection with human immunodeficiency virus (HIV) or 
serologic status reflecting active hepatitis B or hepatitis C infection 
(detected positive by polymerase chain reaction [PCR]). 
 
Inclusion 
Exclusion 
HIV 
Antibody (-) 
Antibody(+)  
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) 
and 
HBcAb (+) 
HBV DNA < 1000 IU/mL 
and anti-viral therapy 
during study treatment 
and perform monthly 
monitoring of HBV DNA 
HBsAg(-) 
and 
HBcAb(+)  
HBV DNA ≥ 1000 IU/ml 
HCV 
Antibody (-) 
or 
Antibody (+) 
HCV RNA “Not detected” 
(<15 IU/mL) 
 
Perform monthly 
monitoring of HCV RNA 
Antibody(+) 
HCV RNA Detected 
Abbreviations: HBcAb; hepatitis B core antibody; HBsAb, hepatitis B surface 
antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV; hepatitis 
C virus; HIV, human immunodeficiency virus 
 
12. Pregnant or lactating women. 
13. Any life-threatening illness, medical condition or organ system 
dysfunction which, in the investigator’s opinion, could compromise 
the subject’s safety, or put the study at risk. 
Page 7














BeiGene (Beijing) Co., Ltd 
BGB-3111-206                           CONFIDENTIAL 
Page:13 of 104
 
Version 4.0, 6 September, 2018  
TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ..............................................................................2 
PROTOCOL AMENDMENT (VERSION 4.0) ........................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
1 
INTRODUCTION .......................................................................................................23 
1.1 
Current Status of Mantle Cell Lymphoma Care ..............................................23 
1.2 
BGB-3111 ........................................................................................................24 
1.3 
Non-Clinical Data of BGB-3111 .....................................................................24 
1.4 
BGB-3111 Global Phase 1 Clinical Trial ........................................................25 
1.5 
BGB-3111 Phase 1 Clinical Trial in China......................................................26 
1.6 
Pharmacokinetics and Pharmacodynamics of BGB-3111 ...............................26 
1.7 
Use of BGB-3111 in Mantle Cell Lymphoma .................................................27 
2 
OBJECTIVES ..............................................................................................................28 
2.1 
Primary Objective ............................................................................................28 
2.2 
Secondary Objectives.......................................................................................28 
2.3 
Exploratory Objectives ....................................................................................28 
3 
STUDY ENDPOINTS .................................................................................................28 
3.1 
Primary Endpoint .............................................................................................28 
3.2 
Secondary Endpoints .......................................................................................28 
3.3 
Exploratory Endpoints .....................................................................................29 
3.4 
Rationale for Endpoint Selection .....................................................................29 
4 
STUDY DESIGN.........................................................................................................31 
4.1 
Summary of Study Design ...............................................................................31 
5 
STUDY POPULATION ..............................................................................................34 
5.1 
Inclusion Criteria .............................................................................................34 
5.2 
Exclusion Criteria ............................................................................................35 
6 
STUDY TREATMENT ...............................................................................................37 
6.1 
Study Treatment ...............................................................................................37 
6.2 
Study Treatment Preparation and Dispensation ...............................................37 
6.2.1 
Packaging and Labeling ....................................................................37 
6.2.2 
Handling and Storage ........................................................................37 
6.2.3 
Compliance and Accountability ........................................................37 
6.2.4 
Disposal and Destruction ...................................................................38 
6.3 
Subject Number and Treatment Assignment ...................................................38 
6.3.1 
Subject Number .................................................................................38 
6.3.2 
Treatment Assignment .......................................................................38 
Page 14


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CCI


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:16 of 104
 
Version 4.0, 6 September 2018 
11.2.3 
Informed Consent ..............................................................................83 
11.2.4 
Investigator Reporting Requirements ................................................83 
11.2.5 
Confidentiality ...................................................................................83 
11.2.6 
Case Report Forms ............................................................................84 
11.2.7 
Drug Accountability ..........................................................................84 
11.2.8 
Inspections .........................................................................................85 
11.2.9 
Protocol Adherence ...........................................................................85 
11.3 
Sponsor Responsibilities ..................................................................................85 
11.3.1 
Protocol Modifications ......................................................................85 
11.3.2 
Study Report and Publications ..........................................................85 
11.4 
Study and Study Center Closure ......................................................................86 
11.5 
Records Retention and Study Files ..................................................................87 
11.5.1 
Study Files and Retention of Records ...............................................87 
11.6 
Provision of Study Results and Information to Investigators ..........................88 
11.7 
Information Disclosure and Inventions ............................................................88 
11.8 
Joint Investigator/Sponsor Responsibilities .....................................................89 
11.8.1 
Access to Information for Monitoring ...............................................89 
11.8.2 
Access to Information for Auditing or Inspections ...........................90 
12 
REFERENCES ............................................................................................................91 
13 
APPENDICES .............................................................................................................93 
 
 
 
Page 17


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CCI


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:18 of 104
 
Version 4.0, 6 September 2018 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC 
Activated B-cell 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ARF 
Alternate reading frame 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
ATM 
Ataxia telangiectasia mutated 
ATP 
Adenosine triphosphate 
AUC 
Area under plasma concentration-time curve 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 
hours  
AV 
Atrioventricular 
BCR 
B-cell receptor 
BID 
Twice daily 
BMI1 
B lymphoma Mo-MLV insertion region 1 homolog 
BOR 
Best overall response 
BP 
Blood pressure 
BTK 
Bruton’s tyrosine kinase 
BUN 
Blood urea nitrogen 
CCND1 
Oncogene that encodes cyclin D1 protein 
CDK 
Cyclin D-dependent kinase 
CERT 
Center for Education and Research on Therapeutics 
CFDA 
China Food and Drug Administration 
CHK2 
Checkpoint kinase 2 
CHOP 
Cyclophosphamide, doxorubicin, vincristine, and prednisone 
CI 
Confidence interval 
CL 
Total apparent clearance of the drug from plasma 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
Page 19


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:19 of 104
 
Version 4.0, 6 September 2018 
CMR 
Complete molecular remission 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
CYP3A 
Cytochrome P450, family 3, subfamily A 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epithelial growth factor receptor 
eGRF 
Estimated glomerular filtration rate  
EOT 
End of treatment 
F 
Bioavailability (systemic availability of the administered dose) 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FGR 
Garden-Rasheed feline sarcoma viral (v-fgr) oncogene homolog 
FFPE 
Formalin-fixed, paraffin-embedded 
FL 
Follicular lymphoma 
FRK 
fyn-related kinase 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
HDL 
Hepatitis C virus 
High density lipoprotein 
HDPE 
High density polyethylene 
HER 
Human epidermal growth factor receptor 
Page 20


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:20 of 104
 
Version 4.0, 6 September 2018 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
50% maximum inhibitory concentration 
ICH 
International Conference of Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IND 
Investigational new drug 
INK4a 
Inhibitor of kinase 4a 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITK 
Interleukin-2-inducible T cell kinase 
IV 
intravenous 
IWCLL  
International Workshop on Chronic Lymphocytic Leukemia  
JAK3 
Janus kinase 3 
KM 
Kaplan-Meier 
LCK 
Lymphocyte-specific protein tyrosine kinase 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LVEF 
Left ventricular ejection fraction 
MCL 
Mantle cell lymphoma 
MDRD 
Modification of Diet in Renal Disease 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MIPI 
Mantle Cell Lymphoma International Prognostic Index 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for 
Adverse Events 
NHL 
Non-Hodgkin’s lymphoma 
nM 
nanomolar 
NTI 
Narrow therapeutic index 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
Page 21


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:21 of 104
 
Version 4.0, 6 September 2018 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetics 
PLCβ2 
Phospholipase C-beta-2 
PLT 
Platelet 
PO 
Per os (orally) 
PP 
Per-protocol  
PR 
Partial response 
PT 
Preferred term or prothrombin time 
QD 
Once daily 
QT 
Interval between the beginning of the QRS complex to the end 
of the T wave 
QTcF 
Interval between the beginning of the QRS complex to the end 
of the T wave as corrected by corrected for heart rate using 
Fridericia's method 
RB1 
Retinoblastoma 1 
RBC 
Red blood cell 
R-CHOP 
Rituximab-cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP) 
RNA 
Ribonucleic acid 
R/R 
Relapsed or refractory 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SLL 
Small lymphocytic lymphoma 
SMC 
Safety Monitoring Committee 
SOC 
System organ class 
SOP 
Standard operating procedure 
SYK 
Spleen tyrosine kinase 
TEAE 
Treatment-emergent adverse event 
TEC 
Tyrosine kinase expressed in hepatocellular carcinoma 
TMD8 
A DLBCL cell line 
Page 22


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:22 of 104
 
Version 4.0, 6 September 2018 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WM 
Waldenström’s macroglobulinemia  
WHO-DD 
World Health Organization Drug Dictionary 
Page 23


BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:23 of 104
 
Version 4.0, 6 September 2018 
1 
INTRODUCTION 
1.1 
Current Status of Mantle Cell Lymphoma Care 
Mantle cell lymphoma (MCL) is diagnosed in 0.51-0.55/100,000 persons per year in the United 
States (US), making up 6% of all non-Hodgkin’s lymphoma (NHL); while the incidence is slightly 
lower in China. This translates into approximately 4,500 new patients each year, similar to global 
incidence (Smedbya, 2011; Wang, 2015). MCL is a cancer of older persons with a median age at 
diagnosis of approximately 60 years with a male preponderance (Barista, 2001; Smedbya, 2011). 
Patients often present with advanced disease; 70% are diagnosed in stage IV. Most commonly, there 
is generalized lymphadenopathy and organomegaly. Approximately 10-20% of patients present with 
bone marrow involvement, and B symptoms (fever, night sweats, and weight loss) are present in 
approximately 40% of patients. Extra-nodal involvement of the gastrointestinal tract, particularly 
the colon, is relatively common. Central nervous system (CNS) involvement is uncommon 
(Skarbnik, 2015). 
The pathognomonic feature of MCL is over expression of cyclin D1, which is a consequence of 
juxtaposition of the proto-oncogene CCND1 on chromosome 11q13 to the immunoglobulin (Ig) 
heavy chain gene at chromosome 14q32. Cyclin D1 can be confirmed by immunohistochemistry in 
almost 100% of specimens. The molecular consequence of cyclin D1 over-expression is 
deregulation of cell cycle control by overcoming the suppressor effect of the retinoblastoma 1 
(RB1) and the cell cycle inhibitor p27. Frequent companion anomalies include secondary 
chromosomal and molecular alterations targeting proteins that regulate the cell cycle and senescence 
(B lymphoma Mo-MLV insertion region 1 homolog (BMI1), inhibitor of kinase 4a (INK4a), 
alternate reading frame (ARF), cyclin D-dependent kinase (CDK)4, and RB1), and interfere with 
the cellular response to deoxyribonucleic acid (DNA) damage (ataxia telangiectasia mutated 
(ATM), checkpoint kinase 2 (CHK2) and p53) (Rickert, 2013). Concomitantly, β2 microglobulin 
and lactate dehydrogenase (LDH) are increased by 56% and 45%, respectively, of patients; these 
markers should be monitored for disease activity and are also prognostic. 
The Mantle Cell Lymphoma International Prognostic Index (MIPI) composites the parameters of 
the Eastern Cooperative Oncology Group (ECOG) performance status, age, leukocyte count, and 
LDH, and classifies patients into low, intermediate, and high risk groups, with corresponding 
median overall survival time of 6 years, 51 months, and 29 months, respectively (Vose, 2013). The 
histological pattern of MCL is also prognostic, with cyclophosphamide, doxorubicin, vincristine, 
and prednisone (CHOP) complete response (CR) rates for mantle-zone/nodular/diffuse patterns of 
Page 24


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BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
Safety and tolerability: Small molecules TKIs have been known to induce QT prolongation but 
BGB-3111 did not incur any such toxicity in its first 171 subjects enrolled in the Phase 1 study in 
Australia; however, continued vigilance is necessary. Off target inhibition caused impaired platelet 
function and bleeding is another adverse event of special interest. In addition, the hematological 
toxicity with Grade 3/4 neutropenia and infection needs to be documented.  
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BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
4 
STUDY DESIGN 
4.1 
Summary of Study Design 
This is a single-arm, open-label, multi-center Phase 2 study in subjects with histologically 
documented MCL who have no response or relapse after ≥ 1 but < 5 prior treatment regimen(s). The 
study is composed of an initial screening phase (up to 28 days), a single-arm treatment phase, and a 
follow-up phase. Subjects who have not progressed at the time of the final analysis and/or study 
closure, or subjects who had PD but are still benefitting from BGB-3111 treatment in the 
assessment of the investigator, will be considered to participate in the extension study for continued 
treatment upon approval from the sponsor. 
Approximately 80 subjects will be enrolled. The primary efficacy analysis will be conducted at 
mature data of overall response rate, no later than 12 months after the last subject received the first 
dose of study drug, and final analysis will be conducted at mature data of secondary endpoints. For 
the primary efficacy analysis, response will be evaluated by an IRC based on central imaging using 
the 2014 modification of the International Working Group on NHL Criteria (Cheson, 2014) 
(Appendix 3). All subjects should undergo positron emission tomography (PET) and contrast 
computerized tomography (CT) at screening. For patients with avid PET diseases at screening, PET 
and contrast CT should be repeated every 12 weeks for the first 96 weeks, and every 24 weeks 
thereafter until disease progression or end of study, whichever comes first. For subjects with non-
avid PET diseases at screening, only contrast CT should be performed every 12 weeks for the first 
96 weeks, and every 24 weeks thereafter until disease progression or end of study, whichever comes 
first. The PET and contrast CT are required for confirmation of CR for all subjects. Endoscopy is 
mandatory to confirm CR for any subject with a documented history of gastrointestinal 
involvement. Bone marrow biopsy will be required for confirmation of CR in subjects with bone 
marrow tumor involvement prior to study drug. 
All subjects will be followed for adverse events (AEs) for 30 additional days after the last dose of 
study drug. All treatment-related AEs and SAEs will be followed until resolution or stabilization. 
Screening phase: Screening evaluations will be performed within 28 days prior to the first dose of 
study drug. Subjects will sign the informed consent form prior to any screening evaluations. Please 
refer to Table 2 for details on screening procedures. Screening evaluations can be repeated within 
the screening period.  
Treatment phase: Subjects will receive the first dose of BGB-3111 at Cycle 1 Day 1. All subjects 
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BGB-3111-206                          CONFIDENTIAL 
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will be treated with 160 mg, administered orally, twice daily and will continue to be treated until 
disease progression, unacceptable toxicity, death, withdrawal of consent, or the study is terminated 
by the sponsor for final analysis. A treatment cycle consists of 28 days.  
Follow-up phase: Subjects will return 30 ± 7 days after the last dose of study drug for safety 
follow-up visit. Assessments to be performed are presented in Table 2. Radiological assessments 
will continue until documented disease progression. If a subject discontinues study drug due to 
reasons other than PD, radiological assessments will continue until subject exhibits first 
progression, withdrawal of consent, death, lost to follow-up, or study termination by sponsor, 
whichever occurs first.  
Survival phase: Subjects will be followed for survival via phone contact (with subject’s guardian, if 
applicable) every 3 months after the subject’s last visit until withdrawal of consent, lost to 
follow-up, death, or the date of data cutoff for the final analysis. 
 
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BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
Figure 1 
Schema for Study BGB-3111-206 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: EOT, end of treatment; FFPE, formalin-fixed, paraffin-embedded (tumor tissue); MCL, mangle cell lymphoma; PD, 
progressive disease  
 
 
 
BGB-3111 
160 mg PO twice daily  
1 cycle=28 days 
until disease progression (PD) or intolerable toxicity 
Discontinue 
due to PD 
Safety Follow-up visit (30 ± 7 days 
after last dose  
Survival Follow-up every 3 months 
Histologically confirmed MCL, FFPE block or at least 5 
unstained slides must be sent to central pathology lab for 
diagnosis verification of MCL. 
Safety Follow-up visit (30 ± 7 days 
after last dose  
Continue efficacy evaluations 
(tumor assessments) until PD 
Survival Follow-up every 3 months 
Discontinue 
due to reason other than PD 
End of Treatment (EOT) 
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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects may be enrolled in the study only if they meet all of the following criteria: 
1. Diagnostic report has to include evidence for morphological and cyclin D1 and B cell markers 
(eg, CD19, CD20, or PAX5) and CD5 co-expression or t (11; 14). The above results are 
detected by immunohistochemistry, cytogenetics or fluorescence in situ hybridization (FISH). 
After enrollment, tumor tissue (formalin-fixed, paraffin-embedded [FFPE]) block or unstained 
slides must be sent to central laboratory for immunohistochemical analysis to confirm MCL. 
The block or slides must have been obtained from within 2 years before treatment is to be 
started or, if not, must have been first sent to the central laboratory for confirmation of 
appropriateness for use for pathology examination and diagnosis.  
2. Men and women, 18-75 years of age. 
3. ECOG performance status of 0-2.  
4. Measurable disease by CT/magnetic resonance imaging (MRI). Measurable disease is defined as 
at least one lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular 
dimensions.  
5. Received at least one but less than five prior regimens for MCL (1 ≤ the number of prior 
regimens < 5). 
6. Documented failure to achieve any response, [stable disease (SD) or progressive disease during 
treatment] or documented progressive disease after response to the most recent treatment 
regimen. 
7. Neutrophils ≥ 1 × 109/L independent of growth factor support within 7 days of study entry. 
8. Platelets ≥ 75 × 109/L independent of growth factor support or transfusion within 7 days of 
study entry (Platelets ≥ 50 × 109/L with bone marrow involvement). 
9. Creatinine clearance of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or estimated 
glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD]). 
10. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of 
normal (ULN). 
11. Total bilirubin ≤ 2 × ULN (unless documented Gilbert’s syndrome). 
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BGB-3111-206                          CONFIDENTIAL 
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12. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) 
≤ 1.5 × ULN. If a factor inhibitor is present with prolongation of the INR or APTT, a patient 
may be enrolled after consultation with the medical monitor. 
13. Subjects may be enrolled who relapse at least 6 months after autologous stem cell transplant. To 
be eligible after transplant, subjects should have no active related infections. 
14. Females of childbearing potential must agree to use highly effective forms of birth control 
throughout the course of the study and at least up to 90 days after last dose of study drug. Highly 
effective forms of birth control include abstinence, hysterectomy, bilateral oophorectomy with 
no menstrual bleeding for 6 months, intrauterine contraception, hormonal methods such as 
contraceptive injection, oral contraceptive, etc. Males must have undergone sterilization–
vasectomy, or utilize a barrier method while the female partner utilizes the effective forms of 
birth control noted above. 
15. Life expectancy of > 4 months. 
16. Able to provide written informed consent and can understand and comply with the requirements 
of the study. 
5.2 
Exclusion Criteria 
Subjects will not be enrolled in the study for any of the following reasons: 
1. Current or history of CNS lymphoma. 
2. Prior exposure to a BTK inhibitor before enrollment. 
3. Prior corticosteroids in excess of prednisone 10 mg/day or its equivalent with antineoplastic 
intent within 7 days of the start of study drug. Prior chemotherapy, targeted therapy, or radiation 
therapy within 3 weeks, antineoplastic therapy with Chinese herbal medication or 
antibody-based therapies within 4 weeks of the start of study drug. 
4. Major surgery within 4 weeks of screening. 
5. Toxicity must recover to ≤ Grade 1 from prior chemotherapy (except for alopecia, absolute 
neutrophil count (ANC), and platelet count). Please refer to Inclusion Criteria 7 and 8 for ANC 
and platelet count, respectively), 
6. History of other active malignancies within 2 years of study entry, with the exception of 
(1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell 
carcinoma of skin; (3) previous malignancy controlled and treated locally (surgery or other 
modality) with curative intent. 
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BGB-3111-206                          CONFIDENTIAL 
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7. Currently clinically significant active cardiovascular disease such as uncontrolled arrhythmia, 
uncontrolled hypertension, congestive heart failure, any Class 3 or 4 cardiac disease as defined 
by the New York Heart Association (NYHA) Functional Classification (Appendix 7), or history 
of myocardial infarction within 6 months of screening. Echocardiogram (ECHO) must 
demonstrate left ventricular ejection fraction (LVEF) less than 50% (AHA, 2017). 
8. QTcF > 450 msecs or other significant ECG abnormalities including second degree 
atrioventricular (AV) block Type II, or third degree AV block.  
9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as 
malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory 
bowel disease, or partial or complete bowel obstruction. 
10. Active infection including infections requiring oral or intravenous antimicrobial therapy. 
11. Known infection with human immunodeficiency virus (HIV), or serologic status reflecting 
active hepatitis B or hepatitis C infection as follows.  
Inclusion 
Exclusion 
HIV 
Antibody (-) 
Antibody(+)   
HBV 
HBsAg (-) and HBcAb (-) 
HBsAg (+) 
HBsAg (-) 
and 
HBcAb (+) 
HBV DNA < 1000 IU/mL 
and anti-viral therapy 
during study treatment 
and perform monthly 
monitoring of HBV DNA 
HBsAg(-) 
and 
HBcAb (+) 
HBV DNA≥1000 IU/ml 
 
HCV 
Antibody (-) 
or 
Antibody (+) 
HCV RNA “Not detected” 
(<15 IU/mL) 
 
Perform monthly 
monitoring of HCV RNA 
Antibody(+) 
HCV RNA Detected 
Abbreviations: HBcAb; hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; 
HBV, hepatitis B virus; HCV; hepatitis C virus; HIV, human immunodeficiency virus 
12. Pregnant or lactating women. 
13. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, or put the study at risk. 
14. Inability to comply with study procedures. 
15. Requires ongoing treatment with medications that are strong cytochrome P450, family 3, 
subfamily A (CYP3A) inhibitors or strong CYP3A inducers. 
16. Has received allogenic hematopoietic stem cell transplantation prior to enrollment. 
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6 
STUDY TREATMENT 
6.1 
Study Treatment  
Subjects will receive BGB-3111 160 mg (two 80-mg white opaque capsules) orally twice daily. It is 
recommended that the capsules be taken approximately 12 hours apart, ± a 2-hour time window. 
The capsules should be swallowed whole with a glass of water. The capsules should not be chewed, 
but in case of breakage, additional water should be imbibed to rinse out the mouth.  
6.2 
Study Treatment Preparation and Dispensation 
6.2.1 Packaging and Labeling 
The capsules of BGB-3111 will be provided in a child-resistant high density polyethylene (HDPE) 
bottle with induction seal and bottle label. The label will include at least space to enter the subject 
number, name of investigator, content and quantity of BGB-3111, protocol number, batch number, 
directions for usage, storage conditions, and precautions. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
6.2.2 Handling and Storage 
The study drug will be dispatched to a study center only after receipt of the required documents in 
accordance with applicable regulatory requirements and the sponsor’s procedures. 
Study drug must be dispensed or administered according to procedures described herein. Only 
subjects enrolled in the study may receive study drug, in accordance with all applicable regulatory 
requirements. Only authorized study center personnel may supply or administer study drug. All 
study drugs must be stored in a secure area with access limited to the investigator and authorized 
study center personnel and under physical conditions that are consistent with study drug-specific 
requirements. The study drug must be kept at the condition as specified on the labels, or according 
to the current IB. 
6.2.3 Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel at each subject visit and 
information provided by the subject and/or caregiver will be captured in the Drug Accountability 
Form. This information must be captured in the source document at each subject visit. 
The investigator is responsible for study drug accountability, reconciliation, and record 
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maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study center personnel must maintain study drug accountability records throughout the 
course of the study. This person will document the amount of study drug received from the sponsor, 
the amount supplied, and/or administered to and returned by subjects (if applicable). 
6.2.4 Disposal and Destruction 
After completion of the study, all unused BGB-3111 will be inventoried and packaged for return 
shipment by the hospital pharmacist or other designated study center personnel. The inventoried 
supplies will be returned to the sponsor or destroyed on site or depot, after receiving written sponsor 
approval.  
6.3 
Subject Number and Treatment Assignment 
6.3.1 Subject Number 
Subjects will be identified by subject number. Each subject enrolled in this study will receive a 
unique subject number which will be assigned when the subject is screened or enrolled in the study. 
Subject will be assigned in chronological order starting with the lowest number. Once a subject 
number has been assigned to a subject, it cannot be reassigned to any other subject. Subject can be 
re-screened if the subject did not previously meet the inclusion and exclusion criteria. Re-screening 
is defined as repeating the screening procedures or tests within the original screening window. A 
new informed consent is not required and subject shall maintain the same subject number as 
originally assigned. 
6.3.2 Treatment Assignment 
All subjects in the study will receive BGB-3111. 
6.3.3 Treatment Blinding 
This is an open-label study. 
6.4 
Dosage and Administration 
BGB-3111 will be dispensed by the study center personnel on Day 1 of each cycle (every 4 weeks) 
during the first year and Day 1 of every other cycle thereafter (every 8 weeks starting on Cycle 13). 
Subjects will be provided with an adequate supply of study drug for self-administration at home. 
The investigator should instruct the subject to take the study drug exactly as prescribed. Subjects 
will be requested to bring their unused medication including empty packaging to the center at each 
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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
Page:45 of 104
 
Version 4.0, 6 September 2018 
6.7.1 
Discontinuation of Treatment 
Subjects may discontinue study drug for one of the following reasons: 
• Death  
• Disease progression 
• Unmanageable and unacceptable toxicity attributed to BGB-3111 
• Pregnancy 
• Subject misses > 28 consecutive days of dosing. 
• Subject withdrew consent, permitted at any time during the trial. 
All subjects who discontinue study drug will have a safety follow-up visit 30 ± 7 days after the last 
dose of study drug to collect AEs and SAEs that may have occurred after the subject discontinued 
from the treatment. The investigator or his/her designee will also continue to collect information on 
new anticancer therapy given after the last dose of study drug. A laboratory assessment will only be 
performed if the subject had an ongoing laboratory abnormality at the previous visit which the 
investigator considered to be related to study drug. If the subject is unable to return to the clinic and 
no laboratory assessment is necessary, the investigator or his/her designee will contact the subject or 
caregiver to collect this information.  
Subjects who are discontinued from study drug for any reason (ie, AE or administrative reasons 
etc.) other than disease progression should not be considered withdrawn from the study. They will 
continue to be followed for efficacy evaluations per schedule outlined in Table 2 until subject 
exhibits first progression, withdrawal of consent, death, lost to follow-up, or study termination from 
sponsor, whichever occurs first. If subjects refuse to return for these visits or are unable to do so, 
every effort should be made to contact them or obtain information by telephone to determine the 
subject’s disease status and survival.  
6.7.2 
Premature Withdrawal 
Subjects will be withdrawn from the study prematurely for one of the following reasons: 
• Study termination by sponsor 
• Significant protocol deviation 
• Lost to follow up 
If the subject is lost to follow up, investigators should try best to contact with the patient to 
determine the reason for withdrawal. The information should be recorded in the source document 
and eCRF. 
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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
Subjects may voluntarily withdraw from the study (ie, withdraw consent) or withdrawn at the 
discretion of the investigator at any time. Subjects lost to follow up should also be recorded on the 
CRF. For subjects who are lost to follow-up, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the subject, eg, dates of telephone calls, 
registered letters, etc.  
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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
7 
STUDY ASSESSMENTS 
7.1 
Study Flow and Visit Schedule 
The study-specific assessments and procedures are shown in Table 2. Pharmacokinetics and 
specimen collection are shown in Table 3.  
 
 
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BGB-3111-206                          CONFIDENTIAL 
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baseline values, age, ECOG, lactate dehydrogenase (LDH) as quotient to the upper limit of normal, 
and the WBC count per 10-6L, and the percentage of Ki-67 positive cells based on local pathology 
report (Hoster, 2008; Hoster, 2014). If Ki-67 is not available, MCL International Prognostic Index 
(MIPI) will be used.  
MIPI-b score will be calculated according to the following formula: 
MIPI-b score = 0.03535 x age (years) + 0.6978 (if ECOG > 1, otherwise 0) + 1.367 × log10 
(LDH/upper limit of normal) + 0.9393 × log10 (WBC count per 10-6L) + 0.02142 x Ki-67 
(%) 
MIPI score will be calculated according to the following formula if Ki-67 is not available: 
MIPI score = 0.03535 x age (years) + 0.6978 (if ECOG > 1, otherwise 0) + 1.367 × log10 
(LDH/upper limit of normal) + 0.9393 × log10 (WBC count per 10-6L) 
Information will also be collected regarding child-bearing potential and any other assessments that 
are done for the purpose of eligibility for inclusion into the study (physical examination, vital signs, 
hematology and blood chemistry, urinalysis, pregnancy test, and ECG). For further details on 
eligibility assessments, please see Table 2. 
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every 24 weeks ± 1 week thereafter, and complete response should be confirmed by PET scan or an 
integrated PET/CT.  
In subjects with bone marrow tumor involvement prior to study drug, CR should be confirmed by 
bone marrow aspirate/biopsy. In subjects with documented gastrointestinal tumor involvement at 
screening, CR should be confirmed by endoscopy. 
7.3.1 Physical Examination 
Evaluation of disease related B symptoms (unexplained fever of ≥ 38°C; unexplained, recurrent 
drenching night sweats; or unexplained loss of > 10% body weight within the previous 6 months) 
and enlargement of liver and spleen is included in the physical examination at each visit. If the 
physical examination is not completed ± 7 days of the radiological tumor assessment, a separate 
physical examination should be performed.  
7.3.2 Radiological Tumor Assessment 
Baseline radiological tumor assessment should be performed within 30 days prior to the first dose.  
All subjects must have CT scan with contrast of neck, chest, abdomen, and pelvis and any other 
disease sites. CT of the brain is only indicated if clinical findings or symptoms suggest CNS 
involvement.  
For screening, all patients must undergo PET and contrast CT. For subjects with PET avid disease at 
screening, PET and contrast CT have to be repeated every 12 weeks for the first 96 weeks, and 
every 24 weeks thereafter, until PD or end of study, whichever comes first.  For subjects without 
PET avid disease, contrast CT is to be repeated every 12 weeks for the first 96 weeks, and every 24 
weeks thereafter,  until there is PD according to the 2014 modification of the International Working 
Group on Non-NHL Criteria (Appendix 3) (Cheson, 2014). The Investigator can determine further 
subject management after confirmation of disease status by local radiologist. 
A CT scan of diagnostic quality performed as part of PET/CT is acceptable, provided 
bi-dimensional nodal and liver/spleen measurements can be made. An MRI may be used in place of 
CT only for anatomic lesions which cannot be adequately visualized by CT, or for subjects who 
cannot undergo CT. All efforts will be made to ensure that the imaging equipment, contrast agent, 
and person (investigator or radiologist) performing the evaluation is kept constant throughout a 
subject’s course on study.  
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BGB-3111-206                          CONFIDENTIAL 
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All CT scans, MRIs, PET scans, and PET/CT scans obtained during the study will be collected and 
archived. De-identified copies of all scans and radiology reports (including those from screening) 
must be provided to the sponsor or designee (eg, central imaging vendor). 
7.3.3 Bone Marrow Assessment 
A unilateral bone marrow aspirate and biopsy (cytology and immunohistochemistry [IHC]) will be 
performed at screening within 60 days prior to the first dose for all subjects, provided there has been 
no intervening therapy between the time of the biopsy and start of study drug. In those subjects who 
had evidence of bone marrow disease at screening, upon achieving a possible CR (eg, physical 
examination or CT scan indicating a possible CR), a bone marrow aspirate and biopsy should be 
obtained to confirm the CR.  
Testing will be performed at the study center’s local laboratory. De-identified copies of all bone 
marrow biopsy/aspirate results must be provided to the sponsor or designee. 
7.3.4 Endoscopy 
Gastrointestinal endoscopy must be performed to confirm CR for any subject with a documented 
history of gastrointestinal involvement.  
7.3.5 Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled date as 
possible unless it is too close in time to the next scheduled evaluation. An exception is made when 
rescheduling becomes, in the investigator’s opinion, medically unnecessary or unsafe because it is 
too close in time to the next scheduled evaluation. In that case, the missed evaluation should be 
abandoned. 
7.4 
Safety 
Safety assessments should be performed at all visits to the study center and throughout the study. 
The list of events and the time when they will be performed are presented in Table 2. 
7.4.1 Adverse Events 
All AEs and SAEs, regardless of the relationship to the study drug, will be collected from the time 
of start of study drug. All subjects will be followed for safety 30 additional days after the last dose 
of study drug. All treatment-related AEs and SAEs will be followed until resolution or stabilization. 
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The accepted regulatory definition for an AE is provided in Section 9.1.1. In addition, SAEs will be 
reported after informed consent has been signed but prior to the administration of the study drug, 
and, after the 30 days after the last dose of study drug, the investigator should report any SAEs that 
are believed to be related to prior study drug treatment. Important additional requirements for 
reporting SAEs are explained in Section 9.9.  
In this study, lymphocytosis will be defined as a ≥ 50% increase in lymphocyte count over baseline, 
and absolute lymphocytosis of ≥ 5 × 109/L, in addition, at least 1 disease parameter (including 
lymph node size, spleen size, hematological parameters [hemoglobin or platelet count]) shows 
significant concurrent improvement. 
As a result of the known mechanism of action of BTK inhibitors, increase in lymphocyte count after 
using such drugs is predictable, and will occur with high frequency. In this study, asymptomatic 
lymphocytosis will not be recorded or reported as an adverse event (including increase in WBC 
caused by it), and will not impact further therapy with the BTK inhibitor.  
In this study, asymptomatic treatment-related lymphocytosis not be considered an AE.  Patients with 
treatment-related lymphocytosis should remain on study treatment and continue with all study 
related procedures. 
7.4.2 Physical Examination, Vital Signs, Height, and Weight 
A complete or targeted physical examination, vital signs (sitting blood pressure, pulse rate, body 
temperature, and respiratory rate), weight, and B symptoms examination will be performed at each 
study visit. Height (cm) is determined at screening/baseline only. B symptoms include unexplained 
weight loss > 10% over previous 6 months, fever (> 38°C), and/or drenching night sweats. 
A complete physical examination includes assessments of cardiovascular, respiratory, abdominal 
and neurological systems as well as lymph nodes/spleen, skin, oropharynx and extremities. Targeted 
physical examinations should be limited to systems of clinical relevance (ie, cardiovascular, 
respiratory, lymph nodes, liver, and spleen), and those systems associated with clinical 
signs/symptoms. A targeted physical examination will be conducted at all visits except 
screening/baseline, at which a complete physical exam is required.  
If the physical examination is not completed ± 7 days of the radiological tumor assessment, a 
separate physical examination should be performed. 
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7.4.3 ECOG Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed at the Screening Visit, 
each visit during study treatment, and at End of Treatment Visits. Appendix 6 will be used to assess 
performance status.  
7.4.4 Echocardiogram 
Echocardiography is to be performed at screening within 30 days prior to first dose. 
7.4.5 Laboratory Evaluations 
Laboratory assessments should be performed at a local certified laboratory. Clinical chemistry, 
hematology, coagulation, urinalysis, serum β2 microglobulin and serum Ig will be performed at the 
time points specified in Table 2 and may also be performed as medically necessary. On Cycle 1 
Day 1, laboratory assessments should be done before the study drug administration. Screening blood 
and urine tests were performed within 72 hours of the first study drug administration do not need to 
be repeated on Cycle 1 Day 1.  
7.4.5.1 
Hematology 
Hematology includes hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, WBC 
count with differential including neutrophils (including bands), lymphocytes, monocytes, 
eosinophils, and basophils. In the event of neutropenia (absolute neutrophil count < 0.75 × 109/L) or 
thrombocytopenia (platelets < 50 × 109/L), these assessments will be conducted as frequently as the 
investigator feels it necessary and until toxicity resolves to ≤ Grade 2 or baseline. 
7.4.5.2 
Serum Chemistry 
Clinical chemistry includes albumin, alkaline phosphatase, AST, ALT, CO2, blood urea nitrogen 
(BUN) or urea, calcium, chloride, creatinine, fasting glucose, LDH, magnesium, phosphorus 
(optional), potassium, sodium, total bilirubin, total protein, and uric acid. In the event of ≥ Grade 3 
clinical chemistry toxicity, these assessments will be conducted as frequently as the investigator 
feels it necessary and until toxicity resolves to ≤ Grade 2.  
7.4.5.3 
Lipid Panel 
The lipid panel includes cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), 
and triglycerides and will be performed at screening only. 
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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
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Version 4.0, 6 September 2018 
8 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedure (SOP), working practice documents, and applicable regulations and guidelines. 
Site audits will be made periodically by the sponsor’s or the contract research organization (CRO)’s 
qualified compliance auditing team (an independent function from the study team responsible for 
conduct of the study).  
8.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements. As defined by International 
Conference of Harmonisation (ICH) guidelines, the CRF is a printed, optical, or electronic 
document designed to record all of the protocol-required information to be reported to the sponsor 
on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  
Completed, original CRFs are the sole property of BeiGene and should not be made available in any 
form to third parties without written permission from BeiGene, except for authorized representatives 
of BeiGene or appropriate regulatory authorities. 
8.2 
Data Management/Coding 
All software applications used in the collection of data will be properly validated following standard 
computer system validation that is compliant with all regulatory requirements. All data, both CRF 
and external data (eg, laboratory data), will be entered into a clinical system. 
The Data Management Plan defines and documents the procedures necessary to ensure data quality. 
These activities must be followed to ensure that data are properly entered, validated, coded, 
integrated, reconciled, and reviewed. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
Version 18.1 or higher. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). Concomitant diseases/medical history will be coded 
using the MedDRA® Version 18.1 or higher. 
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8.3 
Quality Assurance 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, the sponsor may conduct a quality assurance audit. Regulatory agencies may also 
conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during 
or after completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her 
time and the time of his/her personnel to the auditor/inspector to discuss findings and any relevant 
issues. 
 
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9 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol. During the study, when there is a safety 
evaluation, the investigator or study center personnel will be responsible for detecting AEs and 
SAEs, as detailed in this section of the protocol. 
9.1 
Adverse Events 
9.1.1 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not.  
Examples of an AE include:  
• Significant or unexpected worsening or exacerbation of the condition/indication under study.   
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 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) 
• Significant failure of expected pharmacological or biological action.   
Examples of an AE do not include: 
• Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
9.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-patient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an SAE. 
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These should also 
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be considered serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 
Disease progression should not be reported as an AE/SAE, but symptoms meeting the definition of, 
and associated with, disease progression should be reported. 
9.3 
Lack of Efficacy 
“Lack of efficacy” will not be reported as an AE.  The signs and symptoms or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including 
clarifications). 
9.4 
Laboratory Test Abormaties or Other Abormaties 
Abnormal laboratory findings (eg, clinical chemistry, hematology, coagulation, urinalysis) or other 
abnormal assessments (eg, ECGs, X-rays, vital signs, etc.) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE (as 
defined in Section 9.1) or an SAE (as defined in Section 9.2).  Clinically significant abnormal 
laboratory findings or other abnormal assessments that are detected during the study or are present 
at baseline and significantly worsen following the start of the study will be reported as AEs or 
SAEs.  However, clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with the disease being studied, unless judged by the investigator as more severe 
than expected for the subject’s condition, or that are present or detected at the start of the study and 
do not worsen, will not be reported as AEs or SAEs. 
The investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
9.5 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events 
Subjects will be assessed for AEs and SAEs beginning immediately after signing the informed 
consent form and continuing through to follow-up which is 30 ± 7 days of last dose of investigation 
drug.  The Investigator or designee will ask about AEs by asking the following standard questions: 
• How are you feeling?  
• Have you had any medical problems since your last visit?  
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• Have you taken any new medicines since your last visit?  
All AEs and SAEs will be recorded in the source documents. All AEs and SAEs will be reported in 
the eCRF. 
9.6 
Recording of Adverse Events and Serious Adverse Events 
When a SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., 
hospital progress notes, laboratory, and diagnostics reports) relative to the event. The Investigator 
will then record all relevant information regarding an SAE form. It is not acceptable for the 
Investigator to send photocopies of the subject’s medical records to the Sponsor or designee in lieu 
of completion of the appropriate SAE form. However, there may be instances when copies of 
medical records for certain cases are requested by the Sponsor or designee. In this instance, all 
subject identifiers will be blinded on the copies of the medical records prior to submission to the 
Sponsor or designee. 
Investigator must report all SAE to sponsor or the designee of sponsor with 24 hours after 
awareness of SAE which happened during the trial conduction. Investigator should finish SAE form 
and sign and specify the awareness date on SAE form, and then send it to sponsor or the designee of 
sponsor via fax or Email. 
All AE should be recorded in eCRF. The Investigator will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis 
should be documented as the AE or SAE and not the individual signs/symptoms. Adverse events are 
independent components of the study.   
9.7 
Evaluation of AE and SAE 
9.7.1 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study.  When applicable, AEs and SAEs should be assessed and graded based upon the 
NCI-CTCAE Version 4.03 (NCI, 2010). 
9.7.2 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence of 
each AE or SAE. The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
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risk factors, and the temporal relationship of the event to the study drug will be considered and 
investigated. The investigator will also consult the IB, for marketed products, in the determination 
of his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information to 
include in the initial report to the sponsor. However, it is very important that the investigator always 
makes assessment of causality for every event prior to transmission of the SAE report/eCRF to the 
sponsor. The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE report/eCRF accordingly.  
Investigators must also systematically assess the causal relationship of AEs to study drug (including 
any other non-study drugs, radiation therapy, etc.) using the following definitions:  
• 
Definitely related: There is clear evidence to suggest a causal relationship that there is 
reasonable temporal relationship; the positive of de-challenge result (When necessary the 
positive of re-challenge result); the occurrence of AE that could be attributed to the 
pharmacological effect of study treatment.  
• 
Probably related: This causality assessment will be applied for AE that is regarded by the 
investigator as highly positive related to the study treatment that: There is reasonable temporal 
relationship; the occurrence of AE could not be explained by the subject’s medical history, 
concurrent medical condition, or other the subject’s signs or symptoms; the positive of de-
challenge result; the positive of re-challenge result.  
• 
Possibly related: There is some evidence to suggest a causal relationship (e.g., the AE occurred 
within a reasonable time after administration of the study drug). However, the influence of other 
factors may have contributed to the AE (e.g., the subject’s clinical condition, other concomitant 
AEs).  
• 
Unlikely related: There is little evidence to suggest there is a causal relationship. There is 
another reasonable explanation for the AE.  
• 
Unrelated: An AE will be considered “not related” to the use of the product if any of the 
following tests are met:  
o An unreasonable temporal relationship between administration of the product and the onset 
on the AE (e.g., the AE occurred either before, or too long after administration of the product 
for it to be considered product-related);  
o A causal relationship between the product and the AE is biologically implausible (e.g., death 
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as a passenger in an automobile accident);  
o A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related AE). 
The causality for cases assessed with 5-point scale will be mapped to 2-point scale during aggregate 
safety data analysis according to the BeiGene latest mapping rule. 
9.8 
Follow Up of Adverse Event 
After the initial AE or SAE report, the investigator is required to proactively follow each subject 
and provide further information to the sponsor or designee on the subject’s condition. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the subject is lost to follow-up.  Once resolved, the appropriate AE or 
SAE eCRF page(s) will be updated.  The investigator will ensure that follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the AE or 
SAE.  This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
The sponsor or designee may request that the investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or 
causality of the AE or SAE.  The investigator is obligated to assist.  If a subject dies during 
participation in the study or during a recognized follow-up period, the sponsor will be provided with 
a copy of any post-mortem findings, including histopathology.  
New or updated information will be recorded on the originally completed SAE form, with all 
changes signed and dated by the investigator.  The updated SAE form should be resent to the 
sponsor or designee within the time frames outlined in Section 9.9.  
9.9 
SAE Reporting 
9.9.1 
Time Frames for Submitting Reports of Serious Adverse Events  
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
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All SAEs will be reported promptly to the sponsor or designee as described in Table 6 once the 
investigator determines that the AE meets the protocol definition of an SAE.  
Table 6 
Time Frame for Reporting Serious Adverse Events to the Sponsor or Designee  
Type  
Initial Report  
Document  
Follow-up SAE  
Document  
All SAEs  
Within 24 hours of 
first knowledge of 
the AE  
SAE form  
As expeditiously as 
possible  
Updated SAE  
Abbreviations: AE, adverse event; SAE, serious adverse event 
9.9.2 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE (Section 9.2) has occurred in a subject, he/she will 
report the information to the sponsor within 24 hours as outlined in Section 9.9.1. The SAE report 
form will always be completed as thoroughly as possible with all available details of the SAE, 
signed by the investigator and forwarded to the sponsor within the designated time frames. If the 
investigator does not have all information regarding an SAE, he/she will not wait to receive 
additional information before notifying the sponsor of the SAE and completing the form. The form 
will be updated when additional information is received. The investigator will always provide an 
assessment of causality at the time of the initial report as described in Section 9.7.2  
Facsimile transmission of the SAE report form is the preferred method to transmit this information 
to the project contact for SAE receipt. In rare circumstances and in the absence of facsimile 
equipment, notification by telephone or email is acceptable, with a copy of the SAE report form sent 
by overnight mail. Initial notification via the telephone does not replace the need for the investigator 
to complete and sign the SAE report form within the time frames outlined in Section 9.9.1. The 
sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, and 
mailing addresses.  
9.10 Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 9.2. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. Prompt notification of the appropriate project contact by the investigator for SAE 
receipt is essential so that legal obligations and ethical responsibilities towards the safety of other 
subjects are met.  
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The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  
Expedited investigator safety reports are prepared according to the sponsor’s policy and are 
forwarded to investigators as necessary. The purpose of the report is to fulfill specific regulatory and 
GCP requirements regarding the product under investigation.  
When a study center receives an initial or follow-up report or other safety information (eg, revised 
IB) from the sponsor, the responsible person according to local requirements is required to promptly 
notify his/her IRB or IEC.  
9.11 Post-study Adverse Event  
A post-study AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period, 
defined in Section 9.5. 
Investigators are not obligated to actively seek AEs or SAEs in former subjects. However, if the 
investigator learns of any SAE, including a death, at any time after a subject has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will notify 
the sponsor. 
9.12 Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (eg, procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre-or post-treatment period, will be reported promptly 
to the sponsor or designee (Section 9.9). 
9.13 Pregnancy Reporting  
A subject who has a positive pregnancy test result at any time after the study drug administration 
will be immediately withdrawn from participation in the study.  All post-study assessments will be 
collected at the time of discontinuation as described in Table 2. 
If a female subject or the partner of a male subject becomes pregnant while receiving investigational 
therapy or within 90 days for BGB-3111 after the completion of the last dose of study drug, a 
pregnancy report form should be completed and expeditiously submitted to the sponsor to facilitate 
outcome follow-up.  The investigator, or his/her designee, will record pregnancy information on the 
Page 73


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BeiGene (Beijing) Co., Ltd 
BGB-3111-206                          CONFIDENTIAL 
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10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL 
PLAN 
All statistical analyses will be performed by the sponsor or designee after the study is completed and 
the database is locked and released. Data will be listed and summarized using SAS® Version 9.3 or 
higher (SAS Institute, Inc., Cary, North Carolina) according to sponsor agreed reporting standards, 
where applicable. Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP). 
10.1 Primary, Secondary and Exploratory Study Endpoints 
10.1.1 Primary Endpoint 
The primary endpoint of the study is the rate of objective response, defined as the achievement of 
either a partial response (PR) or CR as assessed by the IRC according to the 2014 modification of 
the International Working Group on NHL Criteria (Cheson, 2014) (Appendix 3) at any time on 
study drug. 
10.1.2 Secondary Endpoints 
Efficacy (using response assessment as determined by IRC): 
• 
Progression-free survival (PFS) as assessed by the IRC in subjects with relapsed or refractory 
MCL after administration of BGB-3111: defined as time from treatment initiation to 
documentation of progression or death due to any cause, whichever happens first 
• TTR as assessed by the IRC in subjects with relapsed or refractory MCL after administration of 
BGB-3111: defined as the time from treatment initiation to the first documentation of response  
• DOR as assessed by the IRC in subjects with relapsed or refractory MCL after administration of 
BGB-3111: defined as the time from the first response documentation to the date that PD is 
documented after treatment initiation 
• ORR as assessed by the investigator: defined as the achievement of either a PR or CR as 
assessed by the Investigator at any time on study drug.  
Safety: 
• The incidence, time and severity of treatment-emergent adverse events according to NCI 
CTCAE v4.03 (NCI, 2010) 
Page 75


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Version 4.0, 6 September 2018 
11 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
11.1 Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2 Investigator Responsibilities 
11.2.1 Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” ICH guidelines, and basic principles of “GCP.” 
Investigators and all sub-investigators must provide documentation of their financial interest or 
arrangements with BeiGene, or proprietary interests in the drug being studied. This documentation 
must be provided before participation of the investigator and any sub-investigator. The investigator 
and sub-investigator agree to notify BeiGene of any change reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date that the last 
subject has completed the protocol defined activities. 
11.2.2 Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP and all applicable regulatory requirements, 
including (where applicable) current version of the Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s informed consent form, and any other information that will be presented to potential 
subjects (eg, advertisements or information that supports or supplements the informed consent) are 
reviewed and approved by the appropriate IEC/IRB. The investigator agrees to allow the IEC/IRB 
direct access to all relevant documents. The IEC/IRB must be constituted in accordance with all 
applicable regulatory requirements. The sponsor will provide the investigator with relevant 
document(s)/data that are needed for IEC/IRB review and approval of the study. Before the study 
drug(s) can be shipped to the study center, the sponsor must receive copies of the IEC/IRB approval, 
the approved informed consent form, and any other information that the IEC/IRB has approved for 
presentation to potential subjects. 
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If the protocol, the informed consent form, or any other information that the IEC/IRB has approved 
for presentation to potential subjects is amended during the study, the investigator is responsible for 
ensuring the IEC/IRB reviews and approves (where applicable) these amended documents. The 
investigator must follow all applicable regulatory requirements pertaining to the use of an amended 
informed consent form including obtaining IEC/IRB approval of the amended form before new 
subjects consent to take part in the study using this version of the form. Copies of the IEC/IRB 
approval of the amended informed consent form/other information and the approved amended 
informed consent form/other information must be forwarded to the sponsor promptly. 
11.2.3 Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and before undertaking any study-related procedures. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent. 
Informed consent will be obtained before the subject can participate in the study. The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
11.2.4 Investigator Reporting Requirements 
As indicated in Section 9.1, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. Furthermore, the 
investigator may be required to provide periodic safety updates on the conduct of the study at 
his/her study center and notification of study closure to the IEC/IRB. Such periodic safety updates 
and notifications are the responsibility of the investigator and not of the sponsor. 
11.2.5 Confidentiality 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (not names) should be recorded on any form or biological sample submitted to 
the sponsor, IRB, or laboratory. The investigator must keep a screening log showing codes, names, 
and addresses for all subjects screened and for all subjects enrolled in the trial. 
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The investigator agrees that all information received from BeiGene, including but not limited to the 
IB, this protocol, CRFs, the investigational new drug, and any other study information, remain the 
sole and exclusive property of BeiGene during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from BeiGene. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
11.2.6 Case Report Forms 
For each subject enrolled, a CRF must be completed and signed by the principal investigator or sub-
investigator within a reasonable time period after data collection. This also applies to records for 
those subjects who fail to complete the study (even during a pre-randomization screening period if a 
CRF was initiated). If a subject withdraws from the study, the reason must be noted on the CRF. If a 
subject is withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
11.2.7 Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused study drug. This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition), subject dispensing records and returned or destroyed study 
product. Dispensing records will document quantities received from BeiGene and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, subject 
initials, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction in order to ensure that it complies with BeiGene requirements. At the end of the 
study, following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet BeiGene’s requirements for disposal, arrangements will be made 
between the site and BeiGene or its representative for destruction or return of unused study drug 
supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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to verify adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them. The monitor should have access to any subject records needed to verify the 
entries on the CRFs. The investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
11.8.2 Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor or its designee immediately. The investigator agrees to 
provide to representatives of a regulatory agency or BeiGene access to records, facilities, and 
personnel for the effective conduct of any inspection or audit. 
 
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Version 4.0, 6 September 2018 
12 
REFERENCES 
American Heart Association. Ejection Fraction Heart Failure Measurement. 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/SymptomsDiagnosisofHeartFailure/Eje
ction-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp#.WG0Iiyz9nIV; May 2017. 
Arizona Center for Education and Research on Therapeutics (CERT) “Drugs That Prolong the QT 
Interval and/or Induce Torsades de Pointes.” Available at: https://www.crediblemeds.org. Accessed 
07 August 2017.  
Barista, I et al.Mantle cell lymphoma.Review.Lancet Oncol 2001; 3:141–48. 
BeiGene Investigator’s Brochure, BGB-3111. Edition 4, February 2017. 
Brookmeyer, B et al. A confidence interval for the median survival time, Biometrics 38(1), p29-41, 
1982. 
Cheson, BD et al. Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol.2014;32:3059–
3068. 
Food and Drug Administration Center for Drug Evaluation Research (CDER) and Center for 
Biologics Evaluation and Research (2007). FDA Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics (2007).  
Food and Drug Administration Center for Drug Evaluation Research (CDER). FDA Guidance for 
Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and 
Labeling Recommendations (2012). 
Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073
153.pdf. October 2005. 
Greenwood, M. The natural duration of cancer. Reports of Public Health and Related Subjects, 
HMSO, London, 33:1-26.1926. 
Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-
stage mantle cell lymphoma. Blood 111:558-565, 2008. 
Hoster E, Klapper W, Hermine O, et al. Conﬁrmation of the Mantle-Cell Lymphoma International 
Prognostic Index in Randomized Trials of the European Mantle-Cell Lymphoma Network. J Clin 
Oncol 2014; 32:1338-1346. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Guideline for Industry: E3 Structure and Content of Clinical Study 
Reports. July 1996. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M073113.pdf. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Guideline for Industry: E14 The Clinical Evaluation Of Qt/Qtc 
Interval Prolongation And Proarrhythmic Potential For Nonantiarrhythmic Drugs. May 2005. 
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https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guid
eline.pdf 
National Cancer Institute. Common Toxicity Criteria Version 4.03. Cancer Therapy Evaluation 
Program. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf; 14 June 2010. 
National Comprehensive Cancer Network (NCCN) Guidelines Version 3. 2016 for Non-Hodgkin’s 
Lymphomas; https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf 
Oken MM, et al. Toxicity and Response Criteria of The Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982; 5:649-655. 
Rickert, RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. 
Nature Review Immunol 2013; 13:578. 
Skarbnik, AP, et al. Mantle Cell Lymphoma: State of the Art. Clin Adv Hematol 
Oncol.2015;13(1):44-55. 
Smedbya, KE, et al. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin 
lymphoma subtypes. Sem in Cancer Biol 2011;21:293-298.  
Smith DD, Goldstein L, et al. Modeling absolute lymphocyte counts after treatment of chronic 
lymphocytic leukemia with ibrutinib. Ann Hematol 2015; 94(2):249-56. 
Stephens, Deborah M et al. Ibrutinib in mantle cell lymphoma patients: glass half full? Evidence 
and opinion. Ther Adv Hematol 2015; 6(5):242–252. 
Tam C, et al. The BTK Inhibitor, BGB-3111, is Safe, Tolerable, and Highly Active in Patients with 
Relapsed/Refractory B-Cell Malignancies: Initial Report of a Phase 1 First-in-Human Trial. 2015 
American Society of Hematology (ASH). 
Vose, JM. Mantle cell lymphoma: 2013 Update on diagnosis, risk-stratification, and clinical 
management. Am. J. Hem.2013:88:1083–1088. 
Wang, XM et al. Clinical analysis of 1629 newly diagnosed malignant lymphomas in current 
residents of Sichuan province, China. Hematol Oncol 2015; 10.1002. 
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13 
APPENDICES 
 
 
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Version 4.0, 6 September 2018 
Appendix 1 Signature of Investigator 
PROTOCOL TITLE: 
A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate 
Efficacy and Safety of BGB-3111, a Bruton’s Tyrosine Kinase (BTK) 
Inhibitor, in Subjects with Relapsed or Refractory Mantle Cell 
Lymphoma (MCL) 
PROTOCOL NO: 
 
BGB-3111-206 
Date and Version of Protocol: 
6 September 2018, Version 4.0 
 
This protocol is a confidential communication of BeiGene (Beijing) Co., Ltd. I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol. I will also work in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and good 
clinical practice and applicable laws and regulations. Acceptance of this document constitutes my 
agreement that no unpublished information contained herein will be published or disclosed without 
prior approval from BeiGene (Beijing) Co., Ltd. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the center in which the study will be conducted. Return the signed copy to sponsor or its authorized 
CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________  Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 
 
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Appendix 2 Medications Which Are Known to Prolong the QT Interval and/or 
Induce Torsades de Pointes to be Avoided 
Antiarrhythmics 
amiodarone 
disopyramide 
dofetilide 
flecainide 
ibutilide 
procainamide 
quinidine 
sotalol 
Anticancer 
arsenic trioxide 
vavdetanib 
Antihistamines 
astemizole 
terfenadine 
Antibiotics 
azithromycin 
clarithromycin 
erythromycin 
moxifloxacin 
sparfloxacin 
Antianginal 
bepridil 
Antimalarial 
chloroquine 
halofantrine 
Antipsychotics 
chlorpromazine 
haloperidol 
mesoridazine 
pimozide 
thioridazine 
Antinausea 
domperidone 
droperidol 
dolasetron (intravenous and oral) 
Anti-infective 
pentamidine 
Antilipemic 
probucol 
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Antidpressants 
citalopram 
Opiate agonists 
levomethadyl 
methadone 
GI stimulant 
cisapride 
Arizona Center for Education and Research on Therapeutics (CERT) “Drugs That Prolong the QT Interval 
and/or Induce Torsades de Pointes.” Available at: https://www.crediblemeds.org. Accessed 21 April 2017. 
 
 
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Appendix 3 Non-Hodgkin's Lymphoma LUGANO Response Criteria 
For assessment of Non-Hodgkin's lymphoma  LUGANO response criteria, positron emission 
tomography [PET] should be performed in cooperation with diagnostic contrast computed 
tomography [CT] simultaneously or in different procedures. The PET-CT should be used for 
response assessment in fluorodeoxyglucose (FDG)-avid histologies (using the 5-point scale 
provided in the footnote of the table below); CT is preferred for low or variable FDG avidity, in 
accordance with 2014 modification of the International Working Group on Non-Hodgkin’s 
Lymphoma Criteria (Cheson, 2014). 
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Appendix 4 Strong CYP3A Inhibitors and Inducers 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, elvitegravir, conivaptan, mibefradil, nefazodone 
Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, St. 
John’s wort (hypericum perforatum) 
Abbreviation: CYP3A, cytochrome P450, family 3, subfamily A. 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of concomitant 
medication to check for CYP3A inhibition or induction risks or contact the Medical Monitor of the protocol. 
 
Food and Drug Administration Center for Drug Evaluation Research (CDER). FDA Guidance for Industry: Drug 
Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations. 2012.  
 
 
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Appendix 5 Medications to be Used with Caution (Sensitive CYP2C8, CYP2C9, 
and CYP2C19 Sensitive Substrates or CYP2C8, CYP2C9, and 
CYP2C19 Substrates With a Narrow Therapeutic Index) 
CYP2C8 Substrates 
CYP2C9 Substrates 
CYPC19 Substrates 
repaglinide1 
celecoxib 
Anti-epileptics: 
paclitaxel 
phenytoin2 
S-mephenytoin1,2  
warafarin2 
 
  
Proton Pump Inhibitors  
 
 
lansoprazole1 
 
omeprazole1 
1 Sensitive substrates: Drugs that exhibit an area under plasma concentration-time curve (AUC) ratio (with and 
without inhibitor - AUCi/AUC) of 5-fold or more when co-administered with a known strong inhibitor. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of strong inhibitors may lead to serious safety concerns (eg, 
Torsades de Pointes). 
Note: The list of drugs in this table is not exhaustive. Please refer to the prescribing information of 
concomitant medication to check for drug interaction information or contact the Medical Monitor of the 
protocol. 
Food and Drug Administration Center for Drug Evaluation Research (CDER). FDA Guidance for Industry: 
Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling 
Recommendations. 2012.   
 
 
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Appendix 6 ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
As published by Oken, 1982. Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
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BGB-3111-206                          CONFIDENTIAL 
Page:104 of 104
 
Version 4.0, 6 September 2018 
Appendix 7 New York Heart Association Classification 
NYHA Class 
Symptoms 
I 
• Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, eg, no shortness of breath when walking, climbing stairs, etc. 
II 
• Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
• Marked limitation in activity due to symptoms, even during 
less-than-ordinary activity, eg, walking short distances (20-100 m). 
Comfortable only at rest. 
IV 
• Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound subjects. 
Abbreviations: NYHA, New York Heart Association. 
 
Page 105

SAP_000.pdf: 
BGB-3111-206 (NCT03206970)
A Single-Arm, Open-Label, Multicenter Phase 2 Study to 
Evaluate Efficacy and Safety of BGB-3111, a Bruton's Tyrosine 
Kinase (BTK) Inhibitor, in Subjects With Refractory or Relapsed 
Mantle Cell Lymphoma (MCL)
Document Type: Statistical Analysis Plan
Document Date: 02 April 2018


BeiGene USA, Inc
     BGB-3111-206
 (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 1 of 29
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
BGB-3111-206
Study Protocol 
Title:
A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate 
Efficacy and Safety of BGB-3111, a Bruton’s Tyrosine Kinase (BTK) 
Inhibitor, in Subjects with Relapsed or Refractory Mantle Cell 
Lymphoma (MCL)
Date:
2-Apr-2018
Version:
2.0
DocuSign Envelope ID: 2021C6C4-F1DD-4847-93BB-7DEADDBFBCF0
Page 2




BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 3 of 29
CONFIDENTIAL
TABLE OF CONTENTS
1 
INTRODUCTION
8 
2 
STUDY OVERVIEW
9 
3 
STUDY OBJECTIVES
11 
3.1 
Primary Objectives
11 
3.2 
Secondary Objectives
11 
3.3 
Exploratory Objectives
11 
4 
STUDY ENDPOINTS
11 
4.1 
Primary Endpoints
11 
4.2 
Secondary Endpoints
11 
4.3 
Exploratory Endpoints
12 
5 
SAMPLE SIZE CONSIDERATIONS
12 
6 
STATISTICAL METHODS
12 
6.1 
Analysis Populations
12 
6.2 
Data Analysis General Considerations
13 
6.2.1 
Definitions and Computations
13 
6.2.2 
Conventions
13 
6.2.3 
Handling of Missing Data
14 
6.2.4 
Adjustment for Covariates
14 
6.2.5 
Multiplicity Adjustment
14 
6.2.6 
Data Integrity
14 
6.3 
Subject Characteristics
14 
6.3.1 
Subject Disposition
14 
6.3.2 
Protocol Deviations
14 
6.3.3 
Demographic and Other Baseline Characteristics
14 
6.3.4 
Disease History and Characteristics
15 
6.3.5 
Prior Anti-Cancer Drug Therapies
15 
6.3.6 
Prior and Concomitant Medications
15 
6.3.7 
Medical History
15 
6.4 
Efficacy Analysis
15 
6.4.1 
Primary Efficacy Endpoint
15 
6.4.2 
Secondary Efficacy Endpoints
16 
6.4.3 
Subgroup Analyses
18 
6.4.4 
Exploratory Efficacy Endpoints
18 
6.5 
Safety Analyses
18 
6.5.1 
Extent of Exposure
18 
6.5.2 
Adverse Events
19 
6.5.3 
Laboratory Values
20 
6.5.4 
Vital Signs
20 
6.5.5 
Electrocardiograms (ECG)
20 
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 5 of 29
CONFIDENTIAL
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AEs
adverse events
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the plasma concentration-time curve
BL
Burkitt’s lymphoma
BOR
best overall response
BP
blood pressure
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CRR
complete response rate
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
SMC
safety monitoring committee
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 6 of 29
CONFIDENTIAL
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference of Harmonization
IEC
Independent Ethics Committee
IHC
immunohistochemistry
INR
international normalized ratio
IRC
Independent Review Committee
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LVEF
left ventricular ejection fraction
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MIPI
Mantle Cell Lymphoma International Prognostic Index
MIPI-b
Combined biologic Mantle Cell Lymphoma International 
Prognostic Index
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for 
Adverse Events
NHL
non-Hodgkin’s lymphoma
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PP
per-protocol population
PR
partial response
PT
preferred term
QT
interval between the beginning of the QRS complex to the end 
of the T wave
RBCs
red blood cells
R/R
relapsed or refractory
SAEs
serious adverse events
SAP
statistical analysis plan
SBP
systolic blood pressure
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 7 of 29
CONFIDENTIAL
SD
stable disease
SOC
system organ class
SOPs
standard operating procedures
SSE
significant safety event
TEAEs
treatment emergent adverse events
TTR
time to response
ULN
upper limit of normal
US
United States
WBCs
white blood cells
WHO-DD
World Health Organization Drug Dictionary
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 8 of 29
CONFIDENTIAL
1
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for the protocol BGB-3111-206
amendment 3.0 dated 25-Oct-2017 titled: A Single-Arm, Open-Label, Multicenter Phase 2 Study 
to Evaluate Efficacy and Safety of BGB-3111, a Bruton’s Tyrosine Kinase (BTK) Inhibitor, in 
Subjects with Relapsed or Refractory Mantle Cell Lymphoma (MCL). The focus of this SAP is 
for the planned primary and final analyses specified in the study protocol.
The SAP version 2.0 is an amendment to the initial version of the SAP (v1.0 dated Dec 7, 2017).
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 9 of 29
CONFIDENTIAL
2
STUDY OVERVIEW
This is a single-arm, open-label, multi-center Phase 2 study in subjects with histologically 
documented and confirmed MCL who have relapsed after ≥1 but <5 prior treatment regimen(s).
The study is composed of an initial screening phase (up to 28 days), a single-arm treatment 
phase, and a follow-up phase.  
Approximately 80 subjects will be enrolled.  The primary efficacy analysis will be conducted at 
mature data of overall response rate, no later than 6 months after the last subject received the first 
dose of study drug, and the final analysis will be conducted at mature data of secondary 
endpoints. For the primary efficacy analysis, response will be evaluated based on an Independent 
Review Committee (IRC) using the 2014 International Working Group in Non-Hodgkin’s 
Lymphoma (NHL) criteria. All subjects should undergo positron emission tomography (PET) 
and contrast computerized tomography (CT) at screening. For patients with avid PET diseases at 
screening, PET and contrast CT should be repeated at Weeks 12, 24, and 48, then every 24 
weeks thereafter, and before confirmation of complete remission. For subjects with non-avid 
PET diseases at screening, only contrast CT should be performed at Week 12 and Week 24. 
Contrast CT will be performed at Weeks 36 and 48 and every 24 weeks thereafter until disease 
progression or end of study, whichever comes first. The PET and contrast CT are required for 
confirmation of CR for all subjects. Endoscopy is mandatory to confirm CR for any subject with 
a documented history of gastrointestinal involvement. Bone marrow biopsy will be required for 
confirmation of CR in subjects with bone marrow tumor involvement prior to study drug.
All subjects will be followed for adverse events (AEs) for 30 additional days after the last dose
of study drug.  All treatment-related AEs and SAEs will be followed until resolution or 
stabilization.
Screening phase:  Screening evaluations will be performed within 28 days prior to the first dose 
of study drug.  Subjects will sign the informed consent form prior to any screening evaluations.  
Screening evaluations can be repeated within the screening period.
Treatment phase: Subjects will receive the first dose of BGB-3111 at Cycle 1 Day 1.  All 
subjects will be treated with 160 mg, administered orally, twice daily and will continue to be 
treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the 
study is terminated by the sponsor for final analysis.  A treatment cycle consists of 28 days.
Follow-up phase:  Subjects will return 30±7 days after the last dose of study drug for safety 
follow-up visit.  Radiological assessments will continue until documented disease progression.  
If a subject discontinues study drug due to reasons other than disease progression, radiological 
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BeiGene USA, Inc
                       BGB-3111-206
              (Statistical Analysis Plan)
Version 2.0: 2-Apr-2018
Page 10 of 29
CONFIDENTIAL
assessments will continue until subject exhibits first progression, withdrawal of consent, death, 
lost to follow-up or study termination by sponsor, whichever occurs first.
Survival phase: Subjects will be followed for survival via phone contact (with subject’s
guardian, if applicable) every 3 months after the subject’s last visit until withdrawal of consent, 
lost to follow-up, death, or the date of data cutoff for the final analysis.
Figure 1: Study Scheme
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6.2.3
Handling of Missing Data
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or 
partially 
missing 
dates 
will 
be 
imputed 
conservatively 
for 
prior/concomitant 
medications/procedures, subsequent anti-cancer therapies, adverse events and deaths. Specific 
rules 
for 
handling 
of 
missing 
or 
partially 
missing 
dates 
for 
prior/concomitant 
medications/procedures, subsequent anti-cancer therapies, adverse events, and deaths are 
provided in Appendix A.
By-visit summary of variables with missing data will use only non-missing data, not imputed 
one, unless otherwise specified. Unscheduled visits will not be included in by-visit summaries.  
6.2.4
Adjustment for Covariates
Not applicable.
6.2.5
Multiplicity Adjustment
Not applicable. 
6.2.6
Data Integrity
Before any pre-specified statistical analysis begins, the integrity of the data should be reviewed 
to assure fit-for-purpose. The data set for analysis should be an accurate and complete 
representation of the subjects' relevant outcomes from the clinical database. All data should be 
complete and reviewed up to a pre-specified cutoff date. Consistency checks and appropriate 
source data verification should be complete.
6.3
SUBJECT CHARACTERISTICS
6.3.1
Subject Disposition
The number (percentage) of subjects treated (i.e. safety population), with centrally confirmed 
pathology (i.e. revised safety population), discontinued from study drugs and discontinued from 
the study will be summarized. The primary reason for end of treatment (study drug 
discontinuation) and end of study will be summarized.  
Survival status (alive, death, or lost to follow-up) at the data cutoff date will be summarized 
using the data from the survival follow-ups.
6.3.2
Protocol Deviations
Major protocol deviation criteria will be established and subjects with major protocol deviations 
will be identified and documented before the database lock. Major protocol deviations will be 
summarized for all patients in the safety population. They will also be listed by each category.
6.3.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the safety population. Continuous variables include age, weight, and vital signs; categorical 
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variables include sex, age group (<65 vs. ≥65), and ECOG-PS. A listing of demographic and 
other baseline characteristics will be provided.
6.3.4
Disease History and Characteristics
The number (percentage) of subjects reporting a history of disease and characteristic, as recorded
on the CRF, will be summarized. Disease characteristics include time since first diagnosis of 
MCL (month), disease stage, MCL international prognostic index (MIPI)/Combined biologic 
MCL international prognostic index (MIPI-b) (low, intermediate, high, derived based on CRF 
and central lab data), Ki-67-postive cell percentage categories (based on central lab pathology),
blastoid histology (yes vs no, based on CRF), and confirmation of MCL by central pathology 
(yes vs no, by central lab report). A listing of disease history will be provided.
6.3.5
Prior Anti-Cancer Drug Therapies 
The number of prior anti-cancer drug therapies and prior anti-cancer radiotherapy will be 
summarized. The therapies with the same line of regimen are counted as one prior 
therapy/surgery.    
6.3.6
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes, and will be further classified to the appropriate Anatomical 
Therapeutic Chemical (ATC) code. 
The number (percentage) of subjects reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term by phase in the safety 
population. Prior medications are defined as medications that started before the first dose date. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the subject’s last dose or or 
initiation of a new anti-cancer therapy. A listing of prior and concomitant medications will be 
provided.
6.3.7
Medical History
Medical History will be coded using MedDRA (version 19.0 or newer). The number 
(percentage) of subjects reporting a history of any medical condition, as recorded on the CRF, 
will be summarized by MedDRA system organ class (SOC) and preferred term (SOC) based on
the safety population. A listing of medical history will be provided.
6.4
EFFICACY ANALYSIS
All efficacy analyses will be based on the Revised Safety population. The primary endpoint of 
ORR will also be analyzed using the safety population and the per-protocol population (if 
necessary) as supplementary to the primary analysis.
6.4.1
Primary Efficacy Endpoint
Overall Response Rate (ORR) by IRC
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The primary analysis of ORR will be based on the PET-based assessments by the Independent 
Review Committee (IRC) following the 2014 modification of the International Working Group 
in NHL criteria. ORR is defined as the proportion of subjects achieving a best overall response 
of CR or PR.
A point estimate and a 2-sided Clopper-Pearson 95% confident interval (CI) of ORR will be 
provided. A binomial exact test will be performed to test against the null hypothesis H0:
ORR=0.40 using the significant level of 0.025 (1-sided). Best overall response (BOR) is defined 
as the best response recorded from the start of BGB-3111 until data cut or start of new anti-
cancer treatment. Subjects with no post-baseline response assessment (due to any reason) will be 
considered non-responders for ORR.  The proportion and its corresponding Clopper-Pearson 
95% CI for each of the response categories (CR, PR, stable disease [SD], and progressive disease 
[PD]) will be presented.
6.4.2
Secondary Efficacy Endpoints
Progression Free Survival (PFS)
PFS is defined as the time (in weeks) from the date of first study dose to disease progression or 
death of any cause, whichever occurs first:
PFS=(The earlier of disease progression or death date – the date of first study dose +1)/7.
PFS will be based on the IRC assessments. PFS as assessed by investigator will also be analyzed 
as sensitivity analysis.
Kaplan-Meier methodology will be used to estimate the median and other quantiles of PFS and it 
95% confidence interval. Kaplan-Meier curves will be constructed to provide a visual description 
of the PFS change with time. Two-sided 95% CIs of median and other quantiles, if estimable, 
will be constructed with a generalized Brookmeyer and Crowley method (Brookmeyer, 1982;
Klein 1997) with log-log transformation. PFS rates at selected landmark time points (e.g. 6-
month) will be provided and corresponding 95% confidence intervals will be calculated based on 
the Greenwood’s formula (Kalbfleisch 1980) with log-log transformation.
The duration of the follow-up for PFS will be determined by reverse Kaplan-Meier method 
(Schemper 1996).
PFS will be right-censored based on rules provided in Table 1. These conventions are modified 
based on the May 2007 FDA Guidance for Industry: “Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics” (FDA, 2007).
Note that the frequency of disease assessments is every 12 weeks in the first 48 weeks and every 
24 weeks thereafter. Therefore, missing more than one disease assessment will be interpreted as 
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gaps longer than 24 weeks in the first 48 weeks or gaps longer than 48 weeks thereafter for 
censoring purposes of PFS.
Table 1.
Censoring Rules for Analysis of Progression-Free Survival
No.
Situation
Date of Progression or Censoring
Outcome
1
No baseline and/or post-baseline disease 
assessments
Date of the first dose 
Censored
2
Progression documented on scheduled 
visit or between scheduled visits
Date of first disease assessment 
showing with documented disease 
progression
Progressed
3
Alive without documented disease 
progression at the time of data cut-off or 
withdrawal from study (including lost-to-
follow-up without disease progression)
Date of last disease assessment 
Censored
4
New anticancer treatment started before  
documented disease progression or death
Date of last disease assessment prior 
to or on date of new anticancer 
treatment
Censored
5
Death before first disease assessment
Date of death
Progressed
6
Death or progression after more than one 
missed scheduled disease assessment
Date of last disease assessment 
without documented disease 
progression before missed tumor 
assessments
Censored
Duration of Response (DOR)
Duration of response for responders (CR or PR) is defined as the time interval between the date 
of the earliest qualifying response and the date of PD or death for any cause (whichever occurs 
earlier). Censoring rule for DOR will follow PFS censoring rule. Kaplan-Meier curve will be 
used to estimate median and other quantiles and 95% confidence intervals for duration of 
response. DOR will be based on the IRC assessments, DOR as assessed by investigators will be 
analyzed as sensitivity analysis.
Time to Response (TTR)
Time of response for responders (CR or PR) is defined as the time interval between the first dose 
and the date of the earliest qualifying response. TTR will be summarized by sample statistics 
such as mean, median and standard deviation for responders only. TTR will be based on the IRC 
assessments, TTR as assessed by investigators will be analyzed as sensitivity analysis.
Overall Response Rate (ORR) by Investigator
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x
Total dose received per subject (mg): defined as the cumulative dose of the study drug 
during the treatment period of the study
x
Actual dose intensity (mg/day): defined as the total dose (in mg) received by a subject 
divided by the duration of exposure (in day)
x
Relative dose intensity: defined as the ratio of the actual dose intensity (mg/day) and the 
planned dose intensity.
The number (percentage) of subjects requiring dose reductions, dose interruption, dose missed,
and drug discontinuation due to AEs will be summarized. The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics. Frequency of 
reductions and dose interruptions will be summarized by categories.
6.5.2
Adverse Events
AEs will be graded by the investigators using CTCAE v4.03. The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be coded to 
the MedDRA (Version 19.0 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database.
A TEAE is defined as an AE that has an onset date or a worsening in severity from baseline 
(pretreatment) on or after the date of first dose of study drug up to 30 days following study drug 
discontinuation (Safety Follow-up visit) or initiation of new anticancer therapy, whichever 
comes first.  Only those AEs that were treatment emergent will be included in summary tables.  
All AEs, treatment emergent or otherwise, will be presented in subject data listings.
An overview table, including the incidence of and the number of subjects with TEAEs, 
treatment-emergent serious adverse events (SAEs), treatment-related TEAEs, TEAEs with grade 
3 or above, treatment-related SAEs, TEAEs that led to death, and TEAEs that led to treatment 
discontinuation, dose reduction or dose interruption will be provided. Treatment-related AEs 
include those events considered by the investigator to be possibly or probably related to study 
drug or with missing assessment of the causal relationship.  
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC and PT.  A subject will be counted only once by the highest severity grade according to 
CTCAE v.4.03 within an SOC and PT, even if the subject experienced more than 1 TEAE within 
a specific SOC and PT. 
The number (percentage) of subjects with treatment-emergent SAEs, treatment-related TEAEs, 
TEAEs with grade 3 or above, treatment-related SAEs, TEAEs that led to death, and TEAEs that 
led to treatment discontinuation, dose reduction or dose interruption will be summarized by SOC 
and PT. TEAEs with grade 3 or above will also be summarized by PT in descending order. 
Subject data listings of all AEs, SAEs, treatment-related AEs, grade 3 or above AEs, AEs that 
led to death and AEs that led to treatment discontinuation will be provided.
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8
CHANGES IN THE PLANNED ANALYSIS
The primary efficacy analysis will be conducted no later than 6 months after the last subject 
received the first dose of study drug. In protocol amendment 3 and SAP v1.0, it was specified 
that the primary analysis will be performed 12 months after the last subject received the first 
dose of study drug. As a result, the interim analysis as planned in SAP v1.0 is omitted from this 
version of the SAP.
9
REFERENCES
1. Brookmeyer, B et al. (1982), A confidence interval for the median survival time, 
Biometrics 38(1), p29-41.
2. Cheson, BD et al. (2014), Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 32: 3059–3068.
3. Common Toxicity Criteria Version 4.03. (2010) Cancer Therapy Evaluation Program. 
14 June 2010.
4. Food and Drug Administration Center for Drug Evaluation Research CDER and Center 
for Biologics Evaluation and Research (2007). FDA Guidance for Industry Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics.
5. Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time 
Data, New York: John Wiley & Sons. 
6. Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored 
and Truncated Data, New York: Springer-Verlag.
7. Schemper M., and Smith T.L., (1996), A note on quantifying follow-up in studies of 
failure time, Controlled Clinical Trials, 17: 343-346.
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10
APPENDIX
Appendix A: Missing Data Imputation Rule 
In general, missing or partial dates will not be imputed as data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only.  
A.1 Prior/Concomitant Medications/Procedures
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rules will be applied to 
impute partial dates for medications:
If start date of a medication is partially missing, impute as follows:
x
If both month and day are missing, then set to January 01
x
If only day is missing, then set to the first of the month
If end date of a medication is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
If start date or end date of a medication is completely missing, do not impute.
A.2 Adverse Events
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment emergent by default. The following rules will be applied to impute 
partial dates for adverse events:
If start date of an adverse event is partially missing, impute as follows:
x
If both month and day are missing and year = year of treatment start date, then set to 
treatment start date
x
If both month and day are missing and year ≠year of treatment start date, then set to
January 01
x
If day is missing and month and year = month and year of treatment start date, then set to 
treatment start date
x
If day is missing and month and year ≠month and year of treatment start date, then set to
first day of the month
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x
If start date is completely missing, set to treatment start date as long as adverse event end 
date is not before treatment start date
If end date of an adverse event is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
If end date is completely missing, do not impute.
A.3 Deaths
In case only the day of a death date is missing, the death will be assumed to be on the 1st date of 
the month if the last date of subject known to be alive is earlier that the 1st date of the month, 
otherwise the death date will be assumed to be on 1 day after the last date of subject known to be 
alive.
A.4 Subsequent Anti-cancer Therapies
If the start date of a subsequent anti-cancer therapy is missing, the start date will be assumed to 
be on the 1st date of the month.
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