Conditions: Hepatocellular Carcinoma Unresectable Hepatocellular Carcinoma Metastatic Hepatocellular Carcinoma
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 64
Healthy volunteers: no

Brief summary:
The primary objective of this study was to assess the preliminary antitumor activity as indicated by overall response rate (ORR) of tislelizumab in combination with lenvatinib in participants with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) by central site imaging facility per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Detailed description:

Arms:
arm 1: Participants received lenvatinib based on baseline weight (12 milligrams \[mg\] or 8 mg once daily for participants with a baseline weight of \>= 60 kilograms \[kg\] or \< 60 kg, respectively) along with tislelizumab 200 mg on Day 1 of each 21-day cycle (once every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first.

Interventions: intervention 1: Lenvatinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: Capsules administered orally once daily intervention 2: 200 mg intravenous (IV) infusion administered on Day 1 of each cycle

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 2 Study to Investigate the Preliminary Antitumor Activity, Safety 
and Tolerability of Tislelizumab in Combination with Lenvatinib in 
Patients with Unresectable Locally Advanced or Metastatic Hepatocellular 
Carcinoma 
Protocol Identifier: BGB-A317-211 
Phase: 
2 
Investigational 
Products: 
Tislelizumab (BGB-A317) 
Indication: 
Hepatocellular Carcinoma 
Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
Floor 4, Building D 
No. 780, Cailun Road 
Pilot Free Trade Zone 
Shanghai 201203, P.R. China 
Sponsor Medical 
Monitor: 
BeiGene Co., Ltd. 
26th Floor, Tower D  
Central International Trade Center 
6A Jianguomenwai Avenue  
Chaoyang District 100022  
Beijing, China  
Phone number: 
Email: 
Original Protocol: 
26 October 2019 
Amendment 1.0: 
25 December 2019 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene (Shanghai) Co., 
Ltd., and its subsidiaries. This document is for use by individuals and their designated representatives for 
their confidential review, consideration, and/or participation in investigational trial(s). This document may 
not be copied or distributed for review by any unauthorized individuals without the prior written 
authorization of BeiGene (Shanghai) Co., Ltd., or one of its subsidiaries. Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without prior 
written authorization from BeiGene (Shanghai) Co., Ltd., or one of its subsidiaries. 
NCT Number:
NCT04401800


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        25 December 2019  
 
 
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FINAL PROTOCOL APPROVAL SHEET 
 
BGB-A317-211: A Phase 2 Study to Investigate the Preliminary Antitumor Activity, Safety and 
Tolerability of Tislelizumab in Combination with Lenvatinib in Patients with Unresectable Locally 
Advanced or Metastatic Hepatocellular Carcinoma 
BeiGene (Shanghai) Co., Ltd., Approval: 
 
________
____________________ 
 
Sponsor Medical Monitor 
BeiGene Co., Ltd. 
 
____________________________________ 
Date 
 
 
 
 
26-Dec-2019 | 02:02:18 PST


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        25 December 2019  
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
 
Protocol Title: 
A Phase 2 Study to Investigate the Preliminary Antitumor Activity, Safety 
and Tolerability of Tislelizumab in Combination with Lenvatinib in 
Patients with Unresectable Locally Advanced or Metastatic 
Hepatocellular Carcinoma 
Protocol Identifier: 
 
BGB-A317-211 
 
This protocol is a confidential communication of BeiGene (Shanghai) Co., Ltd., and its subsidiaries. I 
confirm that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical 
practices and the applicable laws and regulations. Acceptance of this document constitutes my agreement that 
no unpublished information contained herein will be published or disclosed without prior written approval 
from BeiGene (Shanghai) Co., Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page. PRINT your name, 
title, and the name and address of the center in which the study will be conducted. Return the 
signed copy to BeiGene or its designee 
 
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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        25 December 2019  
 
 
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PROTOCOL AMENDMENT 1.0 (25DEC2019) 
The primary purpose of this amendment is to revise the inclusion criteria and exclusion criteria to 
clarify the eligible patient population in the study. 
Applicable 
Section 
Description of Revision 
Change: Non-content related changes made throughout the document 
Reason: To provide consistency with other BeiGene tislelizumab protocols and to clarify 
some confusions  
All Sections 
• Administrative updates, correcting typos, editorial changes, and/or style 
and formatting revisions have been made to improve clarity and 
consistency throughout the document. 
Change: Modifications to the definition and responsibility of Safety Monitoring 
Committee (SMC) 
Reason: To clarify the definition and responsibility of SMC and keep consistency with 
other BeiGene tislelizumab protocols 
Section 1.5 
Section 3.1.1 
Section 3.8.2 
• Removed the requirement of efficacy data review 
• Clarified the definition and responsibility of SMC 
Change: Revised the criteria of Concomitant Therapy 
Reason: To clarify the criteria of Prohibited Concomitant Medications/Procedures 
Section 6.1.2 
• Added new criterion of “anticoagulants such as warfarin or similar agents 
requiring therapeutic INR monitoring” in Section 6.1.2 
• In Section 6.1.2 removed criterion of “All of the herbal remedies not 
recommend for use during the study treatment. Patients must notify the 
investigator of all herbal remedies used during the study”, because there is 
similar criterion in Section 6.1.3 (Restricted Concomitant 
Medications/Procedures) 
Change: Updated the background information of tislelizumab 
Reason: To keep consistency with the latest stage of clinical development/product launch 
Section 1.2.1 
Section 8.1 
• Modified the description of clinical development stage from “under 
clinical development for the treatment of several human malignancies” to 
“under clinical development for the treatment of HCC” 


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Change: Revised the references in Assessment of Causality 
Reason: To provide new reference in Assessment of Causality 
Section 8.3.3 
 
• Added “Pharmaceutical Instructions of lenvatinib” as a new reference in 
Section 8.3.3 
Change: Updated the content of mRECIST criterion   
Reason: To clarify the main assessment method 
Appendix 12 
• 
Deleted the section of “AASLD-JNCI Guidelines for Trial Design in 
HCC” from mRECIST criterion   
Change: Revised the administration of contrast agent 
Reason: To clarify the details on administration of contrast agent 
Section 7.4 
• Removed the detail administration of contrast agent for contrast-enhanced 
computed tomography (CT) scans. 
Change: Updated the descriptions of PK analysis method and PK analysis set 
Reason: To clarify the definition of PK analysis set and the analysis method 
Synopsis 
Section 9.1.1 
• Modified the PK analysis set into “The PK analysis set includes patients 
who received at least 1 dose of tislelizumab (lenvatinib) study drug and 
contributed at least 1 post-baseline quantifiable tislelizumab (lenvatinib) 
PK sample.” 
Change: Updated definition of hypertension grade 
Reason: Added the detail definition of hypertension grade in Section 3.8.2 and keep 
consistency with other content of this protocol 
Synopsis 
Section 3.8.2 
• Added “Hypertension will be graded using NCI-CTCAE v 5.0, based on 
BP measurements only (and not on the number of antihypertensive 
medications). Each assessment of BP and BP elevation confirmation 
(systolic and diastolic) should follow Section 7.3.1.” as a note into Section 
3.8.2 to keep consistency with other content of this protocol 
Change: Revised the inclusion criteria of HCC confirmed diagnosis 
Reason: To clarify inclusion criteria and exclude the non-HCC histology patients  


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        25 December 2019  
 
 
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Section 4.1 
 
Appendix 1 
• Changed the criteria of HCC confirmed diagnosis as following: 
unresectable locally advanced or metastatic HCC, which must be 
confirmed by histologically or cytologically. Fibrolamellar, sarcomatoid, 
or mixed cholangiocarcinoma histology confirmed by histologically or 
cytologically is excluded.  
Change: Revised the exclusion criteria  
Reason: To specify the exclusion criteria on Exclusion Criterion #2, #3, #16 and prior #20 
Section 4.2 
• Change the exclusion criterion #2 as “Any clearly known invasion or tumor 
thrombus on first grade/second grade intrahepatic bile duct or extrahepatic bile 
duct” 
• Change the exclusion criterion #3 as “Patients underwent surgical of 
transjugular intrahepatic portosystemic shunt (TIPS) or other forms of 
portosystemic shunt” 
• Merged #16 and prior #20, removed the prior #20 
Change: Updated the Structure of Discontinuation from Study Treatment 
Reason: For more clarification on criterion of discontinuation from study treatment 
Section 3.6.1 
• Merged section of patient discontinuation from study treatment and 
section of sponsor discontinuation from study treatment 
• Added following content “loco-regional therapy” to clarify the criterion of 
discontinuation from study treatment  
Change: Updated the Recommendation Priority on Method of Cardiac Function 
Evaluations 
Reason: To keep consistency with clinical practice and reduce difficulties of operation 
Section 7.3.8 
Appendix 1 
• Changed the recommendation priority as “investigator will decide the 
method (MUGA or echocardiograms) for evaluation of cardiac function” 
Change: Removed Ophthalmologic Examination from safety assessment 
Reason: Consistency with other BeiGene study protocols for tislelizumab 
Prior Section 
7.3.3 
Appendix 1 
• Deleted contents for Ophthalmologic Examination 
Change: Revised the Further Decision of Treatment After Progression via investigator 
assessed based on RECIST v1.1 
Reason: To clarify the further treatment for patient who continue study drugs beyond 
investigator-assessed PD based on RECIST v1.1 


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Section 7.4 
 
 
 
 
Appendix 1 
Synopsis  
• Removed the requirement of judgment by investigator on suspected 
pseudo progression, revised the treatment of investigator-assessed initial 
PD based on RECIST v1.1 as “all patients with initial PD via investigator 
assessed based on RECIST v1.1 should continue study drugs, until iCPD 
(investigator assessed based on iRECIST) is confirmed by repeated 
imaging ≥ 4 weeks later” 
• Clarified the further treatment for patient who continue study drugs 
beyond investigator-assessed initial PD based on RECIST v1.1 as 
following: 
o Tumor assessments are still required to be performed on 
original schedule plan via investigator and central site imaging 
facility based on RECIST v1.1, mRECIST and iRECIST 
respectively 
o Unless investigator-assessed iCPD based on iRECIST, patients 
will continue study drugs, until the patient meet other criterion 
of discontinuation from study treatment (see Section 3.6.1 for 
details) 
• Added the recommended time of repeated imaging after initial 
documentation of PD via investigator based on RECIST v1.1 
Change: Updated the Criterion of Discontinuation from Study Treatment 
Reason: To keep consistency with above modification (further treatment after 
investigator-assessed progression based on RECIST v1.1) and keep all subjects with similar 
treatment duration 
Synopsis  
Section 3.1 
Section 3.3 
Section 3.6.1 
Section 5.3 
Section 9.2.1 
• Clarify that the progression in criterion of discontinuation from study 
treatment:  
o Confirmed progressive disease (iCPD) assessed by investigator 
based on iRECIST  
• Revised the study drugs max treatment duration for each patient in 
criterion of discontinuation from study treatment: 
o 12-month treatment duration completion 
 
Change: Updated the Treatment for Patients Who Are Still Under Response or Disease 
Stable beyond 12-Month Treatment Duration Completion 
Reason: To provide more benefit and clarify the treatment for patients who are still under 
response or disease stable beyond 12-month treatment duration completion 


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Synopsis 
Section 3.6.1 
Section 5.3 
Section 9.2.1 
• 
Changed the treatment as “If patients don’t meet any discontinuation 
criterion, such as investigator-assessed iCPD based on iRECIST, 
unacceptable toxicity, death, withdrawal of consent, or study termination by 
sponsor, lenvatinib and tislelizumab will be administered until patient 
completes his/her 12-month treatment duration of study drugs. After 12-
month treatment duration completion, if the patients are still under the 
response (CR, PR) or stable disease (SD) assessed by investigator based on 
RECIST v1.1 or under the response (complete response [iCR], partial 
response [iPR]), stable disease (iSD) and unconfirmed progression (iUPD) 
assessed by investigator based on iRECIST, and may continue receiving 
benefit based on investigator’s assessment, tislelizumab could be further 
provided by sponsor, this decision must be agreed with medical monitor and 
documented in the study records, patients are also required to be 
reconsented.” 
Change: Revised the Name of Urinalysis 
Reason: To keep consistency with clinical practice 
Section 4.2 
Section 8.8.3 
• Changed the name of urine dipstick testing as “urinalysis” 
 
Change: Revised the Visit Window of D1C2 
Reason: Clarify the D1C2 visit window 
Section 7.3.4 
Appendix 1 
• Modified the D1C2 visit window as “± 1” day 
• Removed the requirement of “After Cycle 1, laboratory safety results 
should be reviewed within 48 hours before study drugs administration” 
 
 


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TABLE OF CONTENTS 
 
FINAL PROTOCOL APPROVAL SHEET ...............................................................................1 
INVESTIGATOR SIGNATURE PAGE....................................................................................2 
PROTOCOL AMENDMENT 1.0 (25DEC2019) .......................................................................3 
TABLE OF CONTENTS ..........................................................................................................8 
LIST OF TABLES ................................................................................................................. 14 
LIST OF FIGURES ................................................................................................................ 15 
SYNOPSIS ............................................................................................................................ 16 
LIST OF ABBREVIATIONS AND TERMS........................................................................ 24 
1. 
INTRODUCTION AND RATIONALES .............................................................. 28 
1.1. 
Background Information on Hepatocellular Carcinoma .......................................... 28 
1.2. 
Tislelizumab as a PD-1 Blocker ............................................................................ 29 
1.2.1. 
Pharmacology ...................................................................................................... 30 
1.2.2. 
Toxicology ........................................................................................................... 30 
1.2.3. 
Clinical Pharmacology.......................................................................................... 31 
1.2.4. 
Clinical Experience With Tislelizumab.................................................................. 31 
1.2.5. 
Clinical Safety of Tislelizumab ............................................................................. 42 
1.2.6. 
Rationale for Selection of Tislelizumab Dose ........................................................ 43 
1.3. 
Lenvatinib as a Receptor Tyrosine Kinase Inhibitor ............................................... 44 
1.3.1. 
Pharmacology ...................................................................................................... 45 
1.3.2. 
Toxicology ........................................................................................................... 45 
1.3.3. 
Clinical Pharmacology.......................................................................................... 46 
1.3.4. 
Pharmacodynamic Properties ................................................................................ 46 
1.3.5. 
Clinical Experience with Lenvatinib in Patients with HCC..................................... 47 
1.3.6. 
Rationale for Lenvatinib Dose Selection in HCC Patients ...................................... 51 
1.4. 
Combination of Lenvatinib and Tislelizumab ........................................................ 51 
1.4.1. 
Rationale for Combination of Lenvatinib and Tislelizumab in the Treatment of 
Advanced Solid Tumors ....................................................................................... 51 
1.4.2. 
Clinical Experience with Lenvatinib in Combination with PD-1 Inhibitor ............... 52 
1.5. 
Benefit-Risk Assessment ...................................................................................... 53 
2. 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 55 
2.1. 
Study Objectives .................................................................................................. 55 


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2.1.1. 
Primary Objectives ............................................................................................... 55 
2.1.2. 
Secondary Objectives ........................................................................................... 55 
2.1.3. 
Exploratory Objectives ......................................................................................... 55 
2.2. 
Study Endpoints ................................................................................................... 55 
2.2.1. 
Primary Endpoints ................................................................................................ 55 
2.2.2. 
Secondary Endpoints ............................................................................................ 56 
2.2.3. 
Exploratory Endpoints .......................................................................................... 56 
3. 
STUDY DESIGN ................................................................................................. 56 
3.1. 
Summary of Study Design .................................................................................... 56 
3.1.1. 
Part 1 (Safety run-in part for lenvatinib in combination with tislelizumab).............. 56 
3.1.2. 
Part 2 ................................................................................................................... 57 
3.2. 
Screening Period .................................................................................................. 58 
3.3. 
Treatment Period .................................................................................................. 58 
3.4. 
End-of-Treatment Visit and Safety Follow-up Phone Calls .................................... 59 
3.5. 
Survival Follow-Up .............................................................................................. 59 
3.6. 
Discontinuation from Study Treatment or from the Study ...................................... 59 
3.6.1. 
Patient Discontinuation from Study Treatment....................................................... 59 
3.6.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) .......... 60 
3.7. 
End of Study ........................................................................................................ 60 
3.8. 
Dose-Limiting Toxicities ...................................................................................... 61 
3.8.1. 
Assessment of Dose-Limiting Toxicity.................................................................. 61 
3.8.2. 
Definition of Dose-Limiting Toxicity .................................................................... 62 
4. 
STUDY POPULATION ....................................................................................... 63 
4.1. 
Inclusion Criteria .................................................................................................. 63 
4.2. 
Exclusion Criteria................................................................................................. 65 
5. 
STUDY TREATMENT ........................................................................................ 67 
5.1. 
Formulation, Packaging, and Handling .................................................................. 67 
5.1.1. 
Tislelizumab......................................................................................................... 67 
5.1.2. 
Lenvatinib ............................................................................................................ 68 
5.2. 
Dosage and Administration ................................................................................... 68 
5.2.1. 
Tislelizumab......................................................................................................... 68 
5.2.2. 
Lenvatinib ............................................................................................................ 68 


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5.3. 
Compliance and Accountability ............................................................................ 69 
5.4. 
Overdose .............................................................................................................. 69 
5.4.1. 
Tislelizumab......................................................................................................... 69 
5.4.2. 
Lenvatinib ............................................................................................................ 70 
5.5. 
Modification and Dose Delay................................................................................ 70 
5.5.1. 
Dose Modification ................................................................................................ 70 
5.5.2. 
Dose Delay........................................................................................................... 70 
6. 
PRIOR AND CONCOMITANT THERAPY ......................................................... 71 
6.1. 
Concomitant Therapy ........................................................................................... 71 
6.1.1. 
Permitted Concomitant Medications/Procedures .................................................... 71 
6.1.2. 
Prohibited Concomitant Medications/Procedures ................................................... 72 
6.1.3. 
Restricted Concomitant Medications/Procedures ................................................... 72 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant Medications....... 73 
7. 
STUDY ASSESSMENTS AND PROCEDURES .................................................. 74 
7.1. 
Screening ............................................................................................................. 74 
7.1.1. 
Demographics and Medical History ...................................................................... 75 
7.1.2. 
Females of Childbearing Potential and Contraception ............................................ 75 
7.1.3. 
Informed Consent and Screening Log.................................................................... 75 
7.1.4. 
Pulmonary Function Tests..................................................................................... 75 
7.2. 
Enrollment ........................................................................................................... 75 
7.3. 
Safety Assessments .............................................................................................. 76 
7.3.1. 
Vital Signs ........................................................................................................... 76 
7.3.2. 
Physical Examinations .......................................................................................... 76 
7.3.3. 
Eastern Cooperative Oncology Group Performance Status ..................................... 76 
7.3.4. 
Laboratory Safety Test.......................................................................................... 77 
7.3.5. 
Hepatitis B and C Testing ..................................................................................... 77 
7.3.6. 
Electrocardiograms ............................................................................................... 78 
7.3.7. 
Multigated Acquisition (MUGA) Scans or Echocardiograms ................................. 78 
7.3.8. 
Adverse Events .................................................................................................... 78 
7.4. 
Tumor and Response Evaluations.......................................................................... 78 
7.4.1. 
Investigator Assessment........................................................................................ 80 
7.4.2. 
Central Site Imaging Facility for Tumor Assessment ............................................. 80 


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7.5. 
Pharmacokinetic Assessment ................................................................................ 80 
7.6. 
Antidrug Antibody Testing ................................................................................... 81 
7.7. 
Visit Windows...................................................................................................... 81 
7.8. 
Unscheduled Visits ............................................................................................... 81 
8. 
SAFETY MONITORING AND REPORTING ...................................................... 81 
8.1. 
Risks Associated with Lenvatinib and Tislelizumab............................................... 81 
8.2. 
General Plan to Manage Safety Concerns .............................................................. 82 
8.2.1. 
Eligibility Criteria................................................................................................. 82 
8.2.2. 
Safety Monitoring Plan ......................................................................................... 82 
8.3. 
Adverse Events .................................................................................................... 83 
8.3.1. 
Definitions and Reporting ..................................................................................... 83 
8.3.2. 
Assessment of Severity ......................................................................................... 83 
8.3.3. 
Assessment of Causality ....................................................................................... 84 
8.3.4. 
Following Adverse Events .................................................................................... 85 
8.3.5. 
Laboratory Test Abnormalities.............................................................................. 85 
8.4. 
Definition of a Serious Adverse Event................................................................... 86 
8.5. 
Suspected Unexpected Serious Adverse Reaction .................................................. 87 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events .................................................................................................... 87 
8.6.1. 
Adverse Event Reporting Period ........................................................................... 87 
8.6.2. 
Reporting Serious Adverse Events ........................................................................ 87 
8.6.3. 
Eliciting Adverse Events....................................................................................... 88 
8.6.4. 
Progressive Disease .............................................................................................. 88 
8.6.5. 
Deaths.................................................................................................................. 89 
8.6.6. 
Pregnancies .......................................................................................................... 89 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees ......................................................... 89 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events.................................... 89 
8.7. 
Management of Adverse Events of Special Interest of Tislelizumab ....................... 90 
8.7.1. 
Infusion-Related Reactions ................................................................................... 90 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms .................................... 91 
8.7.3. 
Immune-related Adverse Events............................................................................ 92 


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8.8. 
Management of Lenvatinib-Specific Adverse Events ............................................. 93 
8.8.1. 
Management of Non-Hematological Toxicities and Hematological Toxicities of 
Lenvatinib ............................................................................................................ 93 
8.8.2. 
Hypertension ........................................................................................................ 96 
8.8.3. 
Proteinuria ........................................................................................................... 98 
8.8.4. 
Renal Failure or Impairment ................................................................................. 99 
8.8.5. 
Cardiac Dysfunction ............................................................................................. 99 
8.8.6. 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)/ Posterior 
Reversible Encephalopathy Syndrome (PRES) ...................................................... 99 
8.8.7. 
Hepatotoxicity .................................................................................................... 100 
8.8.8. 
Arterial Thromboembolic Event .......................................................................... 100 
8.8.9. 
Hemorrhage ....................................................................................................... 100 
8.8.10. 
Gastrointestinal Perforation or Fistula Formation ................................................. 101 
8.8.11. 
Non-gastrointestinal Fistula Formation ................................................................ 101 
8.8.12. 
QT Prolongation ................................................................................................. 101 
8.8.13. 
Diarrhea ............................................................................................................. 102 
8.8.14. 
Thyrotropin Inhibition Impairment/Thyroid Dysfunction Other Than Immune-
Mediated ............................................................................................................ 102 
8.8.15. 
Wound Healing Complications ........................................................................... 102 
8.8.16. 
Palmar plantar erythrodysesthesia (PPE) ............................................................. 103 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.............. 103 
9.1. 
Statistical Analysis ............................................................................................. 103 
9.1.1. 
Analysis Sets ...................................................................................................... 103 
9.1.2. 
Patient Disposition ............................................................................................. 104 
9.1.3. 
Demographic and Other Baseline Characteristics ................................................. 104 
9.1.4. 
Prior and Concomitant Medications .................................................................... 104 
9.2. 
Efficacy Analyses............................................................................................... 104 
9.2.1. 
Primary Efficacy Analyses.................................................................................. 104 
9.2.2. 
Secondary Efficacy Analysis............................................................................... 105 
9.3. 
Safety Analyses .................................................................................................. 106 
9.3.1. 
Dose-Limiting Toxicity Analysis ........................................................................ 106 
9.3.2. 
Extent of Exposure ............................................................................................. 107 
9.3.3. 
Adverse Events .................................................................................................. 107 


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9.3.4. 
Laboratory Analyses ........................................................................................... 107 
9.3.5. 
Vital Signs ......................................................................................................... 108 
9.4. 
Pharmacokinetic Analysis ................................................................................... 108 
9.5. 
Immunogenicity Analyses................................................................................... 108 
9.6. 
Other Exploratory Analyses ................................................................................ 108 
9.7. 
Sample Size Consideration.................................................................................. 108 
9.8. 
Interim Analysis ................................................................................................. 109 
10. 
STUDY COMMITTEES AND COMMUNICATION.......................................... 109 
10.1. 
Safety Monitoring Committee ............................................................................. 109 
10.2. 
Communication .................................................................................................. 109 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ....................................................................................... 109 
11.1. 
Access to Information for Monitoring ................................................................. 109 
11.2. 
Access to Information for Auditing or Inspections ............................................... 110 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL ..................................... 110 
12.1. 
Regulatory Authority Approval ........................................................................... 110 
12.2. 
Quality Assurance .............................................................................................. 110 
12.3. 
Study Site Inspections......................................................................................... 110 
12.4. 
Drug Accountability ........................................................................................... 110 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ............................................. 111 
13.1. 
Ethical Standard ................................................................................................. 111 
13.2. 
Institutional Review Board/Independent Ethics Committee .................................. 111 
13.2.1. 
Protocol Amendments ........................................................................................ 112 
13.3. 
Informed Consent ............................................................................................... 112 
13.4. 
Patient and Data Confidentiality.......................................................................... 112 
13.5. 
Financial Disclosure ........................................................................................... 113 
14. 
DATA HANDLING AND RECORD KEEPING ................................................. 113 
14.1. 
Data Collection and Management Responsibilities............................................... 113 
14.1.1. 
Data Collection .................................................................................................. 113 
14.1.2. 
Data Management/Coding .................................................................................. 114 
14.2. 
Study Records Retention..................................................................................... 114 
14.3. 
Protocol Deviations ............................................................................................ 115 


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14.4. 
Publication and Data Sharing Policy.................................................................... 115 
14.5. 
Study and Study Center Closure .......................................................................... 116 
14.6. 
Information Disclosure and Inventions ................................................................ 117 
15. 
REFERENCES................................................................................................... 118 
16. 
APPENDICES ................................................................................................... 124 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .............................................................. 125 
APPENDIX 2. SCHEDULE OF PK ASSESSMENTS ........................................................ 130 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ........................................... 131 
APPENDIX 4. ECOG PERFORMANCE STATUS ............................................................ 132 
APPENDIX 5. CHILD-PUGH CLASSIFICATION SCORING SYSTEM ........................... 133 
APPENDIX 6. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES......................................................................................................... 134 
APPENDIX 7. CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN 
OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING POTENTIAL” .... 135 
APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION............................................................................................ 137 
APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION..................................................................................... 138 
APPENDIX 10. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT ............................................................................................... 139 
APPENDIX 11. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1............................................................ 149 
APPENDIX 12. MODFIED RECIST (MRECIST) ASSESSMENT FOR 
HEPATOCELLULAR CARCINOMA ................................................................ 158 
APPENDIX 13. IRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN 
TRIALS TESTING IMMUNOTHERAPEUTICS ................................................ 163 
APPENDIX 14. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH LENVATINIB ..................... 174 
APPENDIX 15. BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION............................................................................................ 176 
LIST OF TABLES 
Table 1 Pooled Monotherapy Studies of tislelizumab ............................................................... 34 
Table 2 The most common treatment-related TEAEs in the solid tumor group of 
Tislelizumab Pooled Monotherapy studies............................................................. 36 


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Table 3 The most common treatment-related TEAEs in the hematology group of 
Tislelizumab Pooled Monotherapy studies............................................................. 36 
Table 4 The most common treatment-related TEAEs in total patients of Tislelizumab 
Pooled Monotherapy studies ................................................................................. 37 
Table 5 The most common irAEs in the solid tumor group of Tislelizumab Pooled 
Monotherapy studies............................................................................................. 38 
Table 6 The most common irAEs in the hematology group of Tislelizumab Pooled 
Monotherapy studies............................................................................................. 38 
Table 7 The most common irAEs in total patients of Tislelizumab Pooled Monotherapy 
studies.................................................................................................................. 39 
Table 8 The most common treatment-related TEAEs in Study BGB-900-103 ........................... 41 
Table 9 The most frequent treatment-emergent AEs in the HCC patients of lenvatinib 
monotherapy (Phase 1 Clinical Study) ................................................................... 47 
Table 10 The most common AEs in the HCC patients of lenvatinib monotherapy (Phase 2 
Clinical Study) ..................................................................................................... 49 
Table 11 The most common treatment-emergent adverse events in the HCC patients of 
lenvatinib monotherapy (Phase 3 Clinical Study) ................................................... 50 
Table 12 Lenvatinib Dose Reductions ..................................................................................... 70 
Table 13 Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee.................................................................................... 87 
Table 14 Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab......................................................................................................... 90 
Table 15 Immune-Related Adverse Events .............................................................................. 93 
Table 16 Lenvatinib Dose Modifications Based on non-hematological and hematological 
Drug-Related Toxicities ........................................................................................ 94 
Table 17 Monitoring, Dose Modifications and Discontinuation for Lenvatinib-Specific AEs..... 95 
 
LIST OF FIGURES 
Figure 1. Study Schema .......................................................................................................... 58 


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SYNOPSIS 
Name of Sponsor: 
BeiGene (Shanghai) Co., Ltd 
Investigational Products:  
Tislelizumab (BGB-A317) 
Title of Study: 
A Phase 2 Study to Investigate the Preliminary Antitumor Activity, 
Safety and Tolerability of Tislelizumab in Combination with Lenvatinib 
in Patients with Unresectable Locally Advanced or Metastatic 
Hepatocellular Carcinoma 
Protocol Identifier: 
BGB-A317-211 
Phase of Development:  
Phase 2 
Number of Patients: 
Planned 60-66 patients will be enrolled for part 1 and part 2 (6-12 for 
part 1 and 54 for part 2) 
Study Centers: 
Approximately 10 centers in China 
Study Objectives: 
Primary: 
• 
To assess the preliminary antitumor activity as indicated by overall response rate (ORR) assessed 
by central site imaging facility for tumor assessment per Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v)1.1 of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma 
Secondary: 
• 
To characterize the safety and tolerability of tislelizumab in combination with lenvatinib in 
patients with unresectable locally advanced or metastatic hepatocellular carcinoma 
• 
To assess the preliminary antitumor activity as indicated by ORR assessed by investigators per 
RECIST v1.1 of tislelizumab in combination with lenvatinib in patients with unresectable locally 
advanced or metastatic hepatocellular carcinoma  
• 
To assess the preliminary antitumor activity as indicated by ORR assessed by investigators and 
central site imaging facility for tumor assessment per modified Response Evaluation Criteria in 
Solid Tumors (mRECIST) and Immune-related Response Evaluation Criteria in Solid 
Tumors(iRECIST) respectively of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma  
• 
To assess the preliminary antitumor activity as indicated by duration of response (DOR), disease 
control rate (DCR), and progression-free survival (PFS) assessed by investigators and central site 
imaging facility for tumor assessment per RECIST v1.1, mRECIST and iRECIST respectively of 
tislelizumab in combination with lenvatinib in patients with unresectable locally advanced or 
metastatic hepatocellular carcinoma 
Exploratory: 
• 
To characterize the pharmacokinetic (PK) and immunogenicity of tislelizumab when given in 
combination with lenvatinib in Part I 
• 
To assess OS 
Study Endpoints: 


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Primary Endpoint: 
• 
ORR assessed by central site imaging facility for tumor assessment based on RECIST v1.1 
Secondary Endpoints: 
• 
The safety and tolerability of tislelizumab in combination with lenvatinib will be evaluated by the 
incidence, nature, and severity of adverse events (AEs) and serious AEs (SAEs) per National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, clinical 
laboratory abnormalities, relevant physical exam, ECGs, vital signs and DLTs. 
• 
ORR assessed by investigators based on RECIST v1.1 
• 
ORR assessed by investigators and central site imaging facility respectively based on mRECIST 
and iRECIST 
• 
DOR, DCR, and PFS assessed by investigators and central site imaging facility respectively 
based on RECIST v1.1, mRECIST and iRECIST 
Exploratory Endpoints: 
• 
Serum concentrations of tislelizumab and incidences of anti-tislelizumab-antibodies (ADA) in 
Part I 
• 
OS  
Study Population 
Patients with histologically or cytologically confirmed unresectable locally advanced or metastatic HCC. 
Key Eligibility Criteria 
Adult patients (≥ 18 years of age at the time of voluntarily signing of informed consent) with 
histologically or cytologically confirmed unresectable locally advanced or metastatic HCC. Barcelona 
Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease that is not amenable to or has 
progressed after loco-regional therapy and is not amenable to a curative treatment approach without any 
prior systemic treatment. All patients are also required to an Eastern Cooperative Oncology Group 
(ECOG) performance status score of ≤ 1, and Child-Pugh A classification for liver function. No tumor 
thrombus involving main trunk of portal vein or inferior vena cava. At least one measurable site of 
disease as defined by RECIST v1.1 per radiologically. Life expectancy≥3 months. 
Study Design 
This is an open-label, multicenter Phase 2 clinical study for patients with histologically or cytologically 
confirmed unresectable locally advanced or metastatic HCC. All patients will receive study treatments 
until confirmed progressive disease (iCPD) assessed by investigator based on iRECIST, unacceptable 
toxicity, 12-month treatment duration completion, death, withdrawal of consent, study termination by 
sponsor or patients meet any discontinuation criterion which will be described in protocol (see Section 3.6 
and Section 3.7 for details), whichever comes first. Patients will be closely monitored for safety and 
tolerability throughout the study. This study consists of the following two parts: 


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Part 1 (Safety run-in part [21-day DLT assessment] for lenvatinib in combination with tislelizumab): 
Approximately 6-12 patients with unresectable locally advanced or metastatic HCC will be enrolled in 
this part.  
• 
The safety and tolerability of starting dose for lenvatinib in combination with tislelizumab will be 
evaluated. 3 patients with baseline body weight≥60 kg and 3 patients with baseline body weight
＜60 kg will be enrolled. These patients will be administered with lenvatinib orally once a day 
and tislelizumab (200mg) by intravenous injection (IV), on Day 1 of each 21-day cycle (once 
every 3 weeks, Q3W). The starting dose for lenvatinib in safety run-in part will be based on 
baseline body weight. 12 mg lenvatinib will be administered once daily if baseline body weight of 
patient≥60 kg. 8 mg lenvatinib will be administered once daily if baseline body weight of patient
＜60 kg. 
• 
If ≤1 of 6 patients experience a dose limiting toxicity (DLT) in lenvatinib starting dose cohort, 
this dose level is determined as RP2D (Recommended Phase 2 Dose). The part 2 will be started to 
enroll at RP2D. 
• 
If ＞1 of 6 patients experience a DLT in this cohort, sponsor will decide to terminate the study or 
to start a new cohort to investigate lenvatinib at reduced dose. Lenvatinib dose in the dose 
reduced cohort may be set as 8 mg or 4 mg once daily based on baseline body weight≥60 kg or
＜60 kg, respectively. 6 eligible patients, 3≥60 kg and 3＜60 kg will be enrolled in this cohort. 
Tislelizumab dose is the same, 200 mg IV Q3W.  
• 
If≤1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, this dose level is 
determined as RP2D. The part 2 will start to enroll at RP2D. 
• 
If＞1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, the part 1 will be 
stopped, and part 2 won’t be proceeded.   
The Safety Monitoring Committee (SMC) will determine RP2D of combination treatment based on all 
available safety data.  
Part 2: The planned 54 patients will be enrolled in this part. Each eligible patient will be administered by 
lenvatinib in combination with tislelizumab. Lenvatinib in accordance with recommended dose 
determined in part 1 will be administered orally, once daily continuously, tislelizumab will be 
administered sequentially starting on Cycle 1 Day 1 and every 21 days thereafter.  
The planned 60-66 patients will be enrolled in whole study, including 6-12 patients in part 1 and 54 
patients in part 2. A Simon’s 2 stage design will be used to test the superiority of studied combination 
treatment vs. the historical control. When 30 patients dosed at RP2D level (including patients from both 
part 1 and part 2) are enrolled and all reach their best overall response (BOR) assessed by central site 
imaging facility for tumor assessment based on RECIST v1.1, the preliminary efficiency and safety of 
those 30 patients will be assessed as interim analysis.  


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• 
If within these 30 patients, ≤6 patients achieve response including complete response (CR) and 
partial response (PR) as their BOR assessed by central site imaging facility for tumor assessment 
based on RECIST v1.1, the study will be terminated. 
• 
If within these 30 patients, ＞6 patients achieve response including CR and PR as their BOR 
assessed by central site imaging facility for tumor assessment based on RECIST v1.1, the study 
will continue. 
• 
The enrollment won’t be interrupted after 30 patients were enrolled. 
• 
If patients don’t meet any discontinuation criterion, such as investigator-assessed iCPD based on 
iRECIST, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor, 
lenvatinib and tislelizumab will be administered until patient completes his/her 12-month 
treatment duration of study drugs. After 12-month treatment duration completion, if the patients 
are still under the response (CR, PR) or stable disease (SD) assessed by investigator based on 
RECIST v1.1 or under the response (complete response [iCR], partial response [iPR]), stable 
disease (iSD) and unconfirmed progression (iUPD) assessed by investigator based on iRECIST, 
and may continue receiving benefit based on investigator’s assessment, tislelizumab could be 
further provided by sponsor, this decision must be agreed with medical monitor and documented 
in the study records, patients are also required to be reconsented. 
Study Schema  
 
Abbreviations: QD, once a day; Q3W, every 3 weeks; PO, orally; IV, intravenous injection; LEN, Lenvatinib; TIS, 
Tislelizumab. 
Note: The dose level of tislelizumab is fixed in the entire study. In part 1 whether to proceed to the lenvatinib dose 
reduced cohort will depend on safety observations in lenvatinib starting dose cohort and sponsor’s decision.  
Investigational Products, Dose, and Mode of Administration: 
• 
Tislelizumab will be administered by intravenous injection, on Day 1 of each 21-day cycle (once 
every 3 weeks). The dose of tislelizumab will be fixed as 200 mg. 
• 
Lenvatinib was approved for 1st line HCC treatment in China. It will be administered orally, once 
daily, in a continuous manner. The starting dose and administration of lenvatinib in safety run-in 
part will follow Lenvatinib Package Insert strictly. Lenvatinib dose will be based on baseline 
body weight: 12 mg lenvatinib will be administered once daily if baseline body weight of patient 


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≥ 60 kg, and 8 mg lenvatinib will be administered once daily for patients with baseline body 
weight＜60 kg. The reduced lenvatinib dose is set as 8 mg or 4 mg once daily for patients with 
baseline body weight of ≥ 60 kg or＜60 kg, respectively.  
Study Assessments 
A table of study assessments is provided in Appendix 1. Patients will be closely monitored for safety and 
tolerability throughout the study. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the first dose 
administration of lenvatinib plus tislelizumab at each dose level. For DLT assessment decision, only 
DLTs occurring within 21 days will be evaluated. The following patients will not be considered evaluable 
for DLT, and will be replaced if needed to meet the minimum patient number required for safety 
evaluation: 
• 
Patients who withdraw or are withdrawn from the study before completing the DLT assessment 
window for reasons other than a DLT. 
• 
Patients receiving combination therapy who do not receive ≥ 75% of scheduled lenvatinib and 
≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT assessment window, 
unless they experience a DLT. 
Definition of DLT 
A DLT is defined as any of the following toxicities occurring during the DLT assessment window and 
considered by the investigator to be related to lenvatinib and/or tislelizumab. 
Hematologic 
• 
Grade 4 neutropenia lasting > 7 days 
• 
≥ Grade 3 febrile neutropenia  
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Grade 4 thrombocytopenia lasting > 3 days and requiring transfusion, or any decreased platelet 
count < 15,000/mm3 or < 15.0 x 109/ L 
• 
≥ Grade 4 anemia 
Non-Hematologic 
• 
≥ Grade 4 toxicity 
• 
Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 within 
7 days of initiating optimal supportive care 
Note: The following AEs will not be considered DLTs: 
• 
Grade 3 endocrinopathy that is adequately controlled by hormonal replacement; 


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• 
Grade 3 of tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors); 
• 
Grade 3 rash; 
• 
Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset); 
• 
Grade 3 hypertension that is resolving within 7 days of optimal supportive care; 
Note: Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only 
(and not on the number of antihypertensive medications). Each assessment of BP and BP 
elevation confirmation (systolic and diastolic) should follow Section 7.3.1. 
• 
Clinically insignificant or transient abnormal laboratory findings, including but not limited to 
following: 
o Grade 3-4 alanine aminotransferase elevation, aspartate aminotransferase elevation or 
hyperbilirubinemia without significant related clinical symptoms and judged by 
investigators and medical monitors as non-fatal risk; 
o Grade 3-4 hyperamylasemia or hyperlipasemia that is not associated with symptoms or 
clinical manifestations of pancreatitis and judged by investigators and medical monitors as 
non-fatal risk; 
o Grade 3 proteinuria that is resolving within 7 days of optimal supportive care. 
Tumor Assessments 
Radiological assessment of tumor-response status will be performed approximately every 6 weeks (± 7 
days) in the first year, then every 9 weeks (± 7 days) thereafter.  
Tumor response will be assessed by investigators and central site imaging facility for tumor assessment 
respectively based on mRECIST, RECIST v1.1 and iRECIST.  
After first documentation of response (CR or PR), confirmation of tumor response should occur at 
4 weeks or later after the first response or at the next scheduled assessment time point.   
If radiographic initial PD is observed by the investigator based on RECIST 1.1, patients should continue 
treatment with tislelizumab until iCPD (investigator assessed based on iRECIST) is confirmed by 
repeated imaging ≥ 4 weeks later (but not exceeding 8 weeks from the date of initial documentation of 
PD, repeated imaging on next scheduled tumor assessment visit date, around 6 weeks from the date of 
initial documentation of PD is recommended). The criteria which must be met in order to treat patients to 
continue study drugs beyond initial PD via investigator assessed based on RECIST v1.1 will be described 
in protocol (see Section 7.4 for details). 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed with the 
medical monitor and documented in the study records. In such cases, patients are also required to be 
reconsented. 
Central site imaging facility for tumor assessment 


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Central site imaging facility for tumor assessment is composed of 3 radiology experts at the leading site 
or the site where the leading PI is located, specialized in tumor radiological assessment. The selection of 
these experts will be confirmed by leading PI and medical monitor, documented in study records. The 
executive plan will be described in protocol (see Section 7.4.2 for details). 
Statistical Methods 
Analysis Sets 
• 
The safety analysis set includes all patients who received at least 1 dose of any study drug(s) (any 
component for the combination therapy). This analysis set will be used for all safety analyses. 
• 
The efficacy evaluable analysis set includes all patients within the safety analysis set and with 
both measurable disease at baseline per RECIST v 1.1 and had at least 1 post treatment evaluable 
tumor assessment unless treatment was discontinued due to clinical progression or death before 
the first post treatment tumor assessment. This analysis set will be used for all efficacy analyses. 
• 
DLT evaluable analysis set includes patients who received ≥ 75% of scheduled lenvatinib and 
≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT assessment window. 
This analysis set will be used for the DLT analyses. 
• 
The PK analysis set includes patients who received at least 1 dose of tislelizumab (lenvatinib) and 
contributed at least 1 post-bassline quantifiable tislelizumab (lenvatinib) PK sample.  
DLT Analysis:  
DLTs during the DLT assessment window will be used to determine RP2D of lenvatinib in combination 
with tislelizumab. The DLT events will be summarized descriptively for each combination dosing level in 
the DLT evaluable analysis set. 
Efficacy Analysis: 
The efficacy endpoints (i.e., ORR, DOR, PFS, and DCR) will be assessed by investigators and central site 
imaging facility for tumor assessment respectively based on RECIST v1.1/mRECIST/iRECIST and will 
be summarized to evaluate the antitumor activities of Lenvatinib in combination with tislelizumab.  
• 
ORR is defined as the proportion of patients who had complete response (CR) or partial response 
(PR) as their best overall response (BOR) based achieved during the study.  
• 
DOR is defined as the time interval between the date of the earliest qualifying response (CR or 
PR) and the date of PD or death (whichever occurs earlier). 
• 
DCR is defined as the proportion of patients with BOR of CR, PR or SD.  
• 
PFS is defined as the time from the date of the first dose of study drug(s) to the date of the 
confirmed documentation of PD or death, whichever occurs first.  
• 
OS is defined as the time from the date of the first dose of study drug(s) to the date of death.  


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Observed rates and the binomial exact 95% CI will be calculated for the proportions (ORR, DCR and 
each category of BOR). Hypothesis testing will be done for ORR evaluated based on RECIST v1.1 by 
central site imaging facility for tumor assessment according to the specified Simon’s 2 stage design. 
Time-to-event variables, DOR, PFS, and OS, will be estimated using the Kaplan-Meier (KM) method and 
be plotted over time. Median DOR, PFS, and OS, will be presented by assessor and response evaluation 
criteria along with their 95% CIs, if estimable. PFS rate and OS rate at 6-month and 12-month will also be 
provided. 
Safety Analysis: 
Safety will be determined by the spontaneous reporting of AEs and by laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and ECG findings will 
also be used in determining the safety profile. The severity of AEs will be graded according to the 
CTCAE v5.0. The incidence of DLT events and treatment-emergent adverse events (TEAEs) will be 
reported as the number (percentage) of patients with TEAEs by system organ class (SOC) and preferred 
term (PT). Descriptive summary statistics (i.e., n, mean, standard deviation, median, minimum, maximum 
for continuous variables; n [%] for categorical variables) will be provided for above safety parameters. In 
addition, changes from baseline will also be provided for laboratory and vital signs parameters. 
Sample Size Considerations: 
The planned 60-66 patients will be enrolled in whole study, including 6-12 patients in part 1 and 54 
patients in part 2.  
Part 1 (lenvatinib in combination with tislelizumab safety run-in): Approximately 6 to 12 patients with 
unresectable locally advanced will be enrolled.  
With total of 60 patients at RP2D from both part 1 and part 2, based on Simon’s 2 stage design, we have 
about 95% power to detect a statistical significant difference between ORR (assessed based on RECIST 
v1.1) in studied combination treatment (assumed to be around 40%) to a historical of 18.8% with 1-sided 
alpha as 0.025. Within first 30 pts (including the 6 patients from part 1 and 24 patients from part 2) in the 
efficacy analysis set, if we observe≤6 responders, study will be terminated. Otherwise, study will 
continue. If within the final 60 patients in the efficacy analysis set, we observe≥18 responders, we will 
claim we are statistically superior than a historical control of 18.8% under the settings. Participants 
withdraw due to personal reason or AE before first assessment will be replaced (refer to Analysis Set), 
which might need 4-6 extra participants. 
 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AASLD  
American Association For The Study Of Liver Disease  
ADA 
Antidrug Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity  
AEs 
Adverse Events  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
APHE 
Arterial Phase Hyperenhancement   
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society Of Clinical Oncology 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under The Curve 
BCLC 
Barcelona Clinic Liver Cancer  
BOR 
Best Overall Response 
BP 
Blood Pressure  
CBC 
Complete Blood Count 
CDC 
Complement-Dependent Cytotoxicity  
CEC 
Circulating Endothelial Cells  
CEP 
Circulating Progenitor Cells  
CI 
Confidence Interval  
CK 
Creatine Kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
c-KITR 
C-KIT Receptor  
CK-MB 
Creatine Kinase Mb 
CL 
Systemic Plasma Clearance 
Cmax 
Maximum Plasma Concentration  
CP-A 
Child–Pugh Classes A  
CP-B 
Child–Pugh Classes B 
CR 
Complete Response  
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CYP 
Cytochrome P450 Proteins 
DCR 
Disease Control Rate  
DLT 
Dose Limiting Toxicity 
DOR 
Duration Of Response  
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group  
eCRF  
Electronic Case Report Form  
EFF 
Efficacy Evaluable Analysis Set 
EOT 
End Of Treatment  
ESMO 
European Society For Medical Oncology 
Fc 
Fragment Crystallizable 
FcRIIIA 
Gamma Fragment Crystallizable Region Receptor Iiia  


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Abbreviation 
Definition 
FDA 
US Food And Drug Administration  
FGFR  
Fibroblast Growth Factor Receptors  
FRS2α 
FGF-Receptor Substrate 2Α  
GCP 
Good Clinical Practice  
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practice 
HBcAb 
Hepatitis B Core Antibody 
HBsAg  
Hepatitis B Surface Antigen  
HBV 
Hepatitis B Virus  
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus 
HUVEC 
Human Umbilical Vein Endothelial Cells   
ADL 
Activity Of Daily Living 
ICF 
Informed Consent Form  
ICH 
International Council For Harmonization 
ICU 
Intensive Care Unit 
IECs 
Independent Ethics Committees  
IgG4 
Immunoglobulin G4 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
irAE 
Immune-Related Adverse Event 
IRBs 
Institutional Review Boards  
iRECIST 
Immune-Related Response Evaluation Criteria In Solid Tumors 
IRRC 
Independent Radiologic Review Committee  
IV 
Intravenous Injection  
KIT 
KIT Proto-Oncogenes  
KM 
Kaplan-Meier  
LFT 
Liver Function Testing 
LPI 
Last Patient In  
LVEF 
Left Ventricular Ejection Fraction   
MedDRA® 
Medical Dictionary For Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria In Solid Tumors 
MRI 
Magnetic Resonance Imaging 


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Abbreviation 
Definition 
MTD 
Maximum Tolerated Dose  
MUGA 
Multigated Acquisition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria For 
Adverse Events  
NK cell 
Natural Killer Cell 
NMPA 
National Medical Products Administration 
NSAIDs 
Non-Steroid Anti-Inflammatory Drugs 
NSCLC 
Programmed Cell Death Protein Ligand-1  
NYHA 
New York Heart Association Classification 
ORR 
Overall Response Rate  
OS 
Overall Survival  
PD  
Progressive Disease 
PD-1 
Programmed Cell Death Protein-1 
PDGF-BB 
PDGF-Homodimer BB  
PD-L1 
Programmed Cell Death Protein Ligand-1 
PD-L2 
Programmed Cell Death Protein Ligand-2 
PET  
Positron Emission Tomography  
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic  
PO 
Orally 
PPE 
Palmar Plantar Erythrodysesthesia 
PPES 
Palmar-Plantar Erythrodysesthesia Syndrome  
PR 
Partial Response  
PRES  
Posterior Reversible Encephalopathy Syndrome 
PT 
Preferred Term 
PT 
Prothrombin Time 
Q3W 
Every 3 Weeks   
QD 
Once A Day 
RECIST  
Response Evaluation Criteria In Solid Tumors 
RET 
RET Proto-Oncogenes  
RP2D  
Recommended Phase 2 Dose/Doses 


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Abbreviation 
Definition 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
RSI 
Reference Safety Information 
RTK 
Receptor Tyrosine Kinases 
RTKs 
Receptor Tyrosine Kinases   
SADR 
Serious Adverse Drug Reaction  
SAEs 
Serious Adverse Events 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan  
SCF 
Stem Cell Factor  
SD 
Stable Disease  
SMC 
Safety Monitoring Committee  
SOC 
System Organ Class  
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
sVEGFR 
Soluble VEGFR  
t1/2 
Half-Life  
TACE 
Transarterial Chemoembolization 
TAM 
Tumor Associated Macrophages  
TC-99m 
Technetium-99m 
TEAE 
Treatment Emergent Adverse Events 
TFTs 
Thyroid Function Tests 
TKI 
Tyrosine Kinase Inhibitors 
TME 
Tumor Microenvironment  
TSH 
Thyroid-Stimulating Hormone 
ULN  
Upper Limit Of Normal  
UPCR 
Urine Protein-To-Creatinine Ratio 
Vd 
Volume Of Distribution 
VEGF  
Vascular Endothelial Growth Factor 
 
 


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1. 
INTRODUCTION AND RATIONALES 
1.1. 
Background Information on Hepatocellular Carcinoma 
Liver cancer was the sixth most common type of cancer in 2012, with 782,000 new cases worldwide, the 
fifth most common cancer in men (554,000 cases, 7.5% of the total number of 7410,400) and the ninth in 
women (228,000 cases, 3.4% of the total number of 6657,500) (Ferlay et al 2015). It was also the second 
most common cause of cancer-related mortality worldwide, according to the World Health Organization’s 
GLOBOCAN 2012 database, responsible for an estimated 746,000 deaths in 2012 (Ferlay et al 2015). In 
2015, there was an estimated 466,100 new liver cancer cases and 422,100 liver cancer deaths in China 
(Chen et al 2016), accounting for approximately 50% of the total number of cases and deaths worldwide 
(Torre et al 2015). In 2018, it is estimated that there will be 2215 newly diagnosed liver cancer cases in 
Australia, and 2088 deaths from liver cancer (AIHW 2017). HCC accounts for 80% to 90% of primary 
liver cancer. 
A variety of risk factors are known to cause HCC. These include infection with hepatitis viruses, aflatoxin 
B, tobacco, vinyl chloride, heavy alcohol intake, nonalcoholic fatty liver disease, hemochromatosis, and 
diabetes. Together, hepatitis B virus (HBV) and hepatitis C virus (HCV) account for 80% to 90% of all 
HCC cases worldwide (Bosch et al 2005). Chronic HBV infection is the dominant risk factor for the 
disease in most areas of Asia, with the exception of Japan (El-Serag 2012), while chronic infection with 
HCV is the leading cause of HCC in Western countries and in Japan (Choo et al 2016). 
So far, there are only 2 approved first-line systemic treatment for advanced unresectable HCC by US 
Food and Drug Administration (FDA): sorafenib and lenvatinib. Regorafenib has also been approved by 
FDA as the second line of systemic treatment (Bruix et al 2017). However, sorafenib and regorafenib are 
difficult for patients to tolerate. The most common side effects include hypertension, hemorrhage, hand-
foot skin reaction, diarrhea, sensory neuropathy, weight loss, rash, alopecia, anorexia, and pain in 
abdomen. Additional its efficacy is also unsatisfied, SHARP study shows that in sorafenib group just 7 
patients (2%) had a partial response according to RECIST (NEXAVAR prescribing information). Even 
though lenvatinib shows noninferiority to sorafenib, it still has no decrease of adverse events (AEs) rate. 
Even lenvatinib shows better ORR and PFS, those are still unsatisfied on efficacy for clinical practice. 
(Kudo et al 2018).  
Oxaliplatin in FOLFOX4 chemotherapy is approved in China for unresectable HCC (Chinese 
hepatocellular carcinoma guideline 2017), but more frequent/severe hematological toxicity has been 
observed, including neutropenia, leukopenia, and thrombocytopenia (Qin et al 2013), thus limits 
Oxaliplatin usage in Chinese HCC patients. 
Immune check point-inhibitory receptor, PD-1 is mainly expressed in activated T-cells, plays an 
important role in immune modulation of tumor progression by regulating the key inhibitory signaling in 
the T-cells when engaged by its ligands. Many clinical trial results in solid tumor shows its promising 
efficacy with good tolerability in cancer treatment. So far, only Nivolumab (OPDIVO updated label, 
2018, El-Khoueiry et al 2017) and pembrolizumab (KEYTRUDA updated label, 2018, Zhu AX et al 
2018) are approved in US as second-line monotherapy for advanced HCC after treatment failure with 
sorafenib. There were one-third of patients developing progressive disease (PD) , and the median 


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progression-free survival (PFS) of nivolumab is 4.0 months (2.9 to 5.4) in nivolumab CheckMate040 trial 
(El-Khoueiry et al 2017), one-third of patients developing progressive disease (PD) , and the median PFS 
of pembrolizumab is 4.9 months (95% CI 3.4 to 7.2) in pembrolizumab KEYNOTE224 trial ( Zhu AX et 
al 2018) . In pembrolizumab KEYNOTE240 trial in previously treated patients with advanced HCC, 
KEYNOTE-240 did not meet its co-primary endpoints of OS and PFS compared with placebo plus best 
supportive care (First presentation of data from KEYNOTE-240, 2019). In CheckMate-459, a randomized 
Phase 3 study evaluating nivolumab versus sorafenib as a first-line treatment in patients with unresectable 
HCC, this trial did not achieve statistical significance for its primary endpoint of OS per the pre-specified 
analysis (HR=0.85 [95% CI: 0.72-1.02]; p=0.0752) (Bristol-Myers Squibb Announces Results from 
CheckMate -459 Study, 2019). 
In China as of now there are only 4 therapies approved by National Medical Products Administration 
(NMPA) for patients with patients with unresectable locally advanced or metastatic hepatocellular 
carcinoma, including sorafenib, lenvatinib, FOLFOX4 chemotherapy for first line systemic therapy and 
regorafenib for second line systemic therapy. As mentioned above, these 4 therapies are still unsatisfied 
on efficacy and safety for clinical practice. 
It is believed immunotherapy in combination with TKI could achieve a synergistic effect (see section 1.4 
for details) and due to limited efficacy and poor tolerability of current available monotherapy in HCC 
treatment, , combination therapy is becoming a hot clinical research area in cancer treatment (Masafumi 
Ikeda, et al. 2018 ASCO Annual Meeting).   
Recently, 3 combination treatment studies showed the promising activity in HCC: lenvatinib and 
pembrolizumab combination trial for unresectable HCC (NCT03006926) showed 36.7% ORR in 30 
evaluable patients (0/30 CR, 11/30 PR) based on RECIST1.1 per independent imaging review. Another 
combination trial in HCC, atezolizumab and bevacizumab (NCT02715531), presents 27% ORR by 
independent review facility assessment in 73 evaluable patients (4/73 CR, 16/73 PR). The median PFS 
was 14.9 months. (M.J. Pishvaian, et al 2018). SHR1210 combination treatment with apatinib showed the 
similar result. Of the 16 evaluable HCC patients, the ORR was 43.8% (Xu et al 2018). Although the 
results are promising and suggestive of synergistic effects, optimal anti PD-1/PD-L1 combination 
treatment option are still under investigation. 
1.2. 
Tislelizumab as a PD-1 Blocker 
Immune check point-inhibitory receptor, PD-1 is mainly expressed in activated T-cells including CD8+ 
cytotoxic T-lymphocytes and CD4+ T-helper lymphocytes (Topalian et al 2012, Bersanelli and Buti 
2017). It is believed that PD-1 plays an important role in immune modulation of tumor progression by 
regulating the key inhibitory signaling in the T-cells when engaged by its ligands. The PD-1 signaling 
cascade negatively regulates T-cell receptor and attenuate T-cell proliferation and functional activities, 
leading to T-cell exhaustion. PD-1 expression is markedly up-regulated in tumor-infiltrating lymphocytes, 
while the expression of PD-1 ligand, PD-L1, is significantly increased in tumor cells and tumor-
associated immune cells in the presence of stimulating cytokines such as IFN-γ and IFN-α in the tumor 
microenvironment. Furthermore, the increased PD-1 expression in tumor-infiltrating lymphocytes and/or 
PD-L1 expression in tumor and tumor-associated stromal cells is observed in many types of solid human 


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tumors including, but not limited to, melanoma, squamous cell carcinoma, uveal melanoma, NSCLC, 
head and neck squamous cell carcinoma , triple-negative breast cancer, renal cell carcinoma, bladder 
cancer, and ovarian cancer (Jin and Yoon 2016, ONO 2017, Patel and Kurzock 2015, Van Der Kraak et al 
2016, McDaniel 2016, Gong et al 2011, Liu et al 2017, Saito et al 2013). Several anti-PD-1 agents have 
been approved for the treatment of several cancers. Thus, PD-1 is an established target for cancer 
immunotherapy. 
1.2.1. 
Pharmacology 
Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against PD-1 
under clinical development for the treatment of HCC.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as well as 
high affinity (dissociation constant [KD]=0.15 nM). It competitively blocks binding efforts by both PD-
L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative 
signaling in T cells. In in vitro cell-based assays, tislelizumab was observed to consistently and dose-
dependently enhance the functional activity of human T-cells and preactivated, primary peripheral blood 
mononuclear cells. In addition, tislelizumab has demonstrated antitumor activity in several allogeneic 
xenograft models, in which peripheral blood mononuclear cells were coinjected with human cancer cells 
(A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
The IgG4 variant antibody has very low binding affinity to gamma fragment crystallizable region (Fc) 
receptor IIIA (FcγRIIIA) and complement 1q, a subunit of complement 1, by in vitro assays, suggesting 
either low or no antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity 
(CDC) effects in humans (Labrijn et al 2009). 
Please refer to the tislelizumab IB for additional details regarding nonclinical studies of tislelizumab. 
1.2.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology studies in mice 
and monkeys and in a 13-week, repeat-dose toxicology study in cynomolgus monkeys. The pivotal 
toxicology studies were conducted following GLP regulations. The single-dosing regimens spanned from 
the intended human doses to 10-fold higher than the maximum of the intended human doses, and the 
repeat-dosing regimens spanned to 3-fold higher than the maximum of the intended human doses. 
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue cross-reactivity was 
found in either human or monkey tissues, nor was any effect on cytokine release observed in human 
whole-blood assay. The toxicokinetics profile was well characterized, with dose proportional increases in 
systemic exposure without apparent accumulation or sex difference. Immunogenicity was observed 
without apparent immunotoxicity or effect on the systemic exposure. The NOAEL of tislelizumab in the 
13-week monkey toxicity study was to be considered to be 30 mg/kg. The safety profile of tislelizumab is 
considered adequate to support the current study of BGB-A317-211.  
Please refer to the tislelizumab IB for more detailed information on the toxicology of tislelizumab. 


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1.2.3. 
Clinical Pharmacology 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim PK analysis (data cutoff date 
28 August 2017) was conducted using noncompartmental methods, using serum concentrations from 
patients who received doses of 0.5, 2.0, 5.0, and 10 mg/kg once every 2 weeks, and 2.0 mg/kg, 5.0 mg/kg, 
and 200 mg once every 3 weeks. The Cmax and the AUC increased in a nearly dose-proportional manner 
from 0.5 mg/kg to 10 mg/kg, both after single-dose administration at steady state. Preliminary PK data 
from 27 patients who were administered 1 dose of 200 mg once every 3 weeks showed tislelizumab 
concentrations between the range of concentrations observed for patients who were administered 2 mg/kg 
and 5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first-order elimination shows a 
systemic plasma clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution (Vd) in the central 
and peripheral compartments of 2.89 L and 1.76 L, respectively, and half-life (t1/2) of approximately 
19 days. Race, gender, and body weight were not significant covariates on the CL of tislelizumab, which 
supports fixed-dosing across different ethnic groups. 
1.2.4. 
Clinical Experience With Tislelizumab 
As of 20 May 2019, there are 22 ongoing studies with tislelizumab. Of these, 13 have available 
preliminary data available: 7 monotherapy studies (BGB-A317_Study_001, BGB-A317-102, BGB-A317-
203, BGB-A317-204, BGBA317-207, BGB-A317-208, and BGB-A317-209); 2 chemotherapy 
combination therapy studies (BGB-A317-205 and BGB-A317-206); and 4 investigational agent 
combination therapy studies (BGB-A317/BGB-290_Study_001 [tislelizumab in combination with BGB-
290 (also known as pamiparib, a poly [ADP-ribose] polymerase [PARP] inhibitor)], BGB-
3111_BGBA317_Study_001 [tislelizumab in combination with zanubrutinib (also known as BGB-3111, a 
Bruton’s tyrosine kinase inhibitor)], BGB-900-101 [BGB-A333 (an anti-PD-L1 monoclonal antibody) 
alone and in combination with tislelizumab], and BGB-900-103 [tislelizumab in combination with 
sitravatinib (also known as MGCD516, a receptor tyrosine kinase inhibitor)]).  
Additionally, there are 9 ongoing studies that do not have available clinical data yet, including 7 pivotal 
Phase 3 studies (Studies BGB-A317-301, BGB-A317-302, BGBA317-303, BGB-A317-304, BGB-A317-
305, BGB-A317-306, and BGB-A317-307) and Studies BGB-900-102 and BGB-900-104 that have 
insufficient data.  
Of the ongoing studies, BGB-A317_Study_001, BGB-A317-102, BGB-A317-203, BGB-A317-204, 
BGBA317-207, BGB-A317-208, BGB-A317-209 and BGB-900-103 are considered to be relevant to 
BGB-A317-211 study, available data from BGB-A317_Study_001, BGB-A317-102, BGB-A317-203, 
BGB-A317-204, BGBA317-207, BGB-A317-208, BGB-A317-209 and BGB-900-103 are summarized 
below. 
Please refer to the tislelizumab IB for more detailed information on efficacy and safety of tislelizumab. 
1.2.4.1. 
Study BGB-A317_Study_001 (Monotherapy) 
BGB-A317_Study_001 is a 2-stage study. Phase 1a consists of a dose escalation and dose-finding 
component to establish the maximum tolerated dose (MTD), if any, and recommended Phase 2 dose/doses 


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(RP2D). The primary objective of Phase 1a is to assess the safety and tolerability of tislelizumab in 
patients with advanced tumors. Phase 1b investigates efficacy in select tumor types and further evaluates 
the safety and tolerability of tislelizumab at the selected dose. The primary objective of Phase 1b is to 
assess the antitumor activity of tislelizumab in select tumor types. 
This study was fully enrolled as of 27 October 2017. The MTD was not reached. Data are available from 
451 patients treated on study (116 patients in Phase 1a and 335 patients in Phase 1b). 
Safety results for Study BGB-A317_Study_001 are part of the pooled monotherapy analysis shown in 
Section 1.3.4.8. Preliminary efficacy results are summarized in Section 1.3.4.9. 
1.2.4.2. 
Study BGB-A317_Study_102 (Monotherapy) 
Study BGB-A317-102 is a two-phase, non-randomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors. The dose verification substudy of Phase 1 assessed the 
safety and tolerability of tislelizumab in patients with advanced solid tumors and confirmed the MTD and 
RP2D in Chinese patients. The PK substudy of Phase 1 assesses the PK of the products derived from 2 
manufacturing processes and scales (500L-FMP and 2000L-FMP), and safety and tolerability. An 
indication-expansion Phase 2 study involving 11 groups of indications of interest assesses the efficacy, 
safety, and tolerability of tislelizumab in Chinese patients with malignant solid tumors. This Phase 2 
study utilizes the 200 mg IV Q3W dose and schedule, as it has been confirmed as a tolerable dose in the 
Chinese population. 
This study was fully enrolled as of 31 May 2018. Data are available from 300 patients treated on study. 
Safety results for Study BGB-A317-102 are part of the pooled monotherapy analysis shown in Section 
1.3.4.8. Preliminary efficacy results are summarized in Section 1.3.4.9. PK data are not yet available. 
1.2.4.3. 
Study BGB-A317_Study_ 203 (Monotherapy) 
Study BGB-A317-203 is a single-arm, multicenter, Phase 2 study of tislelizumab monotherapy in patients 
with relapsed or refractory classical Hodgkin lymphoma in China. The primary objective of this study is 
to evaluate the efficacy of tislelizumab in this population. Additionally, safety, PK, and immunogenicity 
are being assessed. Approximately 68 patients were planned to be enrolled into the study to receive 
tislelizumab at a dose of 200 mg IV Q3W. This study was fully enrolled as of 22 November 2017. Data 
are available from the 70 patients treated on study. 
Safety results for Study BGB-A317-203 are part of the pooled monotherapy analysis shown in Section 
1.3.4.8. Efficacy and PK data are currently under evaluation in a marketing application. 
1.2.4.4. 
Study BGB-A317_Study_ 204 (Monotherapy) 
Study BGB-A317-204 is a single-arm, open-label, multicenter, Phase 2 study of tislelizumab 
monotherapy in patients with previously treated, program death ligand-1 positive (PD-L1+), locally 
advanced, or metastatic urothelial bladder cancer. The primary objective of this study is to determine the 
efficacy of tislelizumab in this population. Additionally, safety, PK, immunogenicity, and potential 
predictive biomarkers are being assessed. Tislelizumab 200 mg was administered by IV infusion Q3W at 


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a fixed dose. Approximately 110 patients were to be enrolled in this study. This study was fully enrolled 
as of 31 August 2018. Data are available from all 113 patients treated on study.   
Safety results for Study BGB-A317-204 are part of the pooled monotherapy analysis shown in Section 
1.3.4.8. Efficacy and PK data are currently under evaluation in a marketing application. 
1.2.4.5. 
Study BGB-A317_Study_ 207 (Monotherapy) 
Study BGB-A317-207 is an open-label, non-randomized, multicenter, prospective, Phase 2 study of 
tislelizumab monotherapy in patients with relapsed or refractory mature T- and natural killer (NK)-cell 
neoplasms. The primary objective of this study is to determine the efficacy of tislelizumab in this patient 
population. Additionally, safety, PK, immunogenicity, potential predictive biomarkers, and circulating 
Epstein Barr virus DNA levels are being assessed.  
There are three cohorts of patients: Cohort 1 includes patients with relapsed or refractory extranodal 
NK/T-cell lymphoma (nasal or non-nasal type), with aggressive NK leukemia excluded; Cohort 2 
includes patients with relapsed or refractory mature T-cell neoplasms limited to peripheral T-cell 
lymphomas not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large-cell 
lymphoma; and Cohort 3 includes relapsed or refractory patients with stage IB-IVB cutaneous T-cell 
lymphomas, limited to mycosis fungoides or Sèzary syndrome. Tislelizumab 200 mg is administered IV 
Q3W at a fixed dose.  
As of 20 May 2019, Cohort 1 was closed to enrollment with 22 patients treated. Up to 50 patients are 
planned for enrollment into Cohort 2, and up to 10 patients are planned for enrollment into Cohort 3, for a 
total sample size of up to approximately 80-85 patients. Enrollment for this study is ongoing. As of 20 
May 2019, data are available from 66 patients treated on study.   
Safety results for Study BGB-A317-207 are part of the pooled monotherapy analysis shown in Section 
1.3.4.8. Preliminary efficacy and PK data are not yet available. 
1.2.4.6. 
Study BGB-A317_Study_ 208 (Monotherapy) 
Study BGB-A317-208 is an open-label, single-arm, multicenter Phase 2 study of tislelizumab 
monotherapy in patients with previously treated unresectable hepatocellular carcinoma (HCC). The 
primary objective of this study is to evaluate efficacy in patients previously treated unresectable HCC.  
Additionally, safety, tolerability, PK, immunogenicity, and potential predictive biomarkers are being 
assessed. Tislelizumab 200 mg is administered IV Q3W at a fixed dose.  
This study was fully enrolled as of 27 February 2019. Data are available from all 249 patients treated on 
study.   
Safety results for Study BGB-A317-208 are part of the pooled monotherapy analysis shown in Section 
1.3.4.8. Preliminary efficacy and PK data are not yet available. 
1.2.4.7. 
Study BGB-A317_Study_ 209 (Monotherapy) 
Study BGB-A317-209 is an open-label, single-arm, multicenter, Phase 2 study of tislelizumab 
monotherapy in patients with previously treated locally advanced unresectable or metastatic microsatellite 


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instability-high or mismatch repair deficient solid tumors. The primary objective of this study is to 
evaluate the efficacy of tislelizumab in patients with previously treated locally advanced unresectable or 
metastatic solid tumors that are centrally confirmed as microsatellite instability-high or mismatch repair 
deficient. Additionally, duration of response, time to response, disease control rate, progression-free 
survival, safety, tolerability, PK, immunogenicity, and potential predictive biomarkers are being assessed.  
Tislelizumab 200 mg is administered IV Q3W at a fixed dose. 
Approximately 60 subjects were planned to be enrolled in this study. Enrollment for this study is ongoing.  
As of 20 May 2019, data are available from 24 patients treated on study. 
Preliminary safety results for Study BGB-A317-209 are part of the pooled monotherapy analysis shown 
in Section 1.3.4.8. Preliminary efficacy and PK data are not yet available 
1.2.4.8. 
Pooled Safety Assessment of Monotherapy Studies 
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety assessment 
separately from combination therapy. To enhance the analysis and interpretation of the monotherapy 
safety profile, safety results from the relevant studies are presented based on the underlying tumor types 
included in the study, either as solid tumors or hematologic malignancies. The monotherapy studies 
within the pooled safety analysis are shown in Table 1. 
Table 1 Pooled Monotherapy Studies of tislelizumab 
 
Study  
Total Enrollment (as of 20 
May 2019) 
Study Design 
Monotherapy-Solid Tumors 
BGB-A317-001  
451 (enrollment complete) 
Section 1.3.4.1 
BGB-A317-102 
300 (enrollment complete) 
Section 1.3.4.2 
BGB-A317-204 
113 (enrollment complete) 
Section 1.3.4.4 
BGB-A317-208 
249 (enrollment complete) 
Section 1.3.4.6 
BGB-A317-209 
24 (enrollment complete) 
Section 1.3.4.7 
Monotherapy-Hematology 
BGB-A317-203 
70 (enrollment complete) 
Section 1.3.4.3 
BGB-A317-207  
66 (enrollment complete) 
Section 1.3.4.5 
 
Total 
1273 
 
The relevant pooled studies are presented based on the underlying tumor types included in the study, 
either as solid tumors or hematologic malignancies, and as a total pooled population.  
There were 1137 patients treated in the 5 pooled solid tumor monotherapy studies. Of the 1137 enrolled, 
439 patients (38.6%) remained on study as of 20 May 2019; 208 patients (18.3%) were still receiving 


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tislelizumab treatment, and 231 patients (18.6%) were in follow-up. At the time of data cut-off, 678 
patients had a dosing period of ≥ 2 months, ie, evaluable for treatment assessment beyond 2 months.  
Among them, 201 patients (29.6%) continued to receive tislelizumab treatment.  
There were 136 patients treated in the 2 pooled hematologic malignancies monotherapy studies. Of the 
136 enrolled, 105 patients (77.2%) remained on study as of 20 May 2019; 64 patients (47.1%) were still 
receiving tislelizumab treatment, and 41 patients (30.2%) were in follow-up. At the time of data cut-off, 
107 patients had a dosing period of ≥ 2 months, ie, evaluable for treatment assessment beyond 2 months. 
Among them, 60 patients (56.1%) continued to receive tislelizumab treatment.  
Overall, there were 1273 patients in the Pooled Monotherapy studies. Of the 1273 enrolled, 544 patients 
(42.7%) remained on study as of 20 May 2019; 272 patients (21.4%) were still receiving tislelizumab 
treatment, and 272 patients (21.4%) were in follow-up. At the time of data cut-off, 785 patients had a 
dosing period of ≥ 2 months, ie, evaluable for treatment assessment beyond 2 months. Among them, 261 
patients (33.2%) continued to receive tislelizumab treatment. 
1.2.4.8.1. 
Dose-Escalation DLTs and Determination of the MTD 
Study BGB-A317-001 
A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness, or concomitant medications, occurring in the first 28 days, and meeting any of the 
criteria listed in the study protocol. 
The maximum administered dose in the dose escalation part of the study was 10 mg/kg Q2W. The MTD 
was not identified. Only 1 DLT of Grade 3 colitis occurred with 5 mg/kg Q2W. Based on the results of 
103 patients in the dose-escalation and dose-expansion part of the Phase 1a study, 5 mg/kg Q3W was 
selected to explore tislelizumab activity in multiple tumor types in the Phase 1b study. An additional 
cohort (Phase 1a, Part 3) was added to evaluate fixed dosing at 200 mg Q3W. 
Study BGB-A317-102 
The occurrence of any of the toxicities listed in the study protocol during Cycle 1 were considered a DLT, 
if judged by the Investigator to be possibly, probably, or definitely related to study drug administration.  
No DLTs occurred in Phase 1 dose verification portion of Study BGB-A317-102. The dose of 200 mg 
Q3W was confirmed as the RP2D.  
1.2.4.8.2. 
Treatment-Emergent Adverse Events Assessed as Related to Treatment with in 
Monotherapy Studies 
As of 20 May 2019, Of the 1137 total patients in the solid tumor group within the Pooled Monotherapy 
studies, 734 (64.6%) experienced at least one treatment-related TEAE. The most common treatment-
related TEAEs were list in table 2 below. 


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Table 2 The most common treatment-related TEAEs in the solid tumor group of 
Tislelizumab Pooled Monotherapy studies 
Adverse Event 
Tislelizumab 
The most common treatment-related TEAEs 
 
AST increased 
117 (10.3%) 
ALT increased 
110 (9.7%) 
Fatigue 
90 (7.9%) 
Rash 
88 (7.7%) 
Hypothyroidism 
85 (7.5%) 
 ≥ 1 Treatment-related TEAEs of grade ≥ 3 
 141 (12.4%)  
Treatment-related TEAEs of grade ≥ 3 occurring in ≥1% patients 
 
AST increased 
19 (1.7%) 
ALT increased 
15 (1.3%) 
As of 20 May 2019, within the 136 patients in the hematology group within the Pooled Monotherapy 
studies, 112 (82.4%) experienced at least one treatment-related TEAE. The most common treatment-
related TEAEs were list in table 3 below. 
Table 3 The most common treatment-related TEAEs in the hematology group of 
Tislelizumab Pooled Monotherapy studies 
Adverse Event 
Tislelizumab 
The most common treatment-related TEAEs 
 
Pyrexia 
46 (33.8%) 
Hypothyroidism 
28 (20.6%) 
Pruritus 
16 (11.8%) 
ALT increased 
13 (9.6%) 
AST increased 
11 (8.1%) 


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≥ 1 Treatment-related TEAEs of grade ≥ 3 
21 (15.4%)  
Treatment-related TEAEs of grade ≥ 3 occurring in ≥1% patients 
 
Neutrophil count decreased 
3 (2.2%) 
Lipase increased 
2 (1.5%) 
Anemia 
2 (1.5%) 
Neutropenia 
2 (1.5%) 
Pneumonitis 
2 (1.5%) 
Pneumonia 
2 (1.5%) 
As of 20 May 2019, of the 1,273 total patients treated in the Pooled Monotherapy studies, 846 (66.5%) 
experienced at least one treatment-related TEAE. The most common treatment-related TEAEs were list in 
table 4 below. 
Table 4 The most common treatment-related TEAEs in total patients of Tislelizumab Pooled 
Monotherapy studies 
Adverse Event 
Tislelizumab 
The most common treatment-related TEAEs 
 
AST increased 
128 (10.1%) 
ALT increased 
123 (9.7%) 
Hypothyroidism 
113 (8.9%) 
Rash 
96 (7.5%) 
Pyrexia 
94 (7.4%) 
≥ 1 Treatment-related TEAEs of grade ≥ 3 
163 (12.8%)  
Treatment-related TEAEs of grade ≥ 3 occurring in  ≥1% 
patients 
 
AST increased 
19 (1.5%) 
ALT increased 
15 (1.2%) 


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1.2.4.8.3. 
Special Categories of Immune-Related Adverse Events with in Monotherapy Studies 
As of 20 May 2019, of the 1,137 patients in the solid tumor group for the Pooled Monotherapy studies, 
521 (45.8%) experienced at least one irAE of any grade. The most common irAEs were list in table 5 
below. 
Table 5 The most common irAEs in the solid tumor group of Tislelizumab Pooled Monotherapy 
studies 
Adverse Event 
Tislelizumab 
The most common irAEs of any grade 
 
AST increased 
118 (10.4%) 
ALT increased 
111 (9.8%) 
Rash 
88 (7.7%) 
Hypothyroidism 
85 (7.5%) 
Blood bilirubin increased 
66 (5.8%) 
≥ 1 irAEs of grade ≥ 3 
106 (9.3%)  
The most common irAEs of grade ≥ 3 
 
AST increased 
21 (1.8%) 
Gamma-glutamyltransferase increased 
17 (1.5%) 
ALT increased 
16 (1.4%) 
Pneumonitis 
7 (0.6%) 
As of 20 May 2019, of the 136 patients in the hematology group for the Pooled Monotherapy studies, 81 
(59.6%) experienced at least one irAE of any grade. The most common irAEs were list in table 6 below. 
Table 6 The most common irAEs in the hematology group of Tislelizumab Pooled 
Monotherapy studies 
Adverse Event 
Tislelizumab 
The most common irAEs of any grade 
 
Hypothyroidism 
28 (20.6%) 


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Pruritus 
16 (11.8%) 
ALT increased 
13 (9.6%) 
AST increased 
11 (8.1%) 
Rash 
9 (6.6%) 
≥ 1 irAEs of grade ≥ 3 
15 (11.0%)  
The most common irAEs of grade ≥ 3 
 
Pneumonitis 
2 (1.5%) 
Pneumonia 
2 (1.5%) 
Lipase increased 
2 (1.5%) 
Blood creatine phosphokinase increased 
2 (1.5%) 
As of 20 May 2019, of the 1,273 total patients for the Pooled Monotherapy studies, 602 (47.3%) 
experienced at least one irAE of any grade. The most common irAEs were list in table 7 below. 
Table 7 The most common irAEs in total patients of Tislelizumab Pooled Monotherapy 
studies 
Adverse Event 
Tislelizumab 
The most common irAEs of any grade 
 
AST increased 
129 (10.1%) 
ALT increased 
124 (9.7%) 
Hypothyroidism 
113 (8.9%) 
Rash 
97 (7.6%) 
Pruritus 
78 (6.1%) 
≥ 1 irAEs of grade ≥ 3 
121 (9.5%)  
The most common irAEs of grade ≥ 3 
 
AST increased 
21 (1.6%) 


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Gamma-glutamyltransferase increased 
17 (1.3%) 
ALT increased 
16 (1.3%) 
Pneumonitis 
9 (0.7%) 
Pneumonia 
9 (0.7%) 
1.2.4.8.4. 
Fatal Adverse Events with in Monotherapy Studies 
As of 20 May 2019, 68 patients (5.3%) had a TEAE leading to death. A total of 105 patients (8.2% of the 
total population) died within 30 days of the last study drug dose in the Pooled Monotherapy studies. Of 
these 105 patients, there were 21 patients (1.6% of the total population) who had an AE with a fatal 
outcome within 30 days of the last study drug dose. Of the 536 patients (42.1% of the total population) 
who died more than 30 days after the last study drug dose, 14 patients (1.1% of the total population) died 
as a result of an AE. 
1.2.4.9. 
Pooled Efficacy Assessment of Monotherapy Studies 
Study BGB-A317-001 
BGB-A317_Study_001 is a two-stage study. Phase 1a consists of a dose escalation and dose-finding 
component, and Phase 1b investigates efficacy and safety in select tumor types. 
There were 451 patients treated in the study and 441 patients were included in the efficacy evaluable set. 
Responses were assessed by the Investigator per RECIST v1.1 criteria.  
Across all disease cohorts, there were 5 patients (1.1%) with a CR. A total of 55 patients (12.5%) had a 
confirmed PR. The resulting overall clinical response rate was 13.6%. Additionally, there were 142 
patients (32.2%) with a best overall response of stable disease (SD). A total of 199 patients (45.1%) had a 
best response of PD in this study. 
Study BGB-A317-102 
Study BGB-A317-102 is a two-phase, non-randomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors.  Phase 1 includes a dose verification substudy and a 
substudy of PK evaluation of the products derived from 2 manufacturing processes and scales. Phase 2 is 
an indication expansion study.  
Responses were assessed by the Investigator per the RECIST v1.1 criteria. 
Overall, of the 300 patients treated in Study BGB-A317-102, 249 patients were included in the Efficacy 
Evaluable Analysis Set. The Efficacy Evaluable Analysis Set includes all treated patients who had at least 
1 measurable baseline target lesion and had at least 1 evaluable post-baseline tumor assessment.  
Across all disease cohorts and study phases, there was 1 patient (0.4%) with a CR. A total of 44 patients 
(17.7%) had a confirmed PR. The resulting overall clinical response rate was 18.1%. Additionally, there 


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were 91 patients (36.5%) with a best overall response of SD. A total of 113 patients (45.4%) had a best 
response of PD in this study. 
1.2.4.10. 
Study BGB-900-103 (Combination Therapy)  
Study BGB-900-103 is an open-label, multicenter, non-randomized, Phase 1b study to assess the safety, 
tolerability, PK, and preliminary antitumor activity of sitravatinib in combination with tislelizumab in 
patients with advanced solid tumors. Additionally, potential pharmacodynamic biomarkers, biomarkers of 
efficacy or resistance, immunogenicity of tislelizumab, and overall survival are being assessed. 
Approximately 140 patients were planned to be enrolled in this study. Enrollment for this study is 
ongoing. As of 20 May 2019, data are available from 38 patients treated on study. 
Preliminary efficacy and PK data are not yet available. 
Preliminary Safety 
Of the 38 patients treated, 36 patients (94.7%) remained on study as of 20 May 2019; 31 patients (81.6%) 
were still receiving tislelizumab treatment, and 5 patients (13.2%) were in follow-up. At the time of data 
cut-off, 21 patients had a dosing period ≥ 2 months, ie, evaluable for treatment assessment beyond 2 
months. Among them, 19 patients (90.5%) continued to receive tislelizumab treatment. 
As of 20 May 2019, the median treatment exposure duration for tislelizumab for patients in Study BGB-
900-103 was 2.15 months (range: 0.1 to 6.6), and the median study follow-up duration was 2.68 months 
(range: 0.1 to 6.6). 
Of the 38 total patients treated in Study BGB-900-103, 19 (50.0%) experienced at least 1 TEAE assessed 
as related to tislelizumab by the investigator. The most common treatment-related TEAEs were 
summarized in table 8 below. 
Table 8 The most common treatment-related TEAEs in Study BGB-900-103 
Adverse Event 
Tislelizumab + sitravatinib 
Treatment-related TEAEs 
 
ALT increased 
5 (13.2%) 
AST increased 
3 (7.9%) 
transaminases increased 
3 (7.9%) 
fatigue 
3 (7.9%) 
hypothyroidism 
3 (7.9%) 
≥ 1 treatment-related TEAEs of grade ≥ 3 
4 (10.5%) 


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Treatment-related TEAEs of grade ≥ 3 occurring in ≥ 2 patients 
 
transaminases increased  
2 (5.3%) 
Treatment-related TEAEs of grade ≥ 3 occurring in 1 patients 
 
ALT increased 
1 (2.6%) 
platelet count decreased 
1 (2.6%) 
intestinal obstruction 
1 (2.6%) 
Special Categories of Immune-Related Treatment-Emergent Adverse Events 
Of the 38 total patients treated in Study BGB-900-103, 11 (28.9%) experienced at least 1 potential irAE.  
The potential irAEs occurring in 2 or more patients were ALT increased (5 patients, 13.2%; 1 patient with 
an event ≥ Grade 3); AST increased, transaminases increased, and hypothyroidism (3 patients each, 7.9%; 
2 patients with transaminases increased events ≥ Grade 3); and diarrhea (2 patients, 5.3%). All other 
events occurred in single patients and no additional events ≥ Grade 3 were reported. 
Fatal Adverse Events 
As of 20 May 2019, there had been no fatal AEs reported in Study BGB-900-103. There was 1 patient 
who died more than 30 days after the last dose of study medication.   
This death was attributable to the patients underlying disease under study. 
1.2.5. 
Clinical Safety of Tislelizumab 
According to available clinical studies data (as of 20 May 2019), the safety profile of tislelizumab is 
consistent with the therapeutic class of the drug with a relatively low rate of treatment-related Grade 3 or 
above toxicity. 
Across the monotherapy studies, the safety profile was consistent in the Phase 1 and Phase 2 studies.  
Over half of the patients in these studies experienced a treatment-related TEAE, though related ≥ Grade 3 
events were low (12.7%). Immune-related AEs of any grade were reported in approximately 50% of 
patients but were primarily low grade (9% ≥ Grade 3). These irAEs, however, have well-established 
algorithms for treatment and are therefore considered manageable. 
In studies with tislelizumab plus chemotherapy, the AE profile is consistent with the now well-established 
profile of an immune checkpoint inhibitor in combination with the established AE profile of the standard 
chemotherapy agent. Over 70% of patients in these studies experienced a treatment-related TEAE, though 
≥ Grade 3 events were lower (13% to 33%). 
When combined with another investigational agent, the safety profile of the combination is generally 
consistent with the safety profiles of each drug given as monotherapy and with other agents in the 
checkpoint and PARP inhibitor classes. In these studies, over 50% of patients experienced a treatment-


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related TEAE, though ≥ Grade 3 events were lower (10% to 38%). These data should be interpreted with 
some caution as the sample sizes are relatively small for these ongoing studies. 
Serious Adverse Events and Serious Adverse Events with a Fatal Outcome 
Across the monotherapy studies, the treatment-emergent SAE rate was 33.3% in patients with a variety of 
different disease characteristics. Treatment-related treatment-emergent SAEs were notably lower with a 
rate of 9.6%. In studies with tislelizumab plus chemotherapy, the treatment-emergent SAE rate ranged 
from 30% to 43%. Treatment-related treatment-emergent SAEs were notably lower with a rate ranging 
from 13% to 20%. When combined with another investigational agent, the treatment-emergent SAE rate 
ranges from 33% to 58%, but the treatment-related treatment-emergent SAE rate was 5% to 29%.  These 
data should be interpreted with some caution as the sample sizes for some of these individual studies are 
relatively small. 
There have been 83 TEAEs leading to death (4.9% of the total population [n=1705]) reported as of 20 
May 2019 across all of the active studies with clinical data available. The incidence of TEAEs leading to 
death was low overall across studies, and the AEs associated with an outcome of death were consistent 
with what has been reported for the pharmaceutical class. 
Please refer to the tislelizumab IB for more detailed information on safety of tislelizumab. 
1.2.6. 
Rationale for Selection of Tislelizumab Dose 
The PK, safety, and efficacy data obtained from the first-in-human study BGB-A317_Study_001, as well 
as other clinical study data, were analyzed in aggregate to determine the recommended dose for pivotal 
studies of tislelizumab. The flat dose of 200 mg intravenously (IV) once every 3 weeks was selected for 
further evaluation. The MTD was not identified and only 1 DLT was reported in the first-in-human study. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg once every 
2 weeks and once every 3 weeks were comparable, suggesting no clear dose-dependence across these 
regimens. Similarly, confirmed ORRs in patients treated with tislelizumab 2 mg/kg and 5 mg/kg once 
every 2 weeks ranged between 10% and 15%, compared to a range of 15% to 38% for patients treated at 2 
mg/kg and 5 mg/kg once every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found to be 
independent of body weight, ethnicity, and gender, and the observed serum exposure of a 200-mg dose 
fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose range with comparable 
safety and efficacy rates).  
Additionally, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n = 13), 3 patients (23%) had a BOR of PR, 4 patients (31%) had a BOR of 
stable disease (SD), and 6 patients (46%) had a BOR of PD. Therefore, clinical activity with a 
manageable and tolerable safety profile is expected to be maintained in patients receiving tislelizumab 
200 mg once every 3 weeks. 


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In conclusion, tislelizumab 200 mg once every 3 weeks is the recommended initial dose for combination 
with lenvatinib.  
1.3. 
Lenvatinib as a Receptor Tyrosine Kinase Inhibitor 
Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate 
cell-to-cell communication (Hubbard and Miler 2007). They are a subclass of cell-surface growth-factor 
receptors with an intrinsic, ligand-controlled tyrosine-kinase activity. These single-pass transmembrane 
receptors, which bind polypeptide ligands-mainly growth factors-play key roles in processes such as 
cellular growth, differentiation, metabolism, and motility. In cancer, constitutive and aberrant activations 
of components of those pathways result in increased proliferation, survival, and metastasis. Therefore, 
these signaling pathways became prime targets for cancer therapy. 
Lenvatinib (E7080) is an oral small molecule, multikinase inhibitor, which was discovered in an 
exploratory study for an angiogenesis inhibitor, mainly inhibits vascular endothelial growth factor 
(VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3), fibroblast growth factor (FGF) receptors 
(FGFR1, FGFR2, FGFR3, and FGFR4), KIT, and RET (Tohyama O, et al. J Thyroid Res. 2014). 
Lenvatinib is an extremely effective inhibitor of tumor angiogenesis that simultaneously interferes with 
these tumors angiogenesis-related molecular and suppresses growth signals mediated by VEGFRs and 
FGFRs (Yamamoto Y, et al. Vasc Cell. 2014). Lenvatinib also exhibited antiproliferative activity in 
hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of 
FGF-receptor substrate 2α (FRS2α) phosphorylation (FDA updated label of lenvatinib capsules, 2018 ). 
In vivo study where human cancer cells are transplanted in immune deficient mouse models, lenvatinib 
also demonstrated high anticancer effect in a wide variety of cancers including HCC. In addition, safety 
results in non-clinical studies showed lenvatinib was well tolerated within the therapeutic range. In 
addition to targeting genetically altered oncogenic drivers, lenvatinib targets are expressed in a number of 
immune cell types and promote an immunosuppressive tumor microenvironment (TME), providing 
rationale for combining with PD-1 checkpoint inhibitor therapy. For example, lenvatinib may 
significantly decreased the percentage of tumor associated macrophages (TAM) in mice model with 
hepatocellular carcinoma cell, in addition immune inhibitory molecules were downregulated in tumors. 
And in the same preclinical trial lenvatinib significantly increased the percentage of IFNγ-secreting CD8+ 
T cells (Kato Y, et al. Molecular Cancer Therapeutics 2015 ). In another preclinical trial, in mouse models 
PD-1 inhibitor increased both Th1 and Th2 cytokines, LEN decreased Th2 cytokines, and combination 
treatment increased Th1 cytokines but decreased Th2 cytokines. In the same preclinical trial combination 
of LEN with PD-1 inhibitor showed more potent inhibitory activity against tumor growth compared with 
each single agent (Kato Y, et al. Annals of Oncology 2016).  
Lenvatinib was approved for several solid tumor by FDA including differentiated thyroid cancer at a dose 
of 24 mg once daily, renal cell carcinoma at a dose of 18 mg in combination with 5 mg everolimus once 
daily and hepatocellular carcinoma at a body weight-dependent doses (12 mg for patients greater than or 
equal to 60 kg or 8 mg for patients less than 60 kg) once daily (Lenvatinib Pharmaceutical Instruction. 
2018.), and approved by National Medical Products Administration (NMPA) for hepatocellular 
carcinoma at a body weight-dependent doses (12 mg for patients greater than or equal to 60 kg or 8 mg 
for patients less than 60 kg) once daily (Lenvatinib Pharmaceutical Instruction. 2018.). 


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1.3.1. 
Pharmacology 
There are multiple studies to reported analyses on the pharmacodynamic properties of lenvatinib 
following administration in patients with cancer. A preclinical trial with human thyroid cancer models 
(Tohyama O et al. 2014) shown the half-maximal concentration (IC50) values of lenvatinib for its targets 
are shown following: IC50 for VEGFR1, VEGFR2, VEGFR3, RET proto-oncogenes (RET), ﬁbroblast 
growth factor receptor (FGFR) 1, FGFR 2, FGFR 3, FGFR 4, platelet-derived growth factor receptor 
(PDGFR) alpha and KIT proto-oncogenes (KIT) is 4.7 nmol/L, 3.0 nmol/L, 2.3 nmol/L, 6.4 nmol/L, 61 
nmol/L, 27 nmol/L, 52 nmol/L, 43 nmol/L, 29 nmol/L and 85 nmol/L respectively.  
In vitro angiogenesis model, lenvatinib inhibits both VEGF-driven and FGF-driven tube formation of 
Human Umbilical Vein Endothelial Cells (HUVEC) at almost similar dose (IC50 values are 2.1 nmol/L 
and 7.3 nmol/L, respectively). Next, the effects of lenvatinib on in vivo angiogenesis, which was 
enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the 
mouse dorsal air sac assay. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF 
transfectants) or FGF (KP-1/FGF4 transfectants) was significantly suppressed with oral treatments of 
lenvatinib at 10 and 30 mg/kg. In addition, lenvatinib significantly inhibited bFGF-induced angiogenesis 
in matrigel plug assay, which is driven by recombinant human bFGF and stromal-derived mouse VEGF, 
at even 3 mg/kg. Increase of plasma FGF23 level is PD biomarker for an inhibition of FGFR1 signaling 
and it has been known that plasma FGF23 level is up-regulated by administration of FGFR inhibitors in 
mice. Lenvatinib at 10 mg/kg significantly elevated mice FGF23 levels 24 hours after lenvatinib 
treatment in a dose dependent manner. In conclusion, lenvatinib has potent both VEGF and FGF driven-
antiangiogenic activity in vitro and in vivo. Inhibition of FGFR signaling pathway with lenvatinib was 
also supported by increase of plasma FGF23 levels at the same dose to show an inhibition in FGF-driven 
in vivo angiogenesis model (Ichikawa K, et al. 2015). 
A preclinical trial demonstrated that lenvatinib has potent preclinical antitumor activity in human HCC 
xenograft models with or without amplification/overexpression of fibroblast growth factor 19, 
furthermore, the maximum antitumor effect of lenvatinib was greater than that of sorafenib in this study 
(Matsuki M, et al. 2017). 
1.3.2. 
Toxicology 
Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic 
in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro 
mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; 
however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential 
for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous 
epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures 
approximately 0.02 to 0.09 times the AUC at the recommended clinical dose of 24 mg once daily for 
differentiated thyroid cancer. Follicular atresia of the ovaries was observed in monkeys and rats at 
exposures 0.2 to 0.8 times and 10 to 44 times the AUC at the recommended clinical dose of 24 mg once 


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daily for differentiated thyroid cancer, respectively. In addition, in monkeys, a decreased incidence of 
menstruation was reported at lenvatinib exposures lower than those observed in humans at the 
recommended clinical dose of 24 mg once daily for differentiated thyroid cancer (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
1.3.3. 
Clinical Pharmacology 
After oral administration of lenvatinib, time to peak plasma concentration (Tmax) typically occurred from 
1 to 4 hours post-dose. Administration with a high fat meal did not change bioavailability of lenvatinib, 
but delayed the median Tmax from 2 hours to 4 hours. In patients with solid tumors administered single 
and multiple doses of lenvatinib QD, the maximum lenvatinib plasma concentration (Cmax) and the area 
under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg 
with a median accumulation index varying between 0.96 (20 mg) and 1.54 (6.4 mg). At clinically relevant 
doses (≥12 mg QD), mean accumulation ratios of lenvatinib ranged between 0.96 and 1.28. Plasma 
lenvatinib concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of 
lenvatinib was approximately 28 hours (Lenvatinib FDA Approval Package. 2014).  
In vitro binding of lenvatinib to human plasma proteins ranged from 97.9% to 98.6% (0.3-30 μg/mL). The 
contributions of albumin, α1-acid glycoprotein, and γ-globulin to the human plasma protein binding of 
lenvatinib were estimated to be 93.2%, 6.1%, and 0.7%, respectively. In vitro, the lenvatinib blood-to-
plasma concentration ratio ranged from 0.59 to 0.61 (0.1-10 μg/mL) (Lenvatinib FDA Approval Package. 
2014). 
1.3.4. 
Pharmacodynamic Properties 
In a Phase 1 dose-escalation study of lenvatinib, investigators utilized biomarker analysis of circulating 
endothelial cells (CEC) and circulating progenitor cells (CEP), which reﬂect active vascular turnover and 
angiogenesis, to conduct lenvatinib pharmacodynamic analyses in patients with advanced solid tumors 
(Yamada K et al. 2011). Furthermore, this study also evaluated whether the CEC and CEP were c-KIT 
positive (+) or c-KIT negative (-). The c-KIT receptor (c-KITR) is expressed on endothelial, mast, and 
cancer cells, and it is believed that activation of c-KITR via its ligand, stem cell factor (SCF), induces 
signal transduction pathways that may promote angiogenesis (Marech I et al. 2014). After 14 days of oral 
lenvatinib treatment, c-KIT(+) CEPs and CECs signiﬁcantly decreased, but c-KIT(-) CEPs and CECs did 
not (Yamada K et al. 2011). Change from baseline in c-KIT(+) CEC ratio in cycle 1 (14-day treatment) 
and baseline stromal cell-derived factor 1-alpha (SDF1a), c-KIT(+) CEPs, and c-KIT(+) CEP ratio was 
signiﬁcantly associated with the therapeutic effect of lenvatinib. 
A separate Phase 1 dose-escalation trial of lenvatinib evaluated correlations between pharmacodynamic 
biomarkers and patient clinical outcomes (Koyama N et al. 2014). Plasma pharmacodynamic biomarkers 
measured in this study included the angiogenic proteins IL-6, IL-8, and IL-10, VEGF, PDGF, HGF, SCF, 
and SDF1a. Soluble VEGFR1 (sVEGFR1) and sVEGFR2 were also quantiﬁed. Lenvatinib was orally 
administered twice daily in 3-week cycles (2 weeks of treatment, then 1 week without treatment), and 
blood samples were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. 
Increasing lenvatinib exposure was signiﬁcantly associated with increased levels of VEGF and SDF1 
alpha, decreased sVEGFR2 levels, and tumor shrinkage. Tumor shrinkage was also associated with 


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decreased sVEGFR2 levels; however, maximum tumor shrinkage was speciﬁcally correlated with 
increased levels of SDF1 alpha.  
An expansion of a Phase 1 study of lenvatinib in patients with solid tumors evaluated pharmacodynamics 
of lenvatinib (escalating doses given in 28-day cycles) in patients with melanoma (Hong DS, et al. 2015). 
Serum samples were tested for angiogenesis-related (PDGF-homodimer BB [PDGF-BB], soluble Tie-2, 
angiopoietin-1, soluble E-selectin, and soluble c-KIT) and apoptosis-related markers (cytochrome C and 
M30 neoantigen). High baseline cytochrome C levels and a higher ratio of M30 on cycle 1, day 8 to 
baseline were associated with greater tumor shrinkage. Decreased angiopoietin-1 ratio (2 h to baseline) 
was associated with prolonged PFS. 
1.3.5. 
Clinical Experience with Lenvatinib in Patients with HCC 
Due to limited data accessibility, lenvatinib monotherapy in patients with HCC have been assessed in 3 
completed clinical studies, including one Phase 1 clinical study (Ikeda M et al. 2016), one Phase 2 clinical 
study (Ikeda M et al. 2017) and one Phase 3 clinical study (Kudo M et al. 2018), and there is one on-
going clinical studies of lenvatinib in combination with pembrolizumab in patients with HCC, which has 
released data before (Masafumi Ikeda, et al. 2018 ASCO Annual Meeting), will be briefed in Section 
1.4.2.2. 
1.3.5.1. 
Lenvatinib Monotherapy Phase 1 Clinical Study for Patients with HCC 
This Phase 1, open-label, dose-escalation study of lenvatinib study (Ikeda M et al. 2016) was determine 
the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary 
efﬁcacy of lenvatinib in patients with advanced HCC stratiﬁed by Child–Pugh (CP) classes A and B 
(Llovet JM, et al. 2008).  
A total of 20 patients, 9 in the CP-A and 11 in the CP-B group, were enrolled in this study between 
August 3, 2009,and November 22, 2011; all patients received the study treatment and completed the 
study. Most patients (65%) had undergone targeted therapy/systemic chemotherapy, predominantly with 
sorafenib. The MTD was12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included 
proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most frequent treatment-emergent AEs 
were list in table 9 below. Serious AEs(SAE) were reported in 4 patients in the CP-A and 6 in the CP-B 
group. There were 2 deaths in the CP-B group that occurred due to hematemesis (8mg) or hepatic failure 
(12mg) as a result of progression of HCC after discontinuation of the study drug. Both deaths were 
considered unrelated to the study drug by the investigator. Other SAEs were hyperbilirubinemia (1 patient 
in the CP-A group and 1 patient in the CP-B group), tumor hemorrhage (2 patients in the CP-B group), 
and hepatic encephalopathy (1patient in the CP-A and 1 patient in the CP-B group). 
Table 9 The most frequent treatment-emergent AEs in the HCC patients of lenvatinib 
monotherapy (Phase 1 Clinical Study) 
Adverse Event 
Lenvatinib 
 
All grades 
Grade 3–4 


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Diarrhea 
90% 
10% 
Fatigue 
90% 
5% 
Decreased appetite 
80% 
10% 
Hypertension 
75% 
50% 
Hyperbilirubinemia 
60% 
20% 
Palmar-plantar erythrodysesthesia syndrome (PPES) 
65% 
5% 
Nausea 
60% 
0% 
Vomiting 
50% 
0% 
There was no complete response. Partial response was observed in 1 patient in each of the CP-A 12-mg, 
CP-A 16-mg, and CP-B 8-mg groups. The ORR was 22.2% (2/9) in the CP-A and 9.1% (1/11)in the CP- 
B. Overall, 10 patients (50.0%) had a best overall tumor response of stable disease: 4 in the CP-A group 
(2 each in the 12-mg and 16-mg cohorts) and 6 in the CP-B group (4 in the 8-mg and 2 in the 12-mg 
cohorts). Progressive disease occurred in 2 (22.2%), 4 (36.4%), and 6 (30.0%) patients in the CP-A group, 
CP-B group, and in the overall study, respectively. The DCR was 66.7% in the CP-A and 63.6% in the 
CP-B group. The overall ORR and DCR were 15.0% (95% CI, 3.2–37.9) and 65.0% (95% CI, 40.8–84.6), 
respectively. Any tumor shrinkage from baseline was observed in 14 patients, 7 each in the CP-A and CP-
B groups. 
1.3.5.2. 
Lenvatinib Monotherapy Phase 2 Clinical Study for Patients with HCC 
This Phase 2, open-label study of lenvatinib study (Ikeda M et al. 2017) was to assess the antitumor 
activity and safety of lenvatinib in patients with advanced HCC. Patients in CP class A, with 
histologically/clinically conﬁrmed advanced HCC who did not qualify for surgical resection or local 
therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. Dose interruption 
and sequential reduction of lenvatinib (to 8- and 4-mg QD) were permitted for drug-related adverse 
events. The study drug was discontinued if patient recovery time was beyond 2 weeks.  
Overall, 46 patients were enrolled and received lenvatinib at 14 sites across Japan and Korea between 
July 2010 and June 2011. All patients were included in the safety and efﬁcacy analyses. Median TTP was 
7.4 months (95 % CI: 5.5–9.4) as assessed by independent radiologic review committee (IRRC) per 
mRECIST. Median TTP was 12.8 months (95 % CI: 7.2–14.7) by investigator assessment. Seventeen 
patients (37 %) achieved a partial response and 19 patients (41 %) had stable disease with a DCR of 78 % 
by IRRC based on mRECIST. Eleven patients (24 %) achieved a partial response and 25 patients (54 %) 
had stable disease with a DCR of 78 % by IRRC based on RECIST 1.1. Median OS was 18.7 months (95 
% CI: 12.7–25.1).  
All 46 patients experienced at least one AE. The most common AEs were summarized in table 10 below. 


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Table 10 The most common AEs in the HCC patients of lenvatinib monotherapy (Phase 2 
Clinical Study) 
Adverse Event 
Lenvatinib 
The most common any-grade AEs 
 
Hypertension 
76% 
Palmar-plantar erythrodysesthesia syndrome (PPES) 
65% 
Decreased appetite 
61% 
Proteinuria 
61% 
Serious AEs (SAEs) 
48% 
The most frequently reported SAE 
 
Hepatic encephalopathy 
11% 
Treatment-related deaths 
0% 
In an exploratory analysis of differences in baseline characteristics between patients who did and did not 
require an early dose withdrawal or reduction, body weight and minimum concentration of lenvatinib 
(Ctrough) were identiﬁed as potential differentiators. Median body weight was lower for patients who 
experienced an early dose withdrawal or reduction (54.1 kg) than for those who did not (67.6 kg).  
1.3.5.3. 
Lenvatinib Monotherapy Phase 3 Clinical Study for Patients with HCC 
This an open-label, Phase 3, multicenter, non-inferiority trial (Kudo M et al. 2018) to compare the 
efficacy and safety of lenvatinib versus sorafenib as a first-line treatment for unresectable HCC. This 
study recruited patients with unresectable HCC, who had not received treatment, in CP class A. Patients 
were randomly assigned (1:1) to receive oral lenvatinib (12 mg/day for bodyweight≥60 kg or 8 mg/day 
for bodyweight <60 kg, QD) or sorafenib 400 mg twice-daily in 28-day cycles.  
Between March 1, 2013, and July 30, 2015, 1492 patients were recruited. 954 eligible patients from 20 
countries were randomly assigned to receive lenvatinib (n=478) or sorafenib (n=476). At the time of data 
cutoff (Nov 13, 2016, at 701 deaths), the median duration of follow-up was 27.7 months (IQR 23.3–32.8) 
in the lenvatinib group and 27.2 months (22.6–31.3) in the sorafenib group. Lenvatinib showed non-
inferiority in terms of overall survival compared with sorafenib, 13.6 vs 12.3 months with HR 0.92 (95% 
CI 0.79–1.06). Median time to progression was 8.9 months (95% CI 7.4–9.2) for patients in the lenvatinib 
group compared to 3.7 months (3.6–5.4) for patients in the sorafenib group. Lenvatinib also showed a 
greater objective response rate than did sorafenib (Odds Ratio 3.34; 2.17–5.14, p＜0.0001). In lenvatinib 
group 90 patients (18·8%, 15.3–22.3) achieved objective response and 348 patients (72.8%, 68.8–76.8) 


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had disease control by independent imaging review based on RECIST 1.1. In sorafenib group 31 patients 
(6.5%, 4.3–8.7) achieved objective response and 281 patients (59.0%, 54.6–63.5) had disease control by 
independent imaging review based on RECIST 1.1. In lenvatinib group and sorafenib group mPFS was 
7.3 (5.6–7.5) and 3.6 (3.6–3.9) with HR 0.65 (0.56–0.77, p＜0.0001).  
The median duration of study treatment for patients in the lenvatinib group was 5.7 months (IQR 2.9–
11.1), compared with 3.7 months (1.8–7.4) in the sorafenib group. Total treatment-emergent adverse 
events in lenvatinib group and sorafenib group was 470 (99%) and 472 (99%) respectively. The most 
common treatment-emergent adverse events were shown in table 11 below.  
Table 11 The most common treatment-emergent adverse events in the HCC patients of 
lenvatinib monotherapy (Phase 3 Clinical Study) 
Adverse Event 
Lenvatinib 
The most common treatment-emergent adverse events of any grade 
 
Hypertension 
42% 
diarrhoea 
39% 
Decreased appetite 
34% 
decreased weight 
31% 
Palmar-plantar erythrodysesthesia 
27% 
Total treatment-emergent adverse events of grade ≥ 3 
75% 
The most common treatment-emergent adverse events of grade ≥ 3 
 
Hypertension 
23% 
Decreased weight 
8% 
Increased blood bilirubin 
7% 
Proteinuria 
6% 
Decreased appetite 
5% 
Decreased platelet count 
5% 
Elevated aspartate aminotransferase 
5% 


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Total treatment-emergent fatal adverse events 
2% 
Hepatic failure 
0.6% 
Cerebral haemorrhage 
0.6% 
Respiratory failure 
0.4% 
1.3.6. 
Rationale for Lenvatinib Dose Selection in HCC Patients 
In the Phase 2 study (Ikeda M et al. 2017), a uniform daily dose of 12 mg irrespective of body weight and 
surface area led to dose reduction in a large proportion of patients: dose adjustment in 34 of 46 patients 
(74%) because of treatment-related adverse events and withdrawal in 10 patients (22%) because of 
toxicity. Close examination of patient characteristics indicated that body weight and serum lenvatinib 
levels were likely to be associated with dose reduction or early withdrawal. More precisely, patients who 
had dose reduction or early therapy withdrawal within 30 days of lenvatinib treatment were significantly 
lighter (median weight, 54.1 vs. 67.6 kg) and had a significantly higher minimum plasma concentration of 
lenvatinib (trough concentration [C1D15Ctrough], 62.4 vs. 33.9 ng/mL). 
In a pooled data analysis study (Toshiyuki Tamai et al. 2017), which aimed to identify the lenvatinib 
optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from Phase 1 studies in 
healthy adults and in subjects with mixed tumor types, were analyzed using a population pharmacokinetic 
approach, the conclusion of this study is that the relationship between the lenvatinib area under the 
plasma concentration–time curve (AUC) at steady state and body weight demonstrated an increase in 
AUC as body weight decreased in subjects with HCC. An exposure–response relationship was observed, 
with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. 
The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng·h/mL, respectively, 
to predict the group at high risk for early drug withdrawal or dose reduction. Therefore 12 mg and 8 mg 
starting doses for subjects ≥ 60 kg and < 60 kg, respectively, in subjects with HCC Child-Pugh class A is 
recommended in this study. 
Based on the available data described above, 12 mg and 8 mg starting doses for subjects ≥60 kg and <60 
kg respectively is recommended for patients with HCC Child-Pugh class A. 
1.4. 
Combination of Lenvatinib and Tislelizumab 
1.4.1. 
Rationale for Combination of Lenvatinib and Tislelizumab in the Treatment of 
Advanced Solid Tumors 
Cancer cells face selective pressures while being treated and mutations occurring in individual cancer 
cells represent continuous evolution of the original cancer. Almost all malignancies develop resistance to 
anticancer therapies eventually. This is also the case for checkpoint blockade agents where acquired 
resistance occurs in a large portion of treated patients who achieved an initial meaningful response.(Syn et 
al 2017). 


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Monoclonal antibodies that target either PD-1 or PD-L1, checkpoint inhibitors, can block binding and 
boost the immune response against cancer cells. These drugs have been shown to be helpful in treating 
several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, 
bladder cancer, head and neck cancers, and Hodgkin lymphoma. Cancer cells in most nonresponders to 
single-agent checkpoint inhibitors escape through innate mechanisms that allow the cancer cells to grow 
and survive. However, unlike intrinsic resistance, late relapses are now emerging in patients with prior 
clinical benefit after longer follow-up of clinical trials, suggesting the emergence of acquired resistance 
(Jenkins et al 2018). Strategies to improve the clinical efficacy of checkpoint inhibitors by overcoming 
innate or acquired resistance are needed. 
Combining an immunotherapeutic PD-1 checkpoint inhibitor with an agent that has both immune 
modulatory and antitumor properties could enhance the antitumor efficacy observed with either agent 
alone. The use of TKIs to treat cancer is well established based on robust clinical efficacy achieved with 
well tolerated inhibitors directed toward oncogenic tyrosine kinases. Together, lenvatinib and tislelizumab 
may elicit greater antitumor activity, as lenvatinib is predicted to enhance several steps in the cancer 
immunity cycle that may augment the efficacy of tislelizumab. First, the antitumor activity of lenvatinib 
may promote the release of tumor antigens by killing tumor cell. Second, lenvatinib may significantly 
decreased the percentage of tumor associated macrophages (TAM) in mice model with hepatocellular 
carcinoma cell, in addition immune inhibitory molecules were downregulated in tumors. And in the same 
preclinical trial lenvatinib significantly increased the percentage of IFNγ-secreting CD8+ T cells (Kato Y, 
et al. Molecular Cancer Therapeutics 2015 ). Third, in mouse models, PD-1 inhibitor increased both Th1 
and Th2 cytokines, lenvatinib decreased Th2 cytokines, and combination treatment increased Th1 
cytokines but decreased Th2 cytokines. In the same preclinical trial combination of LEN with PD-1 
inhibitor showed more potent inhibitory activity against tumor growth compared with each single agent 
(Kato Y, et al. Annals of Oncology 2016).  
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to 
checkpoint inhibitor therapy is a rational approach to improving outcomes in patients. In summary, 
selective RTKs inhibit key molecular and cellular pathways strongly implicated in checkpoint inhibitor 
resistance and therefore represent reasonable strategies to enhance or restore antitumor immunity when 
combined with anti-PD-1 or anti-PD-L1 monoclonal antibodies. 
1.4.2. 
Clinical Experience with Lenvatinib in Combination with PD-1 Inhibitor 
As of 01 September 2019, there are 18 ongoing studies with lenvatinib in combination with PD-1 
inhibitors or PD-L1 inhibitors searched via clinicaltrials.gov. 2 ongoing studies with available preliminary 
data: pembrolizumab combination therapy studies NCT03006887 and NCT03006926.  
Of the ongoing studies, available data from NCT03006887 and NCT03006926 are summarized below. 
1.4.2.1. 
NCT03006887 study (pembrolizumab combination study) (Data Cutoff 02 November 
2017) 
NCT03006887 study is an Open-Label Phase Ib trial to confirm the tolerability and safety of lenvatinib in 
combination with pembrolizumab in participants with selected solid tumors (non-small cell lung cancer, 


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predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous 
cell carcinoma of the head and neck, or melanoma). Participants will receive oral lenvatinib capsules at a 
starting dose of 20 mg once a day in combination with intravenous infusion of pembrolizumab 200 mg 
every 3 weeks on a 21-day treatment cycle (NCT03006887_ clinicaltrials.gov). 
As of 2 November 2017, all the 6 pts (3 Urothelial, 3 NSCLC) received lenvatinib 20 mg QD in 
combination with fixed dose of pembrolizumab 200 mg Q3W and completed Cycle 1 without DLT. The 
most common TEAEs (all grade, > or = 3 of pts) were AST increased (6 pts), hypertension (6 pts), ALT 
increased (5 pts), fatigue (5 pts), hypothyroidism (5 pts), decreased appetite (4 pts), nausea (4 pts), 
proteinuria (3 pts), lipase increased (3 pts), thrombocytopenia (3 pts), and WBC decreased (3 pts). Grade 
3 TEAEs (> or = 2 of pts) were AST increased, ALT increased, and gamma-GTP increased (each 2 pts). 
No Grade 4 or 5 TEAEs were observed. Grade 5 AE was pneumonitis (1 pt). One complete and 1 partial 
response were observed in pts with urothelial carcinoma. Pharmacokinetic evaluation is not available as 
of now (Shigehisa Kitano, et al. 2018 JSMO Annual Meeting). 
1.4.2.2. 
NCT03006926 study (pembrolizumab combination study) (Data Cutoff 23 August 2018) 
NCT03006926 study is an open-label, Phase Ib trial to determine safety, efficacy, tolerability and 
pharmacokinetic profile of lenvatinib with pembrolizumab in patients with BCLC stage B or C 
Hepatocellular Carcinoma. Patients receive lenvatinib 12 mg (body weight > or = 60 kg) or 8 mg (body 
weight < 60 kg) orally once daily and pembrolizumab 200 mg intravenously once every 3 weeks. 
Tolerability was evaluated by assessing DLTs during the first cycle in patient for whom no other 
appropriate therapy (including sorafenib) was available (3+3 design part 1). Once tolerability of 
lenvatinib plus pembrolizumab was confirmed, additional patients with no prior systemic therapy of 
unresectable HCC were enrolled (part 2). Tumor assessments of complete or partial response (CR or PR) 
were confirmed > or 4 weeks after initial response (Masafumi Ikeda, et al. 2018 ASCO Annual Meeting). 
As of 23 August 2018, 30 pts were enrolled and received lenvatinib plus pembrolizumab (Part 1, n=6; 
Part 2, n=24) (Masafumi Ikeda, et al. 2019 AACR Annual Meeting). Patients had BCLC stage B (n=9) or 
C (n=21), Child-Pugh scores of 5 (n=26) or 6 (n=4). At data cutoff (Aug 23, 2018), 18 (60%) pts were 
still on study treatment; median duration of follow-up was 9.7 months. Any-grade TEAEs occurred in 28 
patients (93%); the most common any-grade TEAEs were decreased appetite (63%) and hypertension 
(60%). 7 (23%) pts discontinued treatment due to TEAEs, and no new safety signals were identified. 
Efficacy outcomes reported below. 
Efficacy data for this study are based on a data-cut-off of 23 August 2018 and include part 1 and part 2 
patients.   
• 
For all the patients in part 1 and part 2 (n = 30), there were 11 patients with a confirmed 
response and 16 patients with a best overall response (BOR) of stable disease (SD) based on 
RECIST 1.1 per independent imaging review.  
1.5. 
Benefit-Risk Assessment 
Combination therapy with a small molecule inhibitor of the VEGFR pathway may improve the clinical 
efficacy of immunotherapies and overcome resistance to checkpoint inhibitor therapy (refer to 


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Section 1.4.1). For patients with HCC, combination therapy may improve the clinical efficacy of single-
agent immunotherapies (Section 1.1). Based on available tislelizumab and lenvatinib data and the 
publication from other PD-1 or PD-L1 inhibitors and other small molecule inhibitors of the VEGFR 
pathway, the combination of lenvatinib and tislelizumab may elicit greater antitumor activity and have a 
manageable safety profile. However, the risk benefit for this combination has not yet been established. 
Tislelizumab 
As of 20 May 2019, there are currently 22 ongoing studies with tislelizumab monotherapy or combination 
therapy for several tumors. The safety profile is consistent with known class effects of anti-PD-1 
antibodies and included mostly mild/moderate AEs. Very few Grade 3 or Grade 4 irAEs have been 
observed, which are generally reversible and manageable with study drug interruption and/or steroid 
treatment. For further discussion on the safety profile of tislelizumab, please refer to the tislelizumab IB. 
Lenvatinib monotherapy or in combination with pembrolizumab 
Lenvatinib has been evaluated as monotherapy in patients with advanced HCC through 3 clinical studies, 
which has demonstrated the antitumor efficacy, safety and tolerance of lenvatinib in that patients. 
Lenvatinib was approved for hepatocellular carcinoma by FDA(Lenvatinib Pharmaceutical Instruction. 
2018.).  
As of 01 September 2019, there are 18 ongoing studies with lenvatinib in combination with PD-1 
inhibitors or PD-L1 inhibitors. 2 ongoing studies with available preliminary data are NCT03006887 and 
NCT03006926. Based on updated interim results from the NCT03006926 study, FDA has granted 
Breakthrough Therapy designation for pembrolizumab in combination with lenvatinib for the potential 
first-line treatment of patients with advanced unresectable hepatocellular carcinoma (HCC) not amenable 
to locoregional treatment (Third Breakthrough Therapy Designation from FDA 2019).  
Due to the safety assessment of dosage in combination therapy setting with lenvatinib and pembrolizumab 
has been implemented in NCT03006926 study, and no DLTs has been found during the first cycle in 
patient (3+3 design part 1) , when all patients received regular dosages of lenvatinib for HCC as the label 
approved by FDA ( depended on weight, lenvatinib 12 mg if body weight > or = 60 kg, lenvatinib 8 mg if 
body weight < 60 kg, orally once daily), in combination with regular dosages of pembrolizumab for HCC 
as the label approved by FDA (pembrolizumab 200 mg intravenously once every 3 weeks), and no new 
safety signals were identified as well. 
Benefit-risk assessment of tislelizumab in combination with lenvatinib 
According to above analysis, it may be tolerable when patients with HCC receive regular dosages of 
lenvatinib for HCC in combination with regular dosages of tislelizumab for HCC. Considering of safety, 
safety run-in part for combination dosages of lenvatinib and tislelizumab will be performed.  
Based on the efficacy data of pembrolizumab in combination with lenvatinib for the first-line treatment of 
HCC patients, it is believed Tislelizumab in combination with lenvatinib is also an efficious treatment 
option, benefit-risk assessment favors the implementation of this study. 
A Safety Monitoring Committee (SMC) will be established consisting of the sponsor’s clinical, safety, 
and medical team representatives (eg, medical monitor, Clinical Pharmacology, Statistician, and Drug 


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Safety) and investigators, will monitor the preliminary safety of lenvatinib in combination with 
tislelizumab and determine the RP2D of lenvatinib in combination with tislelizumab based on the 
available data in this study.  
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• 
To assess the preliminary antitumor activity as indicated by overall response rate (ORR) assessed 
by central site imaging facility for tumor assessment per Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v)1.1 of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma  
2.1.2. 
Secondary Objectives 
• 
To characterize the safety and tolerability of tislelizumab in combination with lenvatinib in 
patients with unresectable locally advanced or metastatic hepatocellular carcinoma 
• 
To assess the preliminary antitumor activity as indicated by ORR assessed by investigators per 
RECIST v1.1 of tislelizumab in combination with lenvatinib in patients with unresectable locally 
advanced or metastatic hepatocellular carcinoma  
• 
To assess the preliminary antitumor activity as indicated by ORR assessed by investigators and 
central site imaging facility for tumor assessment per modified Response Evaluation Criteria in 
Solid Tumors (mRECIST) and Immune-related Response Evaluation Criteria in Solid 
Tumors(iRECIST) respectively of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma  
• 
To patients assess the preliminary antitumor activity as indicated by duration of response (DOR), 
disease control rate (DCR), and progression-free survival (PFS) assessed by investigators and 
central site imaging facility for tumor assessment per RECIST v1.1, mRECIST and iRECIST 
respectively of tislelizumab in combination with lenvatinib in patients with unresectable locally 
advanced or metastatic hepatocellular carcinoma 
2.1.3. 
Exploratory Objectives 
• 
To characterize the pharmacokinetic (PK) and immunogenicity of tislelizumab when given in 
combination with lenvatinib in Part 1 
• 
To assess overall survival (OS) 
2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoints 
• 
ORR assessed by central site imaging facility for tumor assessment based on RECIST v1.1 


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2.2.2. 
Secondary Endpoints 
• 
The safety and tolerability of tislelizumab in combination with lenvatinib will be evaluated by the 
incidence, nature, and severity of adverse events (AEs) and serious AEs (SAEs) per National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, clinical 
laboratory abnormalities, relevant physical exam, ECGs, vital signs and DLTs. 
• 
ORR assessed by investigators based on RECIST v1.1 
• 
ORR assessed by investigators and central site imaging facility for tumor assessment respectively 
based on mRECIST and iRECIST 
• 
DOR, DCR, and PFS assessed by investigators and central site imaging facility for tumor 
assessment respectively based on RECIST v1.1, mRECIST and iRECIST 
2.2.3. 
Exploratory Endpoints 
• 
Serum concentrations of tislelizumab and incidences of anti-tislelizumab-antibodies in Part 1 
• 
OS 
3. 
STUDY DESIGN 
3.1. 
Summary of Study Design  
This is an open-label, multicenter Phase 2 clinical study for patients with histologically or cytologically 
confirmed unresectable locally advanced or metastatic HCC. All patients will receive study treatments 
until confirmed progressive disease (iCPD) assessed by investigator based on iRECIST, unacceptable 
toxicity, 12-month treatment duration completion, death, withdrawal of consent, study termination by 
sponsor or patients meet any discontinuation criterion which will be described in protocol (see Section 3.6 
and Section 3.7 for details), whichever comes first. There will be approximately 10 centers in China. 
This study consists of the 2 parts. 
3.1.1. 
Part 1 (Safety run-in part for lenvatinib in combination with tislelizumab) 
Since there is no safety data on lenvatinib in combination with tislelizumab in HCC patient, considering 
patient’s safety, a safety run-in part for combination dosages of lenvatinib and tislelizumab will be 
performed. 
DLT Observation Period and Safety Run-in Scheme  
For part 1 safety run-in, a 21-day DLT assessment window will be utilized for each dose of lenvatinib 
confirmation recommendations in combination with tislelizumab. DLTs will be assessed among evaluable 
patients within 21 days after the first dose of study drugs. Only DLTs occurring within 21 days will be 
evaluated. Approximately 6-12 patients with unresectable locally advanced or metastatic HCC will be 
enrolled in this part. 
Dose safety run-in for lenvatinib in combination with tislelizumab will occur in accordance with the 
following procedures. 


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• 
The safety and tolerability of starting dose for lenvatinib in combination with tislelizumab will be 
evaluated. 3 patients with baseline body weight≥60 kg and 3 patients with baseline body weight
＜60 kg will be enrolled. These patients will be administered with lenvatinib orally once a day 
and tislelizumab (200mg) by intravenous injection (IV), on Day 1 of each 21-day cycle (once 
every 3 weeks, Q3W). The starting dose for lenvatinib in safety run-in part will be based on 
baseline body weight. 12 mg lenvatinib will be administered once daily if baseline body weight of 
patient≥60 kg. 8 mg lenvatinib will be administered once daily if baseline body weight of patient
＜60 kg. 
• 
If ≤1 of 6 patients experience a dose limiting toxicity (DLT) in lenvatinib starting dose cohort, 
this dose level is determined as RP2D (recommended phase 2 dose). The part 2 will start to enroll 
at RP2D. 
• 
If ＞1 of 6 patients experience a DLT in this cohort, sponsor will decide to terminate the study or 
to start a new cohort to investigate lenvatinib at reduced dose. Lenvatinib dose in the dose 
reduced cohort may be set as 8 mg or 4 mg once daily based on baseline body weight≥60 kg or
＜60 kg, respectively. 6 eligible patients, 3≥60 kg and 3＜60 kg will be enrolled in this cohort. 
Tislelizumab dose is the same, 200 mg IV Q3W.  
• 
If≤1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, this dose level is 
determined as RP2D. The part 2 will start to enroll at RP2D. 
• 
If＞1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, the part 1 will be 
stopped, and part 2 won’t be proceeded. Depend on incidence, nature, and severity of DLTs, 
sponsor may decide to implement additional test to characterize the pharmacokinetic (PK) of 
lenvatinib in combination with tislelizumab, to determine the potential influence of lenvatinib PK 
profile in combination with tislelizumab. So, samples of plasma will be collected at specified 
times points within a reasonable variation windows for a potential test of lenvatinib PK profile. 
(refer to Appendix 1 and Appendix 2). 
A Safety Monitoring Committee (SMC) will be established consisting of the sponsor’s clinical, safety, 
and medical team representatives (eg, medical monitor, Clinical Pharmacology, Statistician, and Drug 
Safety) and investigators. A planned formal SMC review of safety data will be performed after at least 6 
evaluable patients have completed 21-day DLT assessment in each lenvatinib dose level. The SMC will 
monitor the preliminary safety of lenvatinib in combination with tislelizumab and determine the RP2D of 
lenvatinib in combination with tislelizumab based on the available data (eg, safety and PK data) in this 
study. Study accrual will be held pending data review and lenvatinib RP2D determination by the SMC. 
Note: the definition of evaluable patients for DLT assessment and DLT assessment window please see 
Section 3.8.1. 
3.1.2. 
Part 2  
Target 54 patients will be enrolled in this part. Each eligible patient will be administered by lenvatinib in 
combination with tislelizumab. Lenvatinib in accordance with RP2D determined in part 1 will be 
administered orally, once daily continuously, tislelizumab will be administered sequentially starting on 


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Cycle 1 Day 1 and every 21 days thereafter. The study drug(s) will be administered until they meet a 
discontinuation criterion. (The enrollment won’t be interrupted after 30 patients were enrolled. 
Figure 1). 
Target 60-66 patients will be enrolled in whole study, including 6-12 patients in part 1 and 54 patients in 
part 2. A Simon’s 2 stage design will be used to test the superiority of studied combination treatment vs. 
the historical control. When 30 patients dosed at RP2D level (including patients from both part 1 and part 
2) are enrolled and all reach their best overall response (BOR) assessed by central site imaging facility for 
tumor assessment based on RECIST v1.1, the preliminary efficiency and safety of those 30 patients will 
be assessed as interim analysis. (refer to Section 9.7 for details) 
• 
If within these 30 patients, ≤6 patients achieve response including complete response (CR) and 
partial response (PR) as their BOR assessed by central site imaging facility for tumor assessment 
based on RECIST v1.1, the study will be terminated. 
• 
If within these 30 patients, ＞6 patients achieve response including CR and PR as their BOR 
assessed by central site imaging facility for tumor assessment based on RECIST v1.1, the study 
will continue. 
• 
The enrollment won’t be interrupted after 30 patients were enrolled. 
Figure 1. Study Schema 
 
Abbreviations: QD, once a day; Q3W, every 3 weeks; PO, orally; IV, intravenous injection; LEN, Lenvatinib; TIS, 
Tislelizumab. 
Note: The dose level of tislelizumab is fixed in the entire study. In part 1 whether to proceed to the lenvatinib dose 
reduced cohort will depend on safety observations in lenvatinib starting dose cohort and sponsor’s decision. 
3.2. 
Screening Period 
Screening evaluations will be performed within 28 days prior to the first dose of study drug(s). Patients 
who agree to participate will sign the informed consent form (ICF) prior to undergoing any screening 
procedure. Refer to Section 7.1 for additional details. 
3.3. 
Treatment Period 
After completing all screening activities, patients confirmed to be eligible by the sponsor or designee will 
be enrolled to receive lenvatinib in combination with tislelizumab. All patients will receive study 


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treatments until confirmed progressive disease (iCPD) assessed by investigator based on iRECIST, 
unacceptable toxicity, 12-month treatment duration completion, death, withdrawal of consent, study 
termination by sponsor or patients meet any discontinuation criterion which will be described in protocol 
(see Section 3.6 and Section 3.7 for details), whichever comes first.  
Study procedures of each clinic visit are outlined in Appendix 1 and Appendix 2. 
On days with PK assessments, tislelizumab should be administered in the clinic in accordance with the 
schedule for the PK samples. Assessments should be obtained before study drugs administration unless 
stated otherwise in Appendix 1 and Appendix 2 and should be performed in order of least invasive to 
most invasive assessment. All safety-related assessments must be reviewed and dose modifications, if 
necessary, must be made by the investigator or sub-investigator before study drugs administration. 
3.4. 
End-of-Treatment Visit and Safety Follow-up Phone Calls 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the EOT Visit 
within 30 days after last dose of the study drugs or before initiation of a new anticancer treatment, 
whichever occurs first. If routine laboratory tests (eg, hematology, clinical chemistry) were performed ≤ 7 
days before the EOT Visit, these tests do not need to be repeated. A tumor assessment is not required at 
the EOT Visit if ≤ 6 weeks have passed since the last assessment. If the study drugs were initially 
interrupted due to AEs and then permanently discontinued, the EOT Visit may occur later, but no later 
than the permitted time of dose delay plus 7 days. 
See Appendix 1 for assessments to be performed for the EOT Visit. 
Telephone contact with patients should be conducted to assess irAEs and concomitant medications (if 
appropriate; eg, if associated with an irAE or is a new anticancer therapy) at 60 days and 90 days (± 14 
days) after the last dose of tislelizumab regardless of whether or not the patient starts a new anticancer 
therapy. If patient reports a suspected irAE at a telephone follow-up contact, the investigator should 
arrange an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
Patients who discontinue study treatment prior to iCPD will have their tumors assessed as outlined in 
Section 7.4. 
3.5. 
Survival Follow-Up  
All patients will be followed for survival and further anticancer therapy information after discontinuation 
of study treatment via telephone calls, patient medical records, and/or clinic visits approximately every 
3 months (± 14 days) after the EOT Visit until death, loss to follow-up, withdrawal of consent, or study 
completion by the sponsor.  


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3.6. 
Discontinuation from Study Treatment or from the Study 
3.6.1. 
Patient Discontinuation from Study Treatment 
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients who 
discontinue study treatment for reasons other than iCPD assessed by investigator based on iRECIST, 
should be followed for assessments of antitumor activity (Section 7.4), safety (Section 7.3) and survival 
(Section 3.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the appropriate 
electronic case report form (eCRF). Patients may discontinue study treatment for reasons which include, 
but are not limited to, the following:  
• 
Patient withdrawal of consent 
• 
Pregnancy 
• 
Any medical condition that the investigator or sponsor determines may jeopardize the patient’s 
safety, if he or she were to continue the study treatment 
• 
Use of any concurrent antineoplastic therapy (ie, loco-regional therapy, chemotherapy, hormonal 
therapy, immunotherapy, or standard or investigational agents [including Chinese or other Country 
herbal medicine and Chinese or other Country patent medicines] for the treatment of cancer) 
• 
Patient noncompliance 
• 
iCPD assessed by investigator based on iRECIST  
• 
12-month treatment duration completion  
If patients don’t meet any discontinuation criterion, such as investigator-assessed iCPD based on 
iRECIST, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor, lenvatinib 
and tislelizumab will be administered until patient completes his/her 12-month treatment duration of 
study drugs. After 12-month treatment duration completion, if the patients are still under the response 
(CR, PR) or stable disease (SD) assessed by investigator based on RECIST v1.1 or under the response 
(complete response [iCR], partial response [iPR]), stable disease (iSD) and unconfirmed progression 
(iUPD) assessed by investigator based on iRECIST, and may continue receiving benefit based on 
investigator’s assessment, tislelizumab could be further provided by sponsor, this decision must be agreed 
with medical monitor and documented in the study records, patients are also required to be reconsented. 
3.6.2. 
Patient Discontinuation from Study (End of Study for an Individual Patient) 
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• 
Patient withdrawal of consent 
• 
Death 
• 
Lost to follow up  
• 
Sponsor termination of study 


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3.7. 
End of Study 
The end of study is defined as the date when the last patient’s last visit (LPLV) occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is collected for the last 
patient, whichever occurs later. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study early may 
include, but are not limited to, the following:  
• 
In part 1, ＞1 of 6 patients experience a DLT in lenvatinib initial dose cohort 
• 
In part 1, ＞1 of 6 patients experience a DLT in lenvatinib dose reduced cohort 
• In interim analysis, within these 30 patients, ≤6 patients achieve response including complete 
response (CR) and partial response (PR) as their best overall response (BOR) assessed by central 
site imaging facility for tumor assessment based on RECIST v1.1 (refer to Section 9.7 for details) 
• 
The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
patients  
• 
Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this be 
necessary, prematurely discontinued patients should be seen as soon as possible for an EOT Visit. 
The investigators may be informed of additional procedures to be followed to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be responsible for 
informing Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) of the early 
termination of the study. 
The sponsor has the right to close a site at any time. The decision will be notified to the site in advance. 
Reasons for closing a site may include, but are not limited, to the following:  
• 
Excessively slow recruitment  
• 
Poor protocol adherence  
• 
Inaccurate or incomplete data recording  
• 
Noncompliance with Good Clinical Practice (GCP), applicable laws, and regulations 
• 
Study activity is completed (ie, all patients have been completed and all obligations have been 
fulfilled) 
3.8. 
Dose-Limiting Toxicities 
3.8.1. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the first dose 
of study drugs. For dose reduction decision, only DLTs occurring within 21 days will be evaluated. The 
following patients will not be considered evaluable for DLT, and will be replaced if needed to meet the 
minimum patient number required for dose escalation: 


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• 
Patients who withdraw or are withdrawn from the study before completing the DLT assessment 
window for reasons other than a DLT. 
• 
Patients receiving combination therapy who do not receive ≥ 75% of scheduled lenvatinib and 
≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT assessment window, 
unless they experience a DLT. 
3.8.2. 
Definition of Dose-Limiting Toxicity 
A DLT is defined as any of the following toxicities occurring during the DLT assessment window and 
considered by the investigator to be related to lenvatinib and/or tislelizumab. 
Hematologic 
• 
Grade 4 neutropenia lasting > 7 days 
• 
≥ Grade 3 febrile neutropenia 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Grade 4 thrombocytopenia lasting > 3 days and requiring transfusion, or any decreased platelet count 
< 15,000/mm3 or < 15.0 x 109/L 
• 
≥ Grade 4 anemia 
Non-Hematologic 
• 
≥ Grade 4 toxicity 
• 
Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 within 
7 days of initiating optimal supportive care 
Note: The following AEs will not be considered DLTs: 
• 
Grade 3 endocrinopathy that is adequately controlled by hormonal replacement; 
• 
Grade 3 of tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors); 
• 
Grade 3 rash; 
• 
Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset); 
• 
Grade 3 hypertension that is resolving within 7 days of optimal supportive care; 
Note: Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only 
(and not on the number of antihypertensive medications). Each assessment of BP and BP 
elevation confirmation (systolic and diastolic) should follow Section 7.3.1. 
• 
Clinically insignificant or transient abnormal laboratory findings, including but not limited to 
following: 
o Grade 3-4 alanine aminotransferase elevation, aspartate aminotransferase elevation or 
hyperbilirubinemia without significant related clinical symptoms and judged by 
investigators and medical monitors as non-fatal risk; 


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o Grade 3-4 hyperamylasemia or hyperlipasemia that is not associated with symptoms or 
clinical manifestations of pancreatitis and judged by investigators and medical monitors as 
non-fatal risk; 
o Grade 3 proteinuria that is resolving within 7 days of optimal supportive care. 
All available safety data, including AEs, laboratory assessments, and PK analyses (as available), will be 
reviewed with input from other functional representatives as appropriate.  
A Safety Monitoring Committee (SMC) will be established consisting of the sponsor’s clinical, safety, 
and medical team representatives (eg, medical monitor, Clinical Pharmacology, Statistician, and Drug 
Safety) and investigators. A planned formal SMC review of safety data will be performed after at least 6 
evaluable patients have completed 21-day DLT assessment in each lenvatinib dose level. The SMC will 
monitor the preliminary safety of lenvatinib in combination with tislelizumab and determine the RP2D of 
lenvatinib in combination with tislelizumab based on the available data (eg, safety and PK data) in this 
study. Study accrual will be held pending data review and lenvatinib RP2D determination by the SMC. 
4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and Section 4.2. The 
sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with the 
requirements of the study and the schedule of assessments 
2. Age ≥ 18 but ≤ 70 years on the day of signing the ICF  
3. Unresectable locally advanced or metastatic HCC, which must be confirmed by histologically or 
cytologically. Fibrolamellar, sarcomatoid, or mixed cholangiocarcinoma histology confirmed by 
histologically or cytologically is excluded. 
4. Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease (see Appendix 15 
for details) that is not amenable to or has progressed after loco-regional therapy and is not amenable 
to a curative treatment approach 
5. Did not receive any systemic treatment before and is unwilling to accept standard of care treatment or 
not suitable for standard of care treatment as judged by investigators 
6. No loco-regional therapy to the liver (ie, transarterial chemoembolization [TACE], transcatheter 
embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) within 28 days 
before the first dose of study drugs 
7. At least 1 measurable lesion as defined by RECIST v1.1 
Note: Selected target lesion(s) must meet 1 of 2 criteria: 1) not previously treated with local therapy 
or 2) within the field of prior local therapy but with documented subsequent progression as per 
RECIST v1.1 
8. ECOG Performance Status ≤ 1 (Appendix 4) 


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9. Child-Pugh A classification for liver function (Appendix 5) assessed within 7 days of first dose of 
study drugs 
10. No tumor thrombus involving main trunk of portal vein or inferior vena cava 
11. No prior history of ≥ Grade 2 hepatic encephalopathy before the first dose of study drugs 
12. No clinical evidence of portal hypertension with bleeding esophageal or gastric varices within 6 
months before the first dose of study drugs 
13. Adequate organ function as indicated by the following laboratory values ≤ 7 days before the first dose 
of study drugs: 
a. Patients must not have required a blood or platelet transfusion or growth factor support ≤ 14 
days before sample collection at screening for the following 
i. 
ANC ≥ 1.5 x 109/L 
ii. 
Platelets ≥ 75 x 109/L 
iii. 
Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Appendix 9) 
c. AST, ALP and ALT ≤ 5 x ULN 
d. Serum total bilirubin ≤ 51.3 µmol/L (3 mg/dl)  
e. International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN 
f. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 
g. Serum albumin ≥ 30 g/L 
h. Amylase and lipase ≤ 1.5 x ULN 
14. Adequately controlled blood pressure with or without the use of antihypertensive agents (defined as 
systolic blood pressure ≤ 150 mmHg and diastolic blood pressure ≤ 90 mmHg) at screening and no 
change in antihypertensive therapy within 1 week prior to the first dose of study drugs 
15. If patient has HBV or HCV infection, meets the following criteria as applicable to the infection type:  
For patients with inactive/asymptomatic carrier, chronic, or active HBV: 
o Has HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at Screening  
NOTE: Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV 
DNA should be managed per treatment guidelines. Patients receiving antivirals at screening 
should have been treated for > 2 weeks prior to first dose of study drugs and should continue 
treatment on study. 
For patients with HCV: 
o Infection is evidenced by detectable HCV ribonucleic acid (RNA), which is not eligible to 
enroll  
16. Survival expectation of 3 months or longer after study enrollment 
17. Females of childbearing potential must be willing to use a highly effective method of birth control for 
the duration of the study, and ≥ 120 days after the last dose of study drugs, and have a negative serum 
pregnancy test ≤ 7 days of first dose of study drugs (see Appendix 7 for details) 


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18. Males participant of childbearing potential must be willing to use a highly effective method of birth 
control for the duration of the study and for ≥ 120 days after the last dose of study drugs (see 
Appendix 7 for details) 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible to enroll: 
1. Any known brain or leptomeningeal metastases  
2. Any clearly known invasion or tumor thrombus on first grade/second grade intrahepatic bile duct or 
extrahepatic bile duct 
3. Patients underwent surgical of transjugular intrahepatic portosystemic shunt (TIPS) or other forms of 
portosystemic shunt 
4. Active autoimmune diseases or history of autoimmune diseases that may relapse (Appendix 6).  
Note: Patients with the following diseases are not excluded and may proceed to further screening:  
a. Controlled Type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering factors  
5. Any active malignancy ≤ 2 years before the first dose of study drugs except for specific cancer under 
investigation in this study and any locally recurring cancer that has been treated curatively (eg, 
resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix 
or breast).  
6. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of 
study drugs.  
Note: Patients who are currently or have previously been on any of the following steroid regimens are 
not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)  
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic 
absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye 
allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) 


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7. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected 
calcium despite standard medical management, or ≥ Grade 3 hypoalbuminemia ≤ 14 days before the 
first dose of study drugs 
8. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases including 
pulmonary fibrosis, acute lung diseases, etc 
9. Severe chronic or active infections (including tuberculosis infection, etc) requiring systemic 
antibacterial, antifungal, or antiviral therapy within 14 days prior to first dose of study drugs. Note: 
antiviral therapy is permitted for patients with viral hepatitis   
10. Subjects having ≥ 1+ proteinuria on urinalysis will undergo a 24-hour urine collection for quantitative 
assessment of proteinuria. Subjects with a urine protein ≥1 g/24 hours will be ineligible 
11. Known history of human immunodeficiency virus (HIV) infection 
12. Any major surgical procedure requiring general anesthesia ≤ 28 days before the first dose of study 
drugs 
13. Prior allogeneic stem cell transplantation or organ transplantation 
14. Any of the following cardiovascular criteria  
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, 
≤ 28 days before the first dose of study drugs 
b. Symptomatic pulmonary embolism ≤ 28 days before the first dose of study drugs 
c. Any history of acute myocardial infarction ≤ 6 months before the first dose of study drugs 
d. Any history of heart failure meeting New York Heart Association Classification (NYHA) III 
or IV (Appendix 8) ≤ 6 months before the first dose of study drugs 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of 
study drugs 
f. Any history of cerebrovascular accident ≤ 6 months before the first dose of study drugs 
g. QT corrected (QTc) interval (corrected by Fridericia’s method) > 480 ms  
Note: If QTc interval is > 480 ms on initial ECG, a follow up ECG will be performed to 
exclude result 
h. Current left ventricular ejection fraction (LVEF) < institutional lower limit of normal as 
assessed by echocardiography (ECHO). The same modality used at baseline must be applied 
for subsequent evaluations 
i. 
Any episode of syncope or seizure ≤ 28 days before the first dose of study drugs  
15. Hypersensitivity to tislelizumab or lenvatinib, to any ingredient in the formulation, or to any 
component of the container 


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16. Thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic 
INR monitoring within 6 months before the first dose of study drugs, or requiring use of antiplatelet 
agents during whole study 
17. Clinically significant hemoptysis, tumor hemorrhage or other significant bleeding for any cause 
within 2 weeks prior to the first dose of study drugs 
18. Any systemic chemotherapy within 28 days of the first dose of study drugs or immunotherapy (eg, 
interleukin, interferon, thymosin, etc.), hormone therapy, targeted therapy, or any investigational 
therapies within 14 days or 5 half-lives (whichever is shorter) of first dose of study drugs  
19. Any Chinese herbal or Chinese patent medicine with anticancer activity approved by the China 
National Medical Product Administration (NMPA) (regardless of the type of cancer) used within 14 
days before the first administration of study drugs 
20. Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, 
except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory 
abnormalities) 
21. Administration of live vaccine ≤ 4 weeks before the first dose of study drugs 
Note: seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal 
vaccines are live vaccines and are not allowed 
22. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or 
dependence that will be unfavorable for the administration of study drugs or affect the explanation of 
drug toxicity or AEs or result in insufficient or might impair compliance with study conduct 
23. Concurrent participation in another therapeutic clinical study  
24. Inability to swallow capsules or disease significantly affecting gastrointestinal function such as 
malabsorption syndrome, resection of the complete stomach or small bowel, bariatric surgery 
procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 
25. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical 
intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of 
intervention; cytological confirmation of any effusion permitted) within 7 days before first dose of 
study drugs 
26. Patients with gastrointestinal perforation or any fistula formation (e.g. gastrointestinal fistula 
formation, tracheal fistula, tracheoesophageal fistula, esophageal fistula, skin fistula, female genital 
fistula) ≤ 6 months before the first dose of study drugs 
27. Patients with serious non-healing wound, ulcer, or bone fracture 
28. Patients with medical contraindications that preclude all forms of contrast enhanced imaging(both CT 
and MRI) 
29. Pregnant or breastfeeding woman 


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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling 
5.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial (20R glass, United 
States Pharmacopeia type I), containing a total of 100 mg of antibody in 10 mL of isotonic solution. 
Tislelizumab has been aseptically filled in single-use vials with a Flurotec-coated butyl rubber stopper 
and an aluminum cap. Each vial is packaged into a single carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label.  
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and disposal. Please 
also refer to the Investigator’s Brochure for other details regarding tislelizumab. 
5.1.2. 
Lenvatinib  
Management (ie, handling, storage, administration, and disposal) of Lenvatinib will be in accordance with 
relevant local guidelines, package insert/summary of product characteristics.  
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.2. 
Dosage and Administration 
On days when lenvatinib and tislelizumab dosing are both scheduled, the daily dose of lenvatinib should 
precede tislelizumab infusion.  
5.2.1. 
Tislelizumab 
Tislelizumab (200 mg) will be administered on Day 1 of each 21-day cycle (once every 3 weeks). 
Tislelizumab will be administered by intravenous infusion through an intravenous line containing a 
sterile, nonpyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter. Specific instructions 
for product preparation and administration are provided in the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients must be 
monitored for at least 60 minutes afterward in an area with resuscitation equipment and emergency 
agents. From Cycle 3 onward, a ≥ 30-minute monitoring period is required in an area with resuscitation 
equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, then the 
subsequent infusions may be administered over 30 minutes, which is the shortest time period permissible 
for infusion. Tislelizumab must not be concurrently administered with any other drug (refer to Section 6). 
Guidelines Pharmacy Manual for dose modification, treatment interruption, or discontinuation and for the 
management of irAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 10.  


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5.2.2. 
Lenvatinib 
In part 1, lenvatinib capsules will be administered orally, once daily, in a continuous regimen in 21-day 
cycles. The starting dose for lenvatinib in part 1 will depended on patients’ weight in baseline, 12 mg 
lenvatinib will be administered once daily if baseline body weight of patient≥60 kg, 8 mg lenvatinib will 
be administered once daily if baseline body weight of patient＜60 kg. Depending on safety observations 
and sponsor’s decision, the lenvatinib dose in the subsequent cohort of patients may be reduced as 
following, 8 mg lenvatinib will be administered once daily if baseline body weight of patient≥60 kg, 4 mg 
lenvatinib will be administered once daily if baseline body weight of patient＜60 kg. 
In part 2, SMC will confirm RP2D of the combination treatment dosing of lenvatinib, which can be 
withheld for up to approximately 28 days consecutively.  
Dose modifications of lenvatinib should be performed based on the Section of Management of 
Lenvatinib-Specific Adverse Events (See Section 8.8 for details). Specific instructions for product 
administration are provided in the Pharmacy Manual.   
5.3. 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or appropriately delegated study personnel at each 
patient visit and information provided by the patient. Patients enrolled in the study will be provided with 
patient diaries. The patient is responsible for maintaining the patient diary and will record the number of 
capsules of lenvatinib taken and if any were missed. The site personnel responsible for drug 
accountability will record the quantity of drug dispensed and quantity of drug received after the cycle 
visit. The patient diaries and the pharmacist record of drug will be assessed by the investigator/study 
personnel at each visit. 
The study drugs (lenvatinib and tislelizumab) required for this study, before the data of discontinuation 
from study treatment or from the study (see Section 3.6 for details) will be provided by the sponsor, as 
required by local or country-specific guidance. If patients don’t meet any discontinuation criterion, such 
as investigator-assessed iCPD based on iRECIST, unacceptable toxicity, death, withdrawal of consent, or 
study termination by sponsor, lenvatinib and tislelizumab will be administered until patient completes 
his/her 12-month treatment duration of study drugs. After 12-month treatment duration completion, if the 
patients are still under the response (CR, PR) or stable disease (SD) assessed by investigator based on 
RECIST v1.1 or under the response (complete response [iCR], partial response [iPR]), stable disease 
(iSD) and unconfirmed progression (iUPD) assessed by investigator based on iRECIST, and may 
continue receiving benefit based on investigator’s assessment, tislelizumab could be further provided by 
sponsor, this decision must be agreed with medical monitor and documented in the study records, patients 
are also required to be reconsented.  
The investigational site will acknowledge receipt of study drugs. Any damaged shipments will be 
replaced.  
Accurate records of all study drugs received, dispensed, returned, and disposed should be recorded on the 
site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of study drugs management. 


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5.4. 
Overdose 
5.4.1. 
Tislelizumab 
Any overdose of tislelizumab (defined as ≥ 600 mg in a 24-hour period) or incorrect administration of 
tislelizumab should be noted in the patient’s chart and on the appropriate eCRF. AEs associated with an 
overdose or incorrect administration of study drug will be recorded on the AE eCRF. Any SAEs 
associated with an overdose or incorrect administration are required to be reported within 24 hours of 
awareness via SAE reporting process as described in Section 8.6.2. Supportive care measures should be 
administered as appropriate. 
5.4.2. 
Lenvatinib 
Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Death due to 
multiorgan dysfunction occurred in a patient who received a single dose of lenvatinib 120 mg orally. 
(Lenvatinib Pharmaceutical Instruction. 2018.) Any overdose or incorrect administration of lenvatinib 
should be noted in the patient’s chart and on the appropriate eCRF. AEs associated with an overdose or 
incorrect administration of study drug will be recorded on the AE eCRF. Any SAEs associated with an 
overdose or incorrect administration are required to be reported within 24 hours of awareness via SAE 
reporting process as described in Section 8.6.2. Supportive care measures should be administered as 
appropriate. 
5.5. 
Modification and Dose Delay 
5.5.1. 
Dose Modification 
There will be no dose reductions for tislelizumab in this study. Dose reductions for lenvatinib are 
presented in table 12. Once the dose has been reduced, re-escalation is generally not recommended but 
may be considered on a case-by-case basis. If the administration of lenvatinib is interrupted for reasons 
other than toxicity, then treatment with the study drug may be resumed at the same dose. Criteria for 
treatment modifications and suggested guidelines for the management of some toxicities related to 
lenvatinib are presented in Section 8.8. 
Table 12 Lenvatinib Dose Reductions 
Weight in baseline 
≥60 kg a 
＜60 kg a 
Dose Level -1 
12 mg once daily 
8 mg once daily 
Dose Level -2 
 8 mg once daily  
4 mg once daily 
Dose Level -3 
4 mg once daily 
4 mg every other day 
Dose Level -4 
4 mg every other day 
Discontinue 
a. Based on the previous dose levels, the dose was gradually reduced in the order of 12 mg once a day, 8 mg 
once a day, 4 mg once a day or 4 mg every other day. 
If one study drug is interrupted or discontinued, administration of the other study drug may continue at 
the discretion of the investigator. 


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5.5.2. 
Dose Delay  
Every effort should be made to administer the study drugs according to the planned dose and schedule. In 
the event of significant toxicities, dosing may be delayed and/or reduced based on the guidelines 
provided. Reasons for dose modifications or delays, the supportive measures taken, and the outcome will 
be documented in the patient's chart and recorded in the eCRF. 
Patients may temporarily suspend study treatment if they experience toxicity that is considered related to 
study drugs and requires a dose to be withheld. Patients should resume study drugs as soon as possible 
after the AEs recover to baseline or Grade 1 (whichever is less severe) and within 4 weeks (28 days) for 
lenvatinib or 12 weeks for tislelizumab after last dose of the respective study drug. Lenvatinib should be 
resumed at a reduced dose level as outlined in table 12. If the administration of lenvatinib is interrupted 
for reasons other than toxicity, then treatment with the study drugs may be resumed at the same dose. 
The following dose delays or interruptions will be permitted: 
• 
Tislelizumab can be delayed or interrupted for up to 12 weeks. If a dose is delayed for ≤ 10 days 
before a planned dosing cycle (eg, Cycle 3, Day 1), tislelizumab should be administered (on the 
same day with lenvatinib, if applicable) and all assessments should be conducted according to the 
original cycle (ie, Cycle 3). If the delay is > 10 days, the patient should skip the tislelizumab, and 
tislelizumab will be administered on Day 1 of the next planned cycle (ie, Cycle 4, Day 1). 
• 
Lenvatinib can be interrupted for up to approximately 28 days consecutively. If treatment with 
lenvatinib is delayed for ≥ 14 days, then resumption at a reduced dose should be considered. If 
drug is planned to be interrupted ≥ 28 days, the medical monitor should be contacted before 
permanent patient discontinuation from the study drug. 
The tumor assessment schedule will not be altered even if the administration of study drugs is delayed. 
If the patient is unable to resume lenvatinib or tislelizumab within the permitted timeframe after the last 
dose of study drugs, then the patient should be discontinued from the study drugs. 
Dose modification related to irAEs and infusion-related reactions for tislelizumab are described in 
Appendix 10 and Section 8.7, respectively.  
6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Concomitant Therapy 
6.1.1. 
Permitted Concomitant Medications/Procedures 
Most concomitant medications and therapies deemed necessary in keeping with the local standards of 
medical care at the discretion of the investigator for supportive care (eg, antiemetics, antidiarrheals) and 
in a patient’s interest are allowed.  
Proton pump inhibitors and H2 antagonists should be avoided during treatment on study but are not 
exclusionary. Switching from use of proton pump inhibitors or H2 antagonists to use of antacids is 


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preferred. Use of antacids should be avoided 4 hours before and 2 hours after administration of 
investigational study treatment. 
Systemic corticosteroids given for the control of irAEs must be tapered gradually (see Appendix 10) and 
be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the next 
administration of tislelizumab. The short-term use of steroids as prophylactic treatment (eg, patients with 
contrast allergies to diagnostic imaging contrast dyes) is permitted.  
If patients are known to be hypertensive, have been on a stable dose of antihypertensive therapy for at 
least 1 week before first dose of study drugs, and investigators should therefore ensure that patients 
enrolled to receive treatment with lenvatinib have BP of ≤150/90 mm Hg at the time of study entry. 
Patients with active hepatitis B, defined as either detectable HBsAg or HBV DNA at baseline, must 
initiate treatment 2 weeks prior to first dose of study drugs and continue until 6 months after the last dose 
of study drugs. Patients should continue effective antiviral treatment during the study to decrease 
potential viral re-activation risk. Tenofovir and entecavir are recommended in the American Association 
for the Study of Liver Disease (AASLD) guideline because they lack resistance with long-term use 
(Terrault et al 2016; AASLD/IDSA HCV Guidance Panel, 2015). The investigator might use other 
antiviral agents, if appropriate, following local guidelines. Management of antiviral therapy is at the 
discretion of the Investigator; however, reason(s) must be provided in the CRF if a patient with active 
hepatitis B is not treated with antiviral prophylaxis, and this case should be discussed with the medical 
monitor and the medical monitor agrees.  
Palliative (limited-field) radiation therapy is permitted for pain control or prophylaxis of bone fracture to 
sites of bone disease present at baseline. The lesion being considered for palliative radiation should not be 
a target lesion for RECIST v1.1. The case should be discussed with the medical monitor; the therapy will 
be used if the medical monitor agrees that the conditions required to receive palliative radiation are met. 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the disease is 
permitted if clinically indicated per investigators’ discretion and after consultation with the medical 
monitor. Whenever possible, these patients should undergo a tumor assessment of the lesion(s) before 
receiving the radiotherapy in order to rule out PD. 
6.1.2. 
Prohibited Concomitant Medications/Procedures 
The following medications are prohibited during the study: 
• 
Any concurrent antineoplastic therapy (ie, loco-regional therapy, chemotherapy, hormonal 
therapy, immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicine] for the treatment of cancer) is not allowed. Chinese 
herbal and Chinese patent medicines with anticancer activity are defined as medication with 
approval by the China NMPA for use as anticancer treatment (regardless of the type of cancer). 
• 
Live vaccines within 28 days before first dose of study drugs and 60 days following the last dose 
of study drugs. 
• 
Any antiplatelet agents are prohibited. 
• 
Anticoagulants such as warfarin or similar agents requiring therapeutic INR monitoring. 


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6.1.3. 
Restricted Concomitant Medications/Procedures 
The following medications are restricted during the study:  
• 
Immunosuppressive agents (except to treat a drug-related AE). 
• 
Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or control a 
drug-related AE (per protocol) or for short-term use as prophylactic treatment. 
• 
Patients should avoid alcohol completely and should avoid other addictive drugs during the study.  
• 
Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be 
carefully monitored.  
• 
Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.1.1. 
• 
Herbal remedies are not recommended for use during the study treatment. Patients must notify the 
investigators of all herbal remedies used during the study. 
• 
Opiates and other medication required for palliative management of patients are allowed. Patients 
must notify the investigator of all concurrent medications used during the study. 
Opiates and other medication required for palliative management of patients are allowed. Patients must 
notify the investigator of all concurrent medications used during the study. 
6.2. 
Potential Interactions Between the Study Drugs and Concomitant Medications 
Effect of Other Drugs on Lenvatinib 
Chemotherapeutic drugs: There was no significant effect on pharmacokinetics of any of the three drugs 
by combination of lenvatinib, carboplatin and paclitaxel. 
Effect of Lenvatinib on Other Drugs 
No data showed that lenvatinib could be excluded from the risk of being an inducer of CYP3A4 or P-gp 
in the gastrointestinal tract. That may lead to a decrease in the exposure of oral drugs with CYP3A4/P-gp 
as the substrate. Therefore, this should be fully taken into account when taking drugs with CYP3A4/P-gp 
as the substrate in combination with lenvatinib, in order to ensure the efficacy. So CYP3A4 substrates 
with known narrow therapeutic windows should be used with caution in patients receiving lenvatinib, for 
example, asmidazole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine 
and dihydroergotamine). 
Oral contraceptive 
It is not clear whether lenvatinib reduces the effectiveness of hormonal contraceptives, so women who are 
using oral hormonal contraceptives should increase barrier contraception. 
Drugs That Prolong the QT Interval 
Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor 
electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, 
bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia 


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and III antiarrhythmics. Withhold and resume at reduced dose of lenvatinib upon recovery based on 
severity ( see Section 8.8 for more details).  
Per the International Council for Harmonisation (ICH) E14 guidance, it is recommended to avoid 
medications with potential to prolong QT/QTc or cause Torsades. Please refer to Appendix 14 for a list of 
medications or substances to be avoided or used with caution during treatment with lenvatinib. 
Potential Interaction with Tislelizumab 
Lenvatinib administered in combination with tislelizumab is unlikely to result in clinically relevant drug-
drug interactions based on absorption, metabolism, elimination, or protein binding. Tislelizumab is a 
monoclonal antibody and is administered intravenously, whereas lenvatinib is a small molecule 
therapeutic administered orally. Like most therapeutic proteins, tislelizumab is not expected to be 
metabolized by CYP or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or 
other metabolizing enzymes in terms of inhibition or induction. 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
The study-specific assessments and procedures with allowed time windows are outlined in Appendix 1. 
Patients will be closely monitored for safety and tolerability throughout the study. All assessments must 
be performed and documented in the medical record for each patient. 
All assessments will be performed on the day of the specified visit unless an acceptable time window is 
specified. Assessments scheduled on the day of study treatment administration (Day 1) of each cycle 
should be performed prior to study treatment unless otherwise noted. Laboratory results are required to be 
reviewed prior to dosing. Dosing will occur only if the clinical assessment and local laboratory test values 
(that must be available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other events, the 
visit should be scheduled on the nearest feasible date, with subsequent visits conducted according to the 
planned schedule every 3 weeks from Cycle 1 Day 1. 
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to the first dose of study drugs. Patients 
who agree to participate will sign the ICF prior to undergoing any screening procedure. The screening 
period begins on the first day a screening procedure is conducted. Patients who are suspected or known to 
have serious respiratory concurrent illness or exhibit significant respiratory symptoms unrelated to 
underlying cancer should take a pulmonary function test (refer to Appendix 1 for details). Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess patient 
eligibility according to the latest screening assessment results.  
Results of standard of care tests or examinations performed prior to obtaining informed consent and 
≤ 28 days prior to the first dose of study drugs may be used for the purposes of screening rather than 
repeating the standard of care tests unless otherwise indicated. 


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Procedures conducted during the Screening Visit only are described in this section. For the description of 
other assessments that are conducted during screening, as well as throughout the study, refer to Safety 
Assessments (Section 7.3), Tumor and Response Evaluations (Section 7.4). The PK sampling schedule is 
shown in Appendix 2. 
Rescreening under limited conditions may be allowed after consultation with BeiGene, eg, when a patient 
narrowly misses a laboratory criterion and it is correctable and not due to rapidly deteriorating condition 
or disease progression. Rescreening is allowed only once. 
7.1.1. 
Demographics and Medical History 
Demographic data will include gender, year of birth and age, and race/ethnicity. 
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never); and all medications (eg, prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 30 days before the first dose of study drug. 
Cancer history will include an assessment of prior surgery, prior radiotherapy, and prior drug therapy, 
including start and stop dates, best response, and reason for discontinuation. Radiographic studies 
performed prior to study entry may be collected for review by the investigator. If applicable, 
histologically and cytologically of cancer will include assessment result, date of assessment and 
assessment agency. 
7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer to 
Appendix 7 for contraception guidelines and definitions of “women of childbearing potential” and “no 
childbearing potential”  
7.1.3. 
Informed Consent and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before performing 
any study-specific procedures. ICFs for enrolled patients and for patients who are screened but not 
enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility 
criteria before the first dose of study drugs. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
7.1.4. 
Pulmonary Function Tests 
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant 
respiratory symptoms unrelated to the underlying cancer will undergo pulmonary function testing, which 


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may include, but is not limited to, spirometry and assessment of diffusion capacity done during the 
screening period to assist the determination of suitability on the study. 
7.2. 
Enrollment 
The investigator will assess, and the sponsor or designee will confirm the eligibility of each patient. All 
screening procedure results and relevant medical history must be available before eligibility can be 
determined. All inclusion criteria must be met and none of the exclusion criteria may apply. No eligibility 
waivers will be granted.  
After a patient is screened and the investigator determines the patient is eligible for enrollment, study site 
personnel will complete an Eligibility Authorization Packet and send it to the medical monitor or 
designee to approve the enrollment. Study site personnel should ensure that a medical monitor’s 
confirmation has been received before the study drug administration. 
7.3. 
Safety Assessments 
7.3.1. 
Vital Signs  
Vital signs will include measurements of temperature (˚C), pulse rate, and blood pressure (BP, including 
systolic and diastolic) while the patients keep resting for 10 minutes.  
Each BP assessment and BP elevation confirmation should be performed as following processes:  
o First BP measurement should be performed after the patients keep resting for at least 
10 minutes.  
o The second BP measurement should be repeated at least 10 minutes later, while patients keep 
resting for at least 10 minutes as well.  
o The mean value of 2 measurements at least 10 minutes apart is defined as one BP assessment 
o If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 10 minutes 
apart) is elevated (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), a confirmatory 
assessment should be obtained at least 30 minutes later by performing 2 measurements (at 
least 10 minutes apart) to yield a mean value.  
7.3.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including an evaluation of 
1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 5) respiratory, 
6) gastrointestinal, and 7) neurological systems. Any abnormality identified during screening will be 
graded according to NCI-CTCAE v 5.0 and recorded on the eCRF with appropriate disease/condition 
terms.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations will be 
performed. Changes from baseline will be recorded. New or worsened clinically significant abnormalities 
are to be recorded as AEs on the Adverse Event eCRF. Refer to Section 8.3 regarding AE definitions and 
reporting and follow-up requirements. 


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7.3.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (refer to Appendix 4) will be assessed during the study.  
7.3.4. 
Laboratory Safety Test 
Local laboratory assessments of hematology, serum chemistry, coagulation, and urinalysis will be 
conducted, of which certain elements will be collected as specified in Appendix 1.  
If laboratory tests at screening are not performed within 7 days prior to the administration of study drugs 
on Cycle 1 Day 1, these tests should be repeated and reviewed before study drugs administration. 
Hematology, as specified in Appendix 1, should be performed weekly for the first 2 cycles and at the 
beginning of subsequent cycles in patients who are enrolled in part 1 and be performed for patients 
enrolled in part 2 at the beginning of each cycles. Urinalysis and serum chemistry should be performed 
weekly for the first 2 cycles and at the beginning of subsequent cycles in patients who are enrolled in part 
1 and part 2.  
Urinalysis on routine urinalysis, if urine protein is ≥ 2+ (≥ 1+ in screening) by dipstick, then obtain a 24-
hour urine sample for total protein and a random urine sample for total protein and creatinine to determine 
a protein to creatinine ratio (refer to Section 8.8.3 for detection and confirmation of proteinuria). In 24-
hour protein assessment, to achieve the result prior to study drugs administration on the day of each 
scheduled assessment, the urine sample may be collected 24 hours ahead of schedule in 24-hour protein 
assessment, as specified in Appendix 1.  
Instruction manuals and supply kits will be provided for all central laboratory assessments.  
Investigators may use results from local laboratories for assessing eligibility, safety monitoring, and 
dosing decision. 
In addition, the following tests will be conducted in this study:  
• 
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal 
ligation) must be performed and documented as negative within 7 days prior to administration of 
study drugs. Urine or serum pregnancy tests will be performed during treatment before study drugs 
administration at each cycle and at the EOT Visit. A serum pregnancy test must be performed if the 
urine pregnancy test is positive or equivocal.  
• 
Thyroid function tests (TFTs) (thyroid-stimulating hormone [TSH], free T3, free T4) will be 
performed at screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at the EOT Visit. 
• 
Patients receiving tislelizumab will receive CK and CK-MB testing. If tislelizumab has been 
permanently discontinued, CK and CK-MB testing is no longer required. Patients with a history of 
cardiological disease or after discontinuation of tislelizumab, may receive CK and CK-MB testing if 
clinically indicated. In the event that CK-MB fractionation is not available, please assess troponin I 
and/or troponin T instead. 


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7.3.5. 
Hepatitis B and C Testing 
Testing will be performed by the local laboratory at screening and will include HBV/HCV serology 
(HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], and HCV antibody) 
and viral load assessment (HBV DNA and HCV RNA).  
Patients who have detectable HBV DNA at screening will receive a viral load test every 4 cycles, at the 
EOT Visit. 
7.3.6. 
Electrocardiograms 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. Paper or 
electronic copies of ECG tracings will be kept as part of the patient's study file at the site.  
When coinciding with blood draws, ECG assessment should be performed prior to blood draws. Patients 
should rest in semirecumbent supine position for at least 10 minutes prior to ECG collection. 
7.3.7. 
Multigated Acquisition (MUGA) Scans or Echocardiograms 
Evaluations of cardiac function will be performed at screening and every 12 weeks during treatment. 
Investigator will decide the method (MUGA or echocardiograms) for evaluation of cardiac function. The 
method used for individual patients should be consistent throughout study participation.  
7.3.8. 
Adverse Events 
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0 (NCI-CTCAE 
2017). Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6.  
7.4. 
Tumor and Response Evaluations 
Tumor imaging will be performed within 28 days prior to the first dose of study drugs. Results of 
standard of care tests or examinations performed prior to obtaining informed consent and ≤ 28 days prior 
to the first dose of study drugs may be used for the purposes of screening rather than repeating the 
standard of care tests. During the study, tumor imaging will be performed approximately every 6 weeks 
(± 7 days) in the first year and thereafter approximately every 9 weeks (± 7 days).  
Screening assessments and each subsequent assessment must include contrast-enhanced computed 
tomography (CT) scans or contrast-enhanced magnetic resonance imaging (MRI) of the chest, abdomen, 
and pelvis. Other known or suspected sites of disease must be included in the imaging assessments (neck, 
brain, etc).  
Tumor assessments must include contrast-enhanced CT scans or contrast-enhanced MRI, with preference 
for contrast-enhanced CT, of the chest (if choose MRI as tumor assessment, for chest, a noncontrast or 
contrast-enhanced CT of the chest should be performed instead of MRI of chest), abdomen, and pelvis. 
Unless contraindicated, contrast-enhanced CT scans are recommended in tumor assessments. Other 
known or suspected sites of disease must be included in the imaging assessments (neck, brain, etc). The 
same radiographic procedure used to assess disease sites at screening is required to be used throughout the 


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study (eg, the same contrast protocol for contrast-enhanced CT scans). All known sites of disease must be 
documented at screening and reassessed at each subsequent tumor evaluation. 
• 
Imaging of the brain (MRI or CT) at baseline (≤ 28 days of informed consent) is required for all 
screened patients. Unless contraindicated or not readily available, MRI scans of brain are 
recommended at screening. 
• 
Unless contraindicated, contrast-enhanced CT scans are recommended in tumor assessments. 
• 
If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT of the chest plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
• 
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a contrast-contrast 
diagnostic CT scan. 
• 
Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening if clinically 
indicated. If bone metastases are present at screening and cannot be seen on CT or MRI scans 
afterwards, or clinically indicated, TC-99m or PET bone scans should be repeated when a CR is 
suspected in target lesion or when progression in bone is suspected. 
• CT scans of the neck or extremities should also be performed if clinically indicated and followed 
throughout the study, if there is evidence of metastatic disease in these regions at screening. At 
the investigator’s discretion, other methods of assessment of target lesion and nontarget lesions 
per RECIST v1.1 may be used. 
Tumor response will be assessed using RECIST v1.1, mRECIST and iRECIST respectively (refer to 
Appendix 11, Appendix 12 and Appendix 13).  
After the first documentation of response (CR or PR), confirmation of tumor response should occur at 
4 weeks or later after the first response or at the next scheduled assessment time point.  
If radiographic initial PD is observed by the investigator based on RECIST 1.1, patients should continue 
treatment with tislelizumab until iCPD (investigator assessed based on iRECIST) is confirmed by 
repeated imaging ≥ 4 weeks later (but not exceeding 8 weeks from the date of initial documentation of 
PD, repeated imaging on next scheduled tumor assessment visit date, around 6 weeks from the date of 
initial documentation of PD is recommended). The following criteria must be met in order to treat patients 
to continue study drugs beyond initial PD via investigator assessed based on RECIST v1.1:  
• 
Absence of clinical symptoms and signs of PD (including clinically significant worsening of 
laboratory values) 
• 
Stable ECOG Performance Status ≤ 1 
• 
Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, cord compression) 
that requires urgent alternative medical intervention 
• 
Investigators must obtain written informed consent for treatment beyond radiologic PD and 
inform patients that this practice is not considered standard in the treatment of cancer 


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The decision to continue study drugs beyond investigator-assessed progression must be agreed with the 
medical monitor and documented in the study records. After decision to continue study drugs beyond 
investigator-assessed progression based on RECIST v1.1, the further decision of treatment will follow 
below criterion: 
• 
Tumor assessments are still required to be performed on original schedule plan via investigator 
and central site imaging facility based on RECIST v1.1, mRECIST and iRECIST respectively 
• 
Unless investigator-assessed iCPD based on iRECIST, patients will continue study drugs, until 
the patient meet other criterion of discontinuation from study treatment (see Section 3.6.1 for 
details) 
Patients who discontinue study treatment early for reasons other than iCPD (eg, toxicity) will continue to 
undergo tumor assessments following the original plan until the patient begins a subsequent anticancer 
treatment, withdraws consent, is lost to follow-up, death, or until the study terminates, whichever occurs 
first.  
Tumor assessments are required to be performed on schedule regardless of whether study treatment has 
been administered or held. 
7.4.1. 
Investigator Assessment 
For investigator assessment, the same evaluator should perform assessments, if possible, to ensure 
internal consistency across visits.  
7.4.2. 
Central Site Imaging Facility for Tumor Assessment 
Central site imaging facility for tumor assessment is composed of at least 3 radiology experts at the 
leading site or the site where the leading PI is located, specialized in tumor radiological assessment. The 
selection of these experts will be confirmed by leading PI and medical monitor, documented in study 
records. The executive plan will be described in Protocol of Central Site Imaging Facility. 
7.5. 
Pharmacokinetic Assessment  
The PK concentrations will be determined using serum (tislelizumab) samples collected at specified time 
points within a reasonable variation window. When each PK sample is collected for tislelizumab. (refer to 
Appendix 1 and Appendix 2). The actual collection date and time of each sample collection will be 
recorded on the source document and eCRF. 
Samples of plasma will be collected at specified times points within a reasonable variation windows for a 
potential test for lenvatinib PK profile. (refer to Appendix 1 and Appendix 2). 
In the event of a DLT or significant toxicity, it is recommended that an unscheduled PK serum 
(tislelizumab) sample be drawn as soon as possible. 
Shipping, storage, and handling of samples will be managed through a central laboratory. Analysis of 
samples will be performed using specific validated bioanalytical methods. Instruction manuals and supply 
kits will be provided for all central laboratory assessments. 


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7.6. 
Antidrug Antibody Testing 
Tislelizumab may elicit an immune response. Validated screening and confirmatory assays will be 
employed to detect ADAs at multiple timepoints throughout the study (Appendix 1). The immunogenicity 
evaluation will use a risk-based immunogenicity strategy (Koren et al 2008; Worobec and Rosenberg 
2004a; Worobec and Rosenberg 2004b) to characterize ADA responses to tislelizumab in support of the 
clinical development program. This tiered strategy will include an assessment of whether ADA responses 
correlate with relevant clinical endpoints. (refer to Appendix 1 and Appendix 2). 
Shipping, storage, and handling of samples will be managed through a central laboratory. Instruction 
manuals and supply kits will be provided for all central laboratory assessments. 
7.7. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see Appendix 1). 
All assessments will be performed on the day of the specified visit unless an acceptable time window is 
specified. Assessments scheduled on the day of study treatment administration (Day 1) of each cycle 
should be performed prior to study treatment infusion/dose unless otherwise noted. Laboratory results are 
required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other events, the 
visit should be scheduled on the nearest feasible date (the visit window is provided in Appendix 1), with 
subsequent visits conducted according to the planned schedule every 3 weeks from Cycle 1 Day 1. 
7.8. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request and may 
include vital signs/focused physical examination; ECOG Performance status; AE review; concomitant 
medications and procedures review; radiographic assessments; physical examination of liver, spleen, and 
lymph nodes; disease-related constitutional symptoms; and hematology and chemistry laboratory 
assessments. The date and reason for the unscheduled visit must be recorded in the source documentation.  
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests may be 
performed based on the investigator assessment as appropriate, and the results of these tests should be 
entered on the unscheduled visit eCRF. 
8. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the monitoring and documentation of events that meet the criteria and 
definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated with Lenvatinib and Tislelizumab 
Lenvatinib is a post-market agent in China which has been approved by NMPA for hepatocellular 
carcinoma once daily (Lenvatinib Pharmaceutical Instruction. 2018.). Tislelizumab are investigational 
agents that are currently in clinical development for the treatment of HCC. Limited safety data for 
lenvatinib in combination with tislelizumab in patients are available, and the full safety profiles have not 


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been characterized. The following recommendations are based on results from nonclinical and clinical 
studies of lenvatinib or tislelizumab and published data on other molecules within the same biologic 
classes. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy may 
increase the risk of irAEs, specifically the induction or enhancement of autoimmune conditions. AEs 
observed with anti-PD-1 therapy are presented in Section 8.7. 
The guidelines for management of potential AEs more specific to treatment with lenvatinib or agents in 
the same class of cancer treatment are presented in Section 8.8. 
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, such 
events should be recognized early and treated promptly to avoid potential major complications. Suggested 
workup procedures for suspected irAEs are provided in Appendix 10. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this study. Results from the nonclinical 
toxicology studies of lenvatinib and tislelizumab, clinical data with lenvatinib and tislelizumab, as well as 
the nonclinical/clinical data from other RTK inhibitors and PD-L1/PD-1 inhibitors, were considered. 
Specifically, patients at risk for study-emergent active autoimmune diseases or with a history of 
autoimmune diseases that may relapse, patients who have undergone allogenic stem cell or organ 
transplantation, and patients who have received a live vaccine within 28 days before the first dose of 
study drugs are excluded from the study (see Section 4.2).  
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded according to 
NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) according to the 
schedule in Appendix 1. Clinical laboratory results must be reviewed prior to the start of each cycle.  
Note: Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only (and not on 
the number of antihypertensive medications).    
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs, physical examinations, laboratory measurements (hematology, chemistry, 
etc.), and other assessments. In addition, patients will be closely monitored for the development of any 
signs or symptoms of autoimmune conditions and infection.  
Serum samples will be drawn for determination of antidrug antibody (ADA) to tislelizumab in patients 
who are enrolled in part 1. Administration of tislelizumab will be performed in a setting where emergency 
medical equipment and staff who are trained to respond to medical emergencies are available (see Section 
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All AEs will be recorded during the study (AE from the time of the first dose of study drugs and SAEs 
from the time of signing of informed consent) and for up to 30 days after the last dose of study treatment 
or until the initiation of another anticancer therapy, whichever occurs first. At the EOT, ongoing AEs 
considered related to study treatment will be followed until the event has resolved to baseline or 
≤ Grade 1, the event is assessed by the investigator as stable, the patient is lost to follow-up, the patient 
withdraws consent, or it has been determined that study treatment or participation is not the cause of the 
AE. 
Immune-related AEs will be recorded until up to 90 days after the last dose of tislelizumab, regardless of 
whether the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by 
investigator after treatment discontinuation until patient death, withdrawal of consent, or loss to follow 
up, whichever occurs first. 
Investigators are instructed to report all AEs (including pregnancy-related AEs).  
The potential safety issues anticipated in this study, as well as measures intended to avoid or minimize 
such toxicities, are outlined in the following sections.  
8.3. 
Adverse Events 
8.3.1. 
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 drugs or not.  
Examples of AEs include:  
• 
Worsening of a chronic or intermittent pre-existing condition, including an increase in severity, 
frequency, duration, and/or has an association with a significantly worse outcome  
• 
New conditions detected or diagnosed after study drugs 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 drugs or a 
concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory results, and diagnostics reports) relative to the AE or SAE. The 
investigator will then record all relevant information regarding an AE or SAE in the eCRF. However, 
there may be instances when copies of medical records for certain cases are requested by the sponsor. In 
this instance, all patient identifiers will be blinded on the copies of the medical records prior to 
submission to the sponsor.  
8.3.2. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs and SAEs 
should be assessed and graded based upon the NCI-CTCAE v5.0. 


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Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
• 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)  
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL  
• 
Grade 4: Life-threatening consequences; urgent intervention indicated  
• 
Grade 5: Death related to AE  
Note:  
1. 
The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity (for 
example, Grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or life-
threatening [Grade 4]), whereas seriousness is classified by the criteria based on the regulatory 
definitions. Seriousness serves as the guide for defining regulatory reporting obligations from the 
sponsor to applicable regulatory authorities as described in Section 8.6.2. 
2. 
Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only (and not 
on the number of antihypertensive medications).    
8.3.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drugs and the occurrence of each 
AE or SAE, using best clinical judgment. Alternative causes, such as natural history of the underlying 
diseases, concomitant therapy, other risk factors, and the temporal relationship of the AE or SAE to the 
study drugs should be considered and investigated. The investigator should refer to the Investigator’s 
Brochures of tislelizumab, information regarding lenvatinib in this protocol and Pharmaceutical 
Instructions of lenvatinib (Lenvatinib Pharmaceutical Instruction. 2018) in the determination of his/her 
assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the sponsor. However, it is very important that the investigator always 
makes an assessment of causality for every SAE prior to transmission of the SAE report to the sponsor, 
since the causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality considering follow-up 
information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or “not 
related.” An AE is considered related if there is “a reasonable possibility” that the AE may have been 
caused by the study drug (ie, there are facts, evidence, or arguments to suggest possible causation). 
Several factors should be considered in making this assessment, including:  
• 
Temporal relationship of the AE to the administration of study treatment/study procedure 
• 
Whether an alternative etiology has been identified 


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• 
Mechanism of action of the study drug 
• 
Biological plausibility 
An AE should be considered “related” to study drug if any of the following criteria are met, otherwise the 
event should be assessed as not related: 
• 
There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out 
• 
There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely 
• 
There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of other 
factors may have contributed to the AE (eg, the patient’s clinical condition or other 
concomitant AEs). 
8.3.4. 
Following Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient and 
provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be reviewed at 
subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered chronic, the 
AE or SAE is otherwise explained, the patient is lost to follow up, or the patient withdraws consent. The 
investigator will ensure that follow up includes any supplemental investigations as may be indicated to 
elucidate the nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, radiographic imaging, or consultation with other health 
care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE or 
SAE. The investigator is obligated to assist. If a patient dies during participation in the study or during a 
recognized follow-up period, the sponsor will be provided with a copy of any postmortem findings, 
including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions provided 
by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline and significantly 
worsen during the study. The definition of clinically significant is left to the judgment of the investigator. 
In general, these are the laboratory test abnormalities or other abnormal assessments that:  


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• 
are associated with clinical signs or symptoms, or  
• 
require active medical intervention, or  
• 
lead to dose interruption or discontinuation, or 
• 
require close observation, more frequent follow-up assessments, or  
• 
further diagnostic investigation. 
Abnormalities in liver function tests (ALT, AST, total bilirubin) that are Grade 3 or higher need to be 
reported to the sponsor within 24 hours of occurrence via SAE reporting process as described in Section 
8.6.2.1. Repeat liver function testing (LFT) should be performed according to the schedule in Appendix 10. 
8.4. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose:  
• 
Results in death 
• 
Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in which the 
patient was at risk of death at the time of the AE. It does not refer to an AE, which hypothetically 
might have caused death, if it were more severe 
• 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually involving at least 
an overnight stay) to the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting 
• 
Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere or prevent everyday life functions, 
but do not constitute a substantial disruption 
• 
Is a congenital anomaly/birth defect 
• 
Is considered a significant medical AE by the investigator based on medical judgement (eg, may 
jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
The following are NOT considered SAEs: 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• 
Hospitalization for social/convenience considerations 
• 
Scheduled therapy for the target disease of the study, including admissions for transfusion support 
or convenience 


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8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is both 
unexpected (ie, not present in the Investigator’s Brochure or related information in this protocol) and 
meets the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
8.6.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be reported 
until either 30 days after last dose of study drugs or initiation of new anticancer therapy, whichever occurs 
first. Immune-related AEs (serious or nonserious) should be reported until 90 days after the last dose of 
tislelizumab, regardless of if the patient starts a new anticancer therapy. 
The investigator should report any SAEs that are assessed as related to study drug treatment, at any time 
after treatment discontinuation. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the event must 
be reported promptly (within 24 hours) to the sponsor or designee as described in table 13. 
Table 13 Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe 
for Making 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs 
Within 24 h of 
first knowledge 
of the SAE 
SAE report 
As 
expeditiously 
as possible 
SAE report 
Email or 
fax SAE 
form 
Abbreviations: h, hours; SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE report will 
always be completed as thoroughly as possible with all available details of the SAE and forwarded to the 
sponsor or designee within the designated time frames.  


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If the investigator does not have all information regarding an SAE, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE and completing the form. The 
form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures detailed 
in Section 8.6.2.1 and Section 8.6.2.2. The sponsor has a legal responsibility to notify, as appropriate, 
both the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  
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 IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities and 
investigators for lenvatinib and tislelizumab studies. 
When a study center receives an initial or follow-up report or other safety information (eg, revised 
investigator’s book) from the sponsor, the investigator or designated responsible person is required to 
promptly notify his/her IRB or IEC. The investigator should place copies of Safety Reports from the 
sponsor in the Investigator Site File. 
8.6.3. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions:  
• 
How are you feeling?  
• 
Have you had any medical problems since your last visit?  
• 
Have you taken any new medicines since your last visit?  
8.6.4. 
Progressive Disease 
Progressive disease (including fatal PD), which is expected in this study population and measured as an 
efficacy endpoint, should not be reported as an AE term. Instead, the symptoms, signs, or clinical 
sequelae that result from disease progression should be reported as the AE term(s).  
For instance, a patient presents with pleural effusion resulting from disease progression of metastasis to 
lungs. The event term should be reported as “pleural effusion” instead of PD. If a patient experienced a 
fatal multiorgan failure due to PD, the term “multiorgan failure” should be reported as the SAE with death 
as outcome instead of reporting “fatal disease progression” or “death due to disease progression.”  


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8.6.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is death and 
the cause of death is unknown, then the death is reported as an event, eg, “death,” “death of unknown 
cause,” or “death unexplained.” 
8.6.6. 
Pregnancies 
If a female patient or the partner of a male patient receiving investigational therapy becomes pregnant 
within 120 days after the last dose of tislelizumab or lenvatinib, a pregnancy report form is required to be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, follow up will be no longer 
than 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be 
reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective termination 
of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drugs 
should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review Boards, 
and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drugs experience to identify and 
expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs, and IECs 
based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the expectedness of 
the SAEs using the following reference safety information (RSI) documents: 
• 
tislelizumab IB 
• 
all information of lenvatinib presented in Pharmaceutical Instructions of lenvatinib (Lenvatinib 
Pharmaceutical Instruction. 2018.) 
8.6.8. 
Assessing and Recording Immune-Related Adverse Events 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related (see Section 8.7.3) should be classified as irAEs and identified as such 
in the eCRF AE page until 90 days after the last dose of study treatment. 
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, which are 
commonly seen with immune checkpoint inhibitors, in Appendix 10. 
An extensive list of potential irAEs appears in table 15. All conditions similar to those listed should be 
evaluated to determine whether they are irAEs, based on a similar diagnostic process to those reactions 
that are presented in more detail in Appendix 10. 


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8.7. 
Management of Adverse Events of Special Interest of Tislelizumab 
As a routine precaution, after infusion of tislelizumab on Cycle 1 and Cycle 2 Day 1, patients must be 
monitored for at least 1 hour afterward in an area with resuscitation equipment and emergency agents. 
From Cycle 3 onward, a ≥ 30-minute monitoring period is required in an area with resuscitation 
equipment and emergency agents.  
The management of infusion-related reactions, severe hypersensitivity reactions and irAEs according to 
the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Infusion-Related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, angioedema, 
hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension. 
Severe reactions may include acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock. Patients should be closely monitored for such reactions. Immediate 
access to an Intensive Care Unit (ICU) or equivalent environment and appropriate medical therapy 
(including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen) must be available 
to treat infusion-related reactions.  
Treatment modification for symptoms of infusion-related reactions due to tislelizumab is provided in 
table 14. 
Table 14 Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as 
needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 h. 
Stop infusion. Infusion may be resumed at 50% 
of previous rate once infusion-related reactions 
have resolved or decreased to Grade 1 in 
severity. Any worsening is closely monitored. 
Proper medical management should be instituted 
as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 


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Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drugs treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drugs treatment. 
Hospitalization is recommended 
Abbreviations: h, hours; IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria 
for Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an infusion-related 
reaction, it must remain decreased for all subsequent infusions with premedication. If the patient has a 
second infusion-related reaction (≥ Grade 2) on the slower infusion rate, infusion should be discontinued, 
and the patient should be withdrawn from tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted, as 
indicated per the type of reaction. This includes but is not limited to an antihistamine (eg, 
diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), and if considered indicated 
oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen. In the next cycle, patients should 
receive oral premedication with an antihistamine (eg, diphenhydramine or equivalent) and an antipyretic 
(eg, paracetamol or equivalent), and they should be closely monitored for clinical signs and symptoms of 
an infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to oral or 
IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available medical 
practice as described in the complete guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK). Patients should be instructed to 
report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within minutes 
following administration of the drug/antigen, and characterized by: respiratory distress; laryngeal edema; 
and/or intense bronchospasm; and often followed by vascular collapse or shock without antecedent 
respiratory difficulty; cutaneous manifestations such as pruritus and urticaria with/without edema; and 
gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea), the 
infusion must be immediately stopped and the patient discontinued from the study. 


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The patients will be administered epinephrine injection and dexamethasone infusion if hypersensitivity 
reaction is observed and then the patient should be placed on monitor immediately and ICU should be 
alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion. Alternative 
treatments for fever (ie, paracetamol) may be given to patients at the discretion of the investigator. 
8.7.3. 
Immune-related Adverse Events  
While lenvatinib may have immunostimulatory effects, autoimmune AEs have not been reported in 
clinical trials, including to date in combination with pembrolizumab. However, the potential for lenvatinib 
to exacerbate or promote these AEs when administered in combination with a PD-1 inhibitor should be 
noted. 
Immune-related AEs are of special interest in this study. If the events listed below or similar events occur, 
the investigator should exclude alternative explanations (eg, combination drugs, infectious disease, PD, 
metabolic, toxin, or other neoplastic causes) with appropriate diagnostic tests which may include but are 
not limited to serologic, immunologic, and histologic (if available) data. If alternative causes have been 
ruled out; the AE required the use of systemic steroids, other immunosuppressants, or endocrine therapy 
and is consistent with an immune mediated mechanism of action, the irAE indicator in the eCRF AE page 
should be checked. A clinically relevant overlap in toxicity may arise between an irAE attributed to 
tislelizumab and the nonspecific, most often mild to moderate AE (eg, rash, colitis and abnormalities in 
ALT, AST and total bilirubin) observed with lenvatinib. The time to onset may be helpful in 
distinguishing an AE that may be attributed to autoimmune effects versus nonspecific toxicity. 
A list of potential irAEs is shown below in table 15. All conditions similar to those listed should be 
evaluated in patients receiving tislelizumab to determine whether they are immune-related.  
Recommendation for diagnostic evaluation and management of irAEs is based on European Society for 
Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) guidelines (Haanen et al 
2017, Brahmer et al 2018) and common immune-related toxicities are detailed in Appendix 10. For any 
AEs not included in Appendix 10 please refer to ASCO Clinical Practice Guideline (Brahmer et al 2018) 
for further guidance on diagnostic evaluation and management of immune-related toxicities.  


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Table 15 Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase (ALT/AST) 
elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent diabetes 
mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing irAEs are detailed in Appendix 10. 
In the event of an immune-related AE during study treatment, administration of lenvatinib and 
tislelizumab should be interrupted until the event stabilizes to ≤ Grade 1, unless otherwise noted. If a 
toxicity does not resolve to ≤ Grade 1 within 4 weeks for lenvatinib or 12 weeks for tislelizumab, study 
drugs should be discontinued after consultation with the sponsor. Patients who experience a recurrence of 
the any event at the same or higher severity grade with re-challenge should permanently discontinue 
treatment.  
8.8. 
Management of Lenvatinib-Specific Adverse Events 
The management of lenvatinib-specific adverse events almost refer to Pharmaceutical Instructions of 
lenvatinib (Lenvatinib Pharmaceutical Instruction. 2018.). And patients will be closely monitored for any 
toxicities. 
8.8.1. 
Management of Non-Hematological Toxicities and Hematological Toxicities of 
Lenvatinib 
Non-hematological and hematological toxicities ≥ Grade 3 or Grade 2 intolerable non-hematological and 
hematological toxicities which have underwent active treatment, considered to be related to lenvatinib 
treatment may be managed by lenvatinib interruption, lenvatinib dosage reduction or lenvatinib 
discontinuing treatment, until resolution of toxicity to ≤ Grade 1 or to baseline value, unless otherwise 
noted (see table 16). Mild to moderate non-hematological and hematological toxicities (Grade 1 or 2) 


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generally do not require interruption of lenvatinib, unless Grade 2 toxicities which patients are still 
intolerant even after active treatment. 
If the toxicity is adequately managed by routine supportive care (eg, antiemetics, antidiarrheals, or 
electrolyte supplementation), treatment may be resumed at the same dose; if not, treatment may be 
resumed at a reduced dose as outlined in table 16. Recurrence of the toxicity may be managed similarly. If 
treatment is interrupted for ≥ 28 days, permanent discontinuation from study treatment should be 
considered. Detailed information on dosage modifications based on non-hematological and hematological 
toxicities see table 16. Detailed information on monitoring, dosage modifications and discontinuation see 
table 17. 
Table 16 Lenvatinib Dose Modifications Based on non-hematological and hematological 
Drug-Related Toxicities 
Adverse Event 
Toxicity Gradea 
Management 
Reduction dose and resumption of 
lenvatinib 
Hypertensionb 
Grade 3 (Despite the best 
antihypertensive 
therapy)c 
Interruption 
Resume when hypertension is controlled at 
less than or equal to Grade 2. (refer to 8.8.2 
Hypertension)   
 
Grade 4 
Discontinue 
Permanently discontinue (refer to 8.8.2 
Hypertension)   
Proteinuria 
2 g or greater proteinuria 
in 24 hours 
Interruption 
Withhold until less than 2 grams of 
proteinuria per 24 hours 
Nephrotic syndrome 
-------  
Discontinue 
Permanently discontinue 
Renal Failure or 
Impairment  
Grade 3 
Interruption  
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4a 
Discontinue 
Permanently discontinue 
Cardiac Dysfunction 
Grade 3 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4 
Discontinue 
Permanently discontinue 
Reversible Posterior 
Leukoencephalopathy 
Syndrome (RPLS)/ 
Posterior Reversible 
Encephalopathy 
Syndrome (PRES) 
Any Grade 
Interruption 
If improves to Grade 0 to 1, may consider 
resuming at a reduced dose 
Hepatotoxicityb 
Grade 3 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4a 
Discontinue 
Permanently discontinue 
Arterial Thromboembolic 
Event  
Any Grade 
Discontinue 
Permanently discontinue 
Hemorrhage 
Grade 3 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4 
Discontinue 
Permanently discontinue 


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Gastrointestinal 
Perforation or Fistula 
Formation 
Grade 3 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4 
Discontinue 
Permanently discontinue 
Non-gastrointestinal 
Fistula Formation 
Grade 4 
Discontinue 
Permanently discontinue 
QT Prolongation 
Greater than 500 ms 
Interruption 
Withhold until improves to less than or 
equal to 480 ms or baseline 
Diarrheab 
Grade 3 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
 
Grade 4（Despite best 
medical management） 
Discontinue 
Permanently discontinue 
Other Adverse Reactions 
o 
Persistent or 
intolerable  
o 
Grade 2 or 3 adverse 
reaction which have 
underwent active 
treatment 
o 
Grade 4 laboratory 
abnormalitya 
Interruption 
Withhold until improves to Grade 0 to 1 or 
baseline 
Other Grade 4 adverse 
reaction 
Discontinue 
Permanently discontinue 
a. When the toxicities are grade 4 laboratory abnormalities, if judged to be non-life-threatening by investigator, these grade 4 
toxicities can be treated as grade 3 toxicities. For asymptomatic laboratory abnormalities, such as grade 3 elevations of amylase 
and lipase that are not considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
medical monitor. 
b. Not likely to be immune-mediated based on investigator’s assessment. 
c. Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only (and not on the number of 
antihypertensive medications).    
Table 17 Monitoring, Dose Modifications and Discontinuation for Lenvatinib-Specific AEs 
Starting Dose 
Baseline Weight≥60 kg 
12 mg QD. PO. 
Baseline Weight<60 kg  
8 mg QD. PO. 
Persistent or intolerable Grade 2 or 3f AE which have underwent active treatment a 
AE 
Dose Modification 
Reduced Dose b 
(Baseline Weight ≥60 kg) 
Reduced Dose b 
(Baseline Weight <60 kg) 


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First Occurrence c 
Withhold until improves to 
Grade 0 to 1 or baseline d 
8 mg QD. PO. 
4 mg QD. PO. 
Second Occurrence 
(Same event or new 
event) 
Withhold until improves to 
Grade 0 to 1 or baseline d 
4 mg QD. PO. 
4 mg every other day, PO. 
Third Occurrence 
(Same event or new 
event) 
Withhold until improves to 
Grade 0 to 1 or baseline d 
4 mg every other day, PO. Discontinue 
Grade 4 AE: Discontinue e 
a. 
AEs such as nausea, vomiting and diarrhea should be actively treated before reduction dose or discontinue. 
b. 
Based on the previous dose levels, the dose was gradually reduced in the order of 12 mg once a day, 8 mg once a 
day, 4 mg once a day or 4 mg every other day. 
c. 
Hematological AEs or proteinuria occur for the first time - no dose modification is required. 
d. 
Resume when hematological AEs is controlled at less than or equal to Grade 2 or proteinuria less than 2 grams per 
24 hours. 
e. 
When the toxicities are grade 4 laboratory abnormalities, if judged to be non-life-threatening by investigator, these 
grade 4 toxicities can be treated as grade 3 toxicities. 
f. 
For asymptomatic laboratory abnormalities, such as grade 3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the Sponsor. 
Depend on investigator’s assessment, patients may resume at the same dose in the following cases:  
• 
Grade 3 nausea, vomiting or diarrhea that is treated with supportive care and improves to Grand 0 to 1 or 
baseline within 72 hours 
• 
Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with 
conventional medical treatment within 72 hours 
• 
Grade 3 fatigue that improves to Grand 0 to 1 or baseline within 8 days  
• 
Grade 3 or 4 amylase or lipase elevation that is not associated with symptoms or clinical manifestations of 
pancreatitis 
• 
Grade 3 or 4 alanine aminotransferase and aspartate aminotransferase elevation that is not associated with 
symptoms, other laboratory indication or clinical manifestations of hepatic failure or hepatic encephalopathy, 
that is treated with supportive care and improves to Grand 0 to 1 or baseline within ≤ 72 hours 
Abbreviation: QD, once a day; PO, orally 
8.8.2. 
Hypertension 
Hypertension has been reported in several clinical studies of lenvatinib, which usually occurs in the early 
stages of treatment, for example, hypertension occurred in 45% of patients in REFLECT study receiving 
lenvatinib 8 mg or 12 mg orally once daily, and the median time to onset of new or worsening 
hypertension was 26 days in REFLECT study (Lenvatinib Pharmaceutical Instruction. 2018.). Blood 
pressure should be well controlled before lenvatinib administration. If the patient is known to have 
hypertension, a stable dose of antihypertensive therapy following local guidelines, should be administered 
for at least one week before lenvatinib administration. Severe complications (including aortic dissection) 
with poorly controlled hypertension have been reported. Early detection and active management of 
hypertension are important to reduce the interruption or dose modification of lenvatinib (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
Hypertension should be managed following below guideline:  
Management guideline of lenvatinib-specific hypertension 


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Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. Investigators 
should therefore ensure that patients enrolled to receive treatment with lenvatinib have BP of ≤150/90 
mm Hg at the time of study entry and, if known to be hypertensive, have been on a stable dose of 
antihypertensive therapy for at least 1 week before first dose of study drugs. Early detection and effective 
management of hypertension are important to minimize the need for lenvatinib dose interruptions and 
reductions.  
Regular assessment of BP should be conducted as detailed in the schedule of assessment (refer to 
Appendix 1). Hypertension will be graded using NCI-CTCAE v 5.0, based on BP measurements only 
(and not on the number of antihypertensive medications).    
Each assessment of BP and BP elevation confirmation (systolic and diastolic) should follow Section 
7.3.1. Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg) is confirmed. The choice of antihypertensive treatment should be individualized 
to the patient’s clinical circumstances and follow standard medical practice. For previously normotensive 
patients, appropriate antihypertensive therapy should be started when systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg is first confirmed. For those patients already on antihypertensive medication, 
treatment modification may be necessary if hypertension persists.    
Lenvatinib should be withheld in any instance where a patient is at imminent risk to develop a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled hypertension 
(eg, BP ≥160/100 mm Hg, significant risk factors for cardiac disease, intracerebral hemorrhage, or other 
significant co-morbidities). Once the patient has been on the stable antihypertensive medications for at 
least 48 hours and the BP is controlled, lenvatinib should be resumed as described below.  
Patients with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP monitored on 
Day 15 (or more frequently as clinically indicated) until systolic BP has been ≤150 mm Hg and diastolic 
BP has been ≤95 mm Hg for 2 consecutive treatment cycles. If a repeat event of systolic BP ≥160 mm Hg 
or diastolic BP ≥100 mm Hg occurs, the patient must resume the Day 15 evaluation until systolic BP has 
been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. A diary will 
be provided to the patient to capture the blood pressure evaluations between study visits.  
The following guidelines should be followed for the management of systolic BP ≥160 mmHg or diastolic 
BP ≥100 mmHg confirmed on repeat measurements after at least 30 minutes:  
a. Continue study drug and institute antihypertensive therapy for patients not already receiving this.  
b. For those patients already on antihypertensive medication, the dose of the current agent may be 
increased, if appropriate, or 1 or more agents of a different class of antihypertensive should be 
added.  
c. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists more than 48 hours, despite 
maximal antihypertensive therapy, then lenvatinib administration should be interrupted, and 
restarted at 1 dose level reduction only when systolic BP ≤150 mmHg and diastolic BP ≤95 
mmHg and the patient has been on a stable dose of antihypertensive medication for at least 48 
hours. 


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o If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg, which lasts more than 48 hours, 
recurs on the first dose reduction despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted at an 
additional dose reduction only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg 
and the patient has been on a stable dose of antihypertensive medication for at least 48 hours.   
o If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg, which lasts more than 48 hours, 
recurs on the second dose reduction despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted at a third 
dose reduction dose only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the 
patient has been on a stable dose of antihypertensive medication for at least 48 hours.  
o Additional dose reduction should be discussed with the sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension (life 
threatening consequences):  
a. Institute appropriate medical management  
b. Discontinue lenvatinib 
8.8.3. 
Proteinuria 
Proteinuria has been reported in several clinical studies of lenvatinib, which usually occurs in the early 
stages of treatment, for example, 26% of lenvatinib-treated patients in REFLECT study occurred 
proteinuria, and the incidence of grade 3 was 5.9% in this study. The median time from first lenvatinib 
administration to onset of proteinuria was 6 weeks in REFLECT study. 
If confirmation of lenvatinib-specific proteinuria, withhold and resume at a reduced dose upon recovery 
or permanently discontinue lenvatinib based on severity should refer to table 16 and table 17. If nephrotic 
syndrome occurs, lenvatinib should be discontinued. (Lenvatinib Pharmaceutical Instruction. 2018.).  
Management guideline of lenvatinib-specific proteinuria 
Regular assessment of proteinuria should be conducted as detailed in the schedule of assessment (refer to 
Appendix 1). Guidelines for assessment and management of proteinuria are as follows: 
Grading of proteinuria 
Grading according to NCI-CTCAE v 5.0 will be based on the 24-hour urinary protein result if available. 
Management of proteinuria 
If nephrotic syndrome occurs, lenvatinib should be discontinued. 
Detection and Confirmation: 
1. Perform urinalysis per the schedule of assessment (refer to Appendix 1).  
2. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) and a random 


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urine sample for total protein and creatinine to determine a protein to creatinine ratio is required in the 
following situations:  
o Occurrence of ≥2+ (≥ 1+ in screening) proteinuria on urine dipstick while on study drugs  
o A subsequent increase in severity of urine dipstick proteinuria  
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to verify the grade 
of proteinuria is required when UPCR is ≥2.4. 
4. To achieve the result prior to study drugs administration on the day of each scheduled assessment, the 
urine sample may be collected 24 hours ahead of schedule in 24-hour protein assessment. 
Monitoring： 
Urinalysis for subjects with proteinuria ≥2+ should be performed on Day 15 (or more frequently as 
clinically indicated) until the results have been 1+ or negative for 2 consecutive treatment cycles.   
8.8.4. 
Renal Failure or Impairment 
Renal failure or impairment have been reported in several clinical studies of lenvatinib, for example renal 
impairment occurred in 7.1% of patients receiving lenvatinib in REFLECT study, and the incidence of 
grade 3 was 1.9%. 
The main risk factors identified were dehydration and/or insufficient blood volume caused by 
gastrointestinal toxicity. It is necessary to initiate prompt management of diarrhea or 
dehydration/hypovolemia, to reduce the risk of renal failure or impairment. If confirmation renal failure 
or impairment, withhold and resume at a reduced dose upon recovery or permanently discontinue 
lenvatinib based on severity should refer to table 16 and table 17. (Lenvatinib Pharmaceutical Instruction. 
2018.).  
8.8.5. 
Cardiac Dysfunction 
Serious and fatal cardiac dysfunction have been reported in several clinical studies of lenvatinib, for 
example cardiac dysfunction including congestive heart failure, cardiogenic shock and cardiopulmonary 
failure, occurred in 0.6% of patients receiving lenvatinib in REFLECT study , and the incidence of grade 
3 or greater than grade 3 was 0.4%. 
If confirmation of lenvatinib-specific cardiac dysfunction, withhold and resume at a reduced dose upon 
recovery or permanently discontinue lenvatinib based on severity should refer to table 16 and table 17. 
(Lenvatinib Pharmaceutical Instruction. 2018.). 
8.8.6. 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)/ Posterior Reversible 
Encephalopathy Syndrome (PRES) 
RPLS/ PRES have been reported in several clinical studies of lenvatinib, for example PRES (grade 2) 
occurred in 1 patient (＜1%) receiving lenvatinib in REFLECT study. 


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PRES is a neurological disease characterized by headache, seizures, lethargy, confusion, mental changes, 
blindness and other visual or neurological disorders. It may be accompanied by mild to severe 
hypertension. It is necessary to perform MRI to confirm the diagnosis of PRES. Appropriate treatment 
should be taken to control blood pressure (see Section 8.8.2 Hypertension). Patients with PRES signs or 
symptoms may need interruption, dose modification or discontinue of lenvatinib (see table 16 and table 
17). (Lenvatinib Pharmaceutical Instruction. 2018.). 
8.8.7. 
Hepatotoxicity 
In REFLECT study, hepatic encephalopathy occurred in 8% of lenvatinib-treated patients. Grade 3 to 5 
hepatic encephalopathy occurred in 5% of lenvatinib-treated patients. Grade 3 to 5 hepatic failure 
occurred in 3% of lenvatinib-treated patients (Lenvatinib Pharmaceutical Instruction. 2018.). Patients with 
more severe liver dysfunction and/or greater liver tumor load at baseline are at higher risk of developing 
hepatic encephalopathy and liver failure. Hepatic encephalopathy was more frequent in patients aged 75 
and over. About half of the cases of liver failure and one third of the cases of hepatic encephalopathy 
were reported in patients with PD. 
Due to the elimination of lenvatinib mainly through liver, it is expected that exposure in patients with 
moderate and severe hepatic insufficiency (Child - Pugh B and Child - Pugh C) will increase.  
It’s necessary to monitor patients with HCC closely for signs of hepatic failure, including hepatic 
encephalopathy. If confirmation of lenvatinib-specific hepatotoxicity, withhold and resume at a reduced 
dose upon recovery or permanently discontinue lenvatinib based on severity should refer to table 16 and 
table 17. (Lenvatinib Pharmaceutical Instruction. 2018.). 
For cases where transaminase increases are not likely to be immune-mediated, treatment management 
decisions should be made per investigator discretion in consideration of clinical factors. 
8.8.8. 
Arterial Thromboembolic Event 
There have been reports of arterial thromboembolism (cerebrovascular accident, transient ischemic attack 
and myocardial infarction) in patients treated with lenvatinib, for example arterial thromboembolism 
occurred in 2.3% of patients receiving lenvatinib in REFLECT study, and 0.45% of patients (10 patients) 
with arterial thromboembolism occurred including 5 cases of myocardial infarction and 5 cases of 
cerebrovascular events, fatal outcomes in REFLECT study. 
The safety of resuming lenvatinib after an arterial thromboembolic event has not been established and 
lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the 
previous 6 months. 
If confirmation of lenvatinib-specific arterial thromboembolic event, permanently discontinue lenvatinib  
should refer to table 16 and table 17. (Lenvatinib Pharmaceutical Instruction. 2018.). 
8.8.9. 
Hemorrhage 
Severe tumor-related bleeding, including fatal bleeding, occurred in clinical trials, in REFLECT study 
24.6% of the patients reported bleeding, of which 5.0% were grade 3 or above. The incidence of grade 3 


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was 3.4%, and grade 4 was 0.2%. Seven patients (1.5%) had grade 5 including cerebral hemorrhage, 
upper gastrointestinal hemorrhage, intestinal hemorrhage and tumor hemorrhage. The median time from 
first dose to the first occurrence of bleeding was 11.9 weeks.  
Because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after 
treatment with lenvatinib, the invasion extent of large vessels (such as carotid artery) should be 
considered. Some hemorrhagic cases are secondary to tumor contraction and fistula formation, such as 
tracheoesophageal fistula. Fatal intracranial hemorrhage has been reported in some patients with or 
without brain metastasis. Hemorrhage (e.g. trachea, abdomen and lung) was also reported as well. A fatal 
case of hepatic tumor hemorrhage in a HCC patient was reported. 
If confirmation of lenvatinib-specific hemorrhage, withhold and resume at a reduced dose upon recovery 
or permanently discontinue lenvatinib based on severity should refer to table 16 and table 17. (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
8.8.10. 
Gastrointestinal Perforation or Fistula Formation 
Severe gastrointestinal perforation or fistula formation occurred in clinical trials, for example 
gastrointestinal perforation or fistula formation occurred in 1.9 % of patients receiving lenvatinib in 
REFLECT study. 
In most cases, gastrointestinal perforation or fistula formation occurred in patients with risk factors, such 
as those who have previously undergone surgery or radiotherapy. 
If confirmation of lenvatinib-specific gastrointestinal perforation or fistula formation, withhold and 
resume at a reduced dose upon recovery or permanently discontinue lenvatinib based on severity should 
refer to table 16 and table 17. (Lenvatinib Pharmaceutical Instruction. 2018.). 
8.8.11. 
Non-gastrointestinal Fistula Formation 
The risk of fistula formation may increase in patients treated with lenvatinib. In clinical trials and post-
marketing experience, cases of gastrointestinal or non-gastrointestinal fistula formation or enlargement 
(e.g. tracheal fistula, tracheoesophageal fistula, esophageal fistula, skin fistula, female genital fistula) 
were observed. Previous surgery and radiotherapy may be high risk factors. In order to avoid 
deterioration, lenvatinib should not be started in patients with fistula. Patients with esophageal or 
tracheobronchial fistula formation and any grade 4 fistula formation should be permanently discontinued 
of lenvatinib, refer to table 16 and table 17. (Lenvatinib Pharmaceutical Instruction. 2018.). Due to 
limited data on the use of interruption or dose reduction to manage fistula formation, but deterioration is 
observed in some cases, caution should be exercised. And lenvatinib may have adverse effects on wound 
healing. 
8.8.12. 
QT Prolongation 
Incidence of reported prolonged QT/QTc intervals in patients treated with lenvatinib was higher compare 
with placebo. prolonged QT/QTc occurred in 6.9 % of patients receiving lenvatinib, and the incidence of 
prolongation of QTcF more than 500 ms was 2.4% in REFLECT study. ECG should be monitored in all 
patients and special attention should be paid to patients with congenital long QT syndrome, congestive 


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heart failure, bradyarrhythmia and those receiving drugs to prolong the QT interval, including Ia and III 
antiarrhythmic drugs. If the QT is greater than 500 ms, then lenvatinib should be interrupted. When the 
prolongation of the QTc is less than 480 ms or baseline, the lenvatinib should be resume at a reduced 
dose. Electrolyte disorders (such as hypokalemia, hypocalcemia or hypomagnesemia) can increase the 
risk of prolonged QT, so electrolyte abnormalities in all patients should be monitored and actively treated 
before lenvatinib administration. 
If confirmation of lenvatinib-specific QT prolongation, withhold and resume at a reduced dose upon 
recovery or permanently discontinue lenvatinib based on severity should refer to table 16 and table 17. 
(Lenvatinib Pharmaceutical Instruction. 2018.). 
8.8.13. 
Diarrhea 
Frequent diarrhea was reported in patients treated with lenvatinib, which usually occurs in the early stages 
of treatment. For example, diarrhea occurred in 38.7% of patients receiving lenvatinib, of which 4.2% 
were grade 3 or above in REFLECT study.  
Medical management of diarrhea should be carried out immediately to prevent dehydration. If 
confirmation of lenvatinib-specific diarrhea, withhold and resume at a reduced dose upon recovery or 
permanently discontinue lenvatinib based on severity should refer to table 16 and table 17. (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
Patients should be counseled that diarrhea is a possible side effect and advised to take loperamide or a 
similar medication as needed if diarrhea develops. 
Investigators should also evaluate whether diarrhea may be attributable to the irAE of colitis. As with 
other small molecule RTK inhibitors, the presence of abdominal pain, mucus, or blood in the stool or 
peritoneal signs should raise the index of suspicion for immune-mediated colitis, as these features are 
generally not observed with lenvatinib treatment-associated diarrhea. The diarrhea observed with 
lenvatinib generally improves within several days of interrupting study medication, with close 
observation may help establish the most likely causality.  
8.8.14. 
Thyrotropin Inhibition Impairment/Thyroid Dysfunction Other Than Immune-
Mediated 
The cases of hypothyroidism have reported in patients treated with lenvatinib, and lenvatinib can impairs 
exogenous thyroid suppression. For example, TSH levels were higher than the upper limit of normal 
values in 69.6% of patients treated with lenvatinib in REFLECT study.  
Hypothyroidism should be treated according to standard treatment of local guideline in order to maintain 
normal thyroid function, for example hormone replacement therapy if applicable. (Lenvatinib 
Pharmaceutical Instruction. 2018.). 
8.8.15. 
Wound Healing Complications 
No formal study has been carried out on the influence of lenvatinib on wound healing. Delayed wound 
healing has been reported in some patients treated with lenvatinib. Patients who underwent major surgery 
recently should not receive treatment of lenvatinib. (Lenvatinib Pharmaceutical Instruction. 2018.). 


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8.8.16. 
Palmar plantar erythrodysesthesia (PPE) 
Palmar plantar erythrodysesthesia (PPE) has been reported in several studies of lenvatinib. Measures that 
can be taken to manage PPE include avoidance of exposure of hands and feet to hot water when washing 
dishes or bathing, or to other sources of heat, avoidance of activities that cause unnecessary force or 
friction (rubbing) on the hands or feet, avoiding contact with harsh chemicals such as cleaning products, 
use of tools or household items that result in pressure on the hands, such as garden tools, knives, and 
screwdrivers, and wearing of loose fitting, well-ventilated shoes and clothes. Treatment may include use 
of topical moisturizing agents, topical anesthetics, or topical anti-inflammatory medications such as 
corticosteroid creams. In more severe cases, dose interruption and reduction may be warranted. 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
9.1. 
Statistical Analysis 
The 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) per sponsor agreed reporting standards, where applicable. 
Details of the statistical analyses will be included in a separate Statistical Analysis Plan (SAP). 
The following descriptive statistics will be used to summarize the trial data on the basis of their nature 
unless otherwise specified:  
• 
Continuous variables: number of non-missing observations, mean, standard deviation, median, 
minimum, and maximum  
• 
Categorical variables: frequencies and percentages  
• 
Time-to-event variables: number of non-missing observations (N), median, minimum and 
maximum. Kaplan-Meier (KM) event rates may also be provided if applicable for specific time to 
event variables 
9.1.1. 
Analysis Sets 
• 
The safety analysis set (SAF) includes all patients who received at least 1 dose of any study drug 
(any component for the combination therapy). 
• 
The efficacy evaluable analysis set (EFF) includes all dosed patients with measurable disease at 
baseline per RECIST v1.1 and who had at least one evaluable post-baseline tumor assessment 
unless treatment was discontinued due to clinical disease progression or death before the first post 
treatment tumor assessment. 
• 
DLT evaluable analysis set for lenvatinib and tislelizumab combination includes patients who 
received at least 75% of the assigned total dose of lenvatinib and ≥ 67% (approximately two-
thirds) of the assigned total dose of tislelizumab for the DLT assessment window. Additionally, 
patients who had a DLT event will also be considered evaluable. 


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• 
The PK analysis set includes patients who received at least 1 dose of tislelizumab (lenvatinib) 
study drug and contributed at least 1 post-baseline quantifiable tislelizumab (lenvatinib) PK 
sample.  
9.1.2. 
Patient Disposition 
The number of patients treated, discontinued from study drug(s) and/or study, and those with major 
protocol deviations will be counted. The primary reason for study drug(s) discontinuation will be 
summarized according to the categories in the eCRF. The end of study status (alive, dead, withdrew 
consent, or lost to follow-up) at the data cut-off date will be summarized using the data from the eCRF.  
Major protocol deviations will be summarized and listed by each category. 
9.1.3. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics of the safety analysis set will be summarized using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial cancer 
diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables include prior 
number of systemic treatment, gender, ECOG, country, race, and metastatic site. 
9.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary drug 
codes. Concomitant medications will be further coded to the appropriate Anatomical Therapeutic 
Chemical (ATC) code indicating therapeutic classification. Prior and concomitant medications will be 
summarized and listed by drug and drug class in the Clinical Study Report (CSR) for this protocol. Prior 
medications will be defined as medications that stopped before the day of first dose of study drugs. 
Concomitant medications will be defined as medications that 1) started before the first dose of study 
drugs and were continuing at the time of the first dose of study drugs, or 2) started on or after the date of 
the first dose of study drugs up to 30 days after the patient’s last dose. A listing of prior and concomitant 
medications will be included in the clinical study report (CSR) for this trial. In addition, telephone 
contacts with patients should be conducted to assess irAEs and concomitant medications (if appropriate, 
eg, associated with an irAE or is a new anticancer therapy) at 60 and 90 days (±14 days) after the last 
dose of tislelizumab regardless of whether or not the patient starts a new anticancer therapy.   
9.2. 
Efficacy Analyses 
9.2.1. 
Primary Efficacy Analyses 
No hypothesis testing will be done for Part 1 safety run-in. 
Hypothesis testing of ORR in the EFF evaluated based on RECIST v1.1 by central site imaging facility 
for tumor assessment will be the primary efficacy analysis.  
The ORR in studied BGB-A317 combination treatment is assumed as 40% in patients with previously 
treated unresectable HCC. The historical rate in a similar population is estimated as 18.8% for mono 
Lenvatinib. The null and alternative hypotheses are set as follows:  


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H0: ORR = 18.8% 
Ha: ORR > 18.8% 
A Simon’s 2 stage design will be used to test the superiority of studied combination treatment vs. the 
historical control. When 30 patients dosed at RP2D level (including patients from both part 1 and part 2) 
are enrolled, the preliminary efficiency and safety of those 30 patients will be assessed as interim 
analysis.  
• 
If within these 30 patients, ≤6 patients achieve response including complete response (CR) and 
partial response (PR) as their best overall response (BOR) assessed by central site imaging 
facility for tumor assessment based on RECIST v1.1, the study will be terminated. 
• 
If within these 30 patients, ＞6 patients achieve response including CR and PR as their BOR 
assessed by central site imaging facility for tumor assessment based on RECIST v1.1, the study 
will continue. 
If patients don’t meet any discontinuation criterion, such as investigator-assessed iCPD based on 
iRECIST, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor, lenvatinib 
and tislelizumab will be administered until patient completes his/her 12-month treatment duration of 
study drugs. After 12-month treatment duration completion, if the patients are still under the response 
(CR, PR) or stable disease (SD) assessed by investigator based on RECIST v1.1 or under the response 
(complete response [iCR], partial response [iPR]), stable disease (iSD) and unconfirmed progression 
(iUPD) assessed by investigator based on iRECIST, and may continue receiving benefit based on 
investigator’s assessment, tislelizumab could be further provided by sponsor, this decision must be agreed 
with medical monitor and documented in the study records, patients are also required to be reconsented. 
The primary efficacy analysis will be conducted when mature response rate data have been observed, 
estimated as no more than 6 months after the last subject received the first dose of study drug. 
9.2.2. 
Secondary Efficacy Analysis  
For following proportion endpoints: 
• 
ORR assessed by investigators based on RECIST v1.1 
• 
ORR assessed by investigators and central site imaging facility for tumor assessment respectively 
based on mRECIST and iRECIST.  
• 
DCR assessed by investigators and central site imaging facility based on RECIST v1.1, 
mRECIST, and iRECIST 
Two-sided Clopper-Pearson 95% confidence interval (CI) of ORR or DCR will be constructed to assess 
the precision of the point estimates. 
The KM method will be used to estimate the key secondary endpoint DOR assessed by investigators and 
central site imaging facility based on RECIST v1.1, mRECIST, and iRECIST, and corresponding 
quantiles (including the medians), if estimable, in the responders. A two-sided 95% CIs of median, if 


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estimable, will be constructed with a generalized Brookmeyer and Crowley method (Brookmeyer and 
Crowley, 1982).  
The DOR censoring rule will follow the FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (FDA, 2007).  
PFS, another time to event endpoint, assessed by investigators and central site imaging facility based on 
RECIST v1.1, mRECIST, and iRECIST, will be similarly analyzed in the efficacy evaluable population 
using the KM method as described above. The KM estimates of PFS will be plotted over time. The PFS 
time point estimates, defined as the percentages of patients in the analysis population who remain alive 
and progression-free at the specified time points (ie, 3 or 6 month), will be estimated using the KM 
method along with the corresponding 95% CI constructed using Greenwood’s formula (Greenwood, 
1926).  
9.3. 
Safety Analyses 
All subjects who are exposed to (or started receiving) any study drug (any component for the combination 
therapy) will be evaluated for safety. Safety will be determined by the spontaneous reporting of AEs and 
by laboratory values (hematology, clinical chemistry, coagulation, and urinalysis). Vital signs, physical 
examinations, and ECGs findings will also be used in determining the safety profile. The severity of AEs 
will be graded according to the CTCAE v5.0. The incidence of DLT events and TEAEs will be reported 
as the number (percentage) of patients with TEAEs by system organ class (SOC) and preferred term (PT). 
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables), and changes from baseline will be determined for 
laboratory parameters and vital signs. 
9.3.1. 
Dose-Limiting Toxicity Analysis  
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the first dose 
administration of lenvatinib plus tislelizumab at each dose level. For DLT assessment decision, only 
DLTs occurring within 21 days will be evaluated. The following patients will not be considered evaluable 
for DLT, and will be replaced if needed to meet the minimum patient number required for safety 
evaluation: 
• 
Patients who withdraw or are withdrawn from the study before completing the DLT assessment 
window for reasons other than a DLT. 
• 
Patients receiving combination therapy who do not receive ≥ 75% of scheduled lenvatinib and 
≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT assessment window, 
unless they experience a DLT. 
The DLT events will be summarized descriptively for each combination dosing level in the DLT 
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9.3.2. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles received 
(number and percentage of patients), duration of exposure (days), cumulative total dose received per 
patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs or other reasons will be summarized for each study drug.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.3. 
Adverse Events 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA®). AEs will be coded to MedDRA (v18.1 or higher) by 
lower-level term, preferred term, and primary SOC. 
DLT will be summarized at each dose cohort in part 1. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug(s) and up to 30 days following study drug(s) 
discontinuation or initiation of new anticancer therapy, whichever occurs first. TEAE classification also 
applies to irAEs recorded up to 90 days after the last dose of tislelizumab, regardless of whether the 
patient starts a new anticancer therapy. Only those AEs that were treatment-emergent will be included in 
summary tables. All AEs, treatment emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by SOC and 
preferred term. A patient will be counted only once by the highest severity grade per NCI-CTCAE v.5.0 
within an SOC and preferred term, even if the patient experienced more than 1 TEAE within a specific 
SOC and preferred term. The number (percentage) of patients with TEAEs will also be summarized by 
relationship to the study drug. TEAEs include those events considered by the investigator to be related to 
study treatment or with missing assessment of the causal relationship. SAEs, deaths, TEAE with 
≥ Grade 3 severity, irAE, treatment-related TEAEs, and TEAEs that led to treatment discontinuation, dose 
interruption, dose reduction, or dose delay will be summarized. 
9.3.4. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated for each 
laboratory parameter as appropriate. Abnormal laboratory values will be flagged and identified as those 
outside (above or below) the normal range. Reference (normal) ranges for laboratory parameters will be 
included in the CSR for this protocol. Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, maximum for continuous variables; n [%] for categorical variables) for laboratory 
parameters and their changes from baseline will be calculated. Laboratory values will be summarized by 
visit and by worst postbaseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 or higher will be summarized by NCI-
CTCAE grade. Parameters with NCI-CTCAE grading in both high and low directions (eg, glucose, 
potassium, sodium) will be summarized separately. 


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9.3.5. 
Vital Signs 
Specific vital signs, eg, blood pressure and temperature, will be summarized and listed. The change from 
baseline will also be presented.  
9.4. 
Pharmacokinetic Analysis  
Blood samples for PK analysis of tislelizumab will be collected at specified time points (Appendix 2). 
The actual collection date and time of each blood sample will be recorded. The timing of PK samples may 
be altered and/or PK samples may be obtained at additional time points upon sponsor approval to ensure 
thorough PK monitoring.  
The tislelizumab concentration data collected sparsely at predose and around Tmax will be tabulated and 
summarized by visit/cycle. Descriptive statistics will include means, standard deviations, medians, and 
ranges as appropriate. 
Additional PK, including population PK analyses, may be conducted as appropriate, and the results of 
such analysis may be reported separately from the CSR. 
9.5. 
Immunogenicity Analyses 
Samples to assess anti-tislelizumab-antibodies will be collected. The immunogenicity results will be 
summarized using descriptive statistics by the number and percentage of patients who develop detectable 
ADA. The incidence of positive ADA and neutralizing ADA will be reported for evaluable patients. The 
effect of immunogenicity on PK, efficacy, and safety may be evaluated if data allow. 
9.6. 
Other Exploratory Analyses 
OS will be similarly analyzed in the efficacy evaluable population using the KM method as described 
above (Session 9.2.2). The KM estimates of OS will be plotted over time. The OS time point estimates 
will be calculated similarly as above. 
9.7. 
Sample Size Consideration 
The number of dose levels examined and the emerging toxicities of the combination therapy will 
determine the sample size. The study plans to enroll approximately 60-66 patients, including 6-12 patients 
in part 1 and 54 patients in part 2.  
Sample size for Part 1 (lenvatinib in combination with tislelizumab safety run-in) will depend on the 
number of dose levels examined and the emerging toxicities of the combination therapy. It is expected 
approximately 6 to 12 patients with unresectable locally advanced will be enrolled.  
With total of 60 patients at RP2D from both part 1 and part 2, based on Simon’s 2 stage design, we have 
about 95% power to detect a statistical significant difference between ORR (assessed based on RECIST 
v1.1) in studied combination treatment (assumed to be around 40%) to a historical of 18.8% with 1-sided 
alpha as 0.025. Within first 30 pts (including the 6 patients from part 1 and 24 patients from part 2) in the 
efficacy analysis set, if we observe ≤ 6 responders, study will be terminated. Otherwise, study will 
continue. If within the final 60 patients in the efficacy analysis set, we observe ≥18 responders, we will 
claim we are statistically superior than a historical control of 18.8% under the settings. Participants 


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withdraw due to personal reason or AE before first assessment will be replaced, which might need 4-6 
extra participants. 
9.8. 
Interim Analysis 
For Part 2, one futility interim analysis will be conducted based on the Simon 2-stage design (see Section 
9.2.1for details). 
10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Safety Monitoring Committee 
An SMC will be established consisting of the sponsor’s clinical, safety, and medical team representatives 
(eg, medical monitor, Clinical Pharmacology, Statistician, and Drug Safety) and investigators. All 
available safety data, including AEs, laboratory assessments, and PK analyses (as available), will be 
reviewed with input from other functional representatives as appropriate. Based on a review of these data 
and in consultation with the investigators, a determination will be made regarding dose and/or safety 
management. 
10.2. 
Communication 
Sponsor plans to have regular communications with all study sites (study investigators and coordinators) 
regarding: 
• 
Study enrollment status  
• 
Decisions on RP2D of lenvatinib in combination with tislelizumab 
• 
Any significant safety findings  
• 
Considerations for protocol amendments 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator must maintain adequate and accurate records to ensure that the conduct of the study may 
be fully documented. Such records include, but are not limited to, the protocol, protocol amendments, 
ICFs, and documentation of IRB/IEC and governmental approvals. In addition, at the end of the study, the 
investigator will receive patient data, which will include an audit trail containing a complete record of all 
changes to such data.  
11.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the investigator’s 
source documentation in order to verify the data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The monitor should have access to any patient records needed to verify the entries on the 


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eCRFs. The investigator agrees to cooperate with the monitor to ensure that any problems detected during 
these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any time 
during or after completion of this 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. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct study with the investigational drug from the appropriate 
regulatory agency in accordance with applicable country-specific regulatory requirements or file the 
protocol with the appropriate regulatory agency before the study is initiated at a study center in that 
country. 
12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may conduct a 
quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant 
documents and to allocate his/her time and the time of his/her personnel to the auditor/inspector to discuss 
findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard operating 
procedures, working practice documents, and applicable regulations and guidelines. Site audits may be 
made periodically by the sponsor’s or the contract research organization’s (CRO’s) qualified compliance 
auditing team, which is an independent function from the study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, patients’ 
medical records, and eCRFs. The investigator is to permit national and local health authorities; sponsor 
study monitors, representatives, and collaborators; and IRB/IEC members to inspect all facilities and 
records relevant to this study.  
12.4. 
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), patient drug dispensation records, and returned or destroyed study product. 


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Dispensation records will document quantities received from BeiGene’s designated depot or its designee 
and quantities dispensed to patients, including batch/lot number, date dispensed, patient identifier number, 
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(s) 
disposal/destruction to ensure that it complies with BeiGene’s requirements specified in the Pharmacy 
Manual. At appropriate times during the conduct of the study or at the end of the study, the study site will 
dispose of and/or destroy all unused study drug(s) supplies following drug inventory reconciliation by the 
monitor. These including empty containers, according to these procedures. If the site cannot meet 
BeiGene’s requirements specified in the Pharmacy Manual for disposal, arrangements will be made 
between the site and BeiGene or its representative for destruction or return of unused study drug(s) 
supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study. A patient diary will be provided to each patient to record the 
lenvatinib dose taken each day. Any missed doses with explanation should be recorded in the diary. The 
diary should be returned to the site personnel for review and will be reviewed by the investigator/study 
personnel on a regular basis. 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS 
13.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full conformance with 
the ICH E6 guideline for GCP and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the greater protection to 
the individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting information 
must be submitted to the IRB/IEC by the principal investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. In addition, any patient recruitment materials must be approved by 
the IRB/IEC.  
The principal investigator is responsible for providing written summaries of the status of the study to the 
IRB/IEC annually or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. Investigators are also responsible for promptly informing the IRB/IEC of any 
protocol amendments. In addition to the requirements for reporting all AEs to the sponsor, investigators 
must comply with requirements for reporting SAEs to the local health authority and IRB/IEC. 
Investigators may receive written investigational new drug (IND) safety reports or other safety-related 
communications from the sponsor. Investigators are responsible for ensuring that such reports are 
reviewed and processed in accordance with health authority requirements and the policies and procedures 
established by their IRB/IEC and archived in the site’s study file.  


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13.2.1. 
Protocol Amendments 
All protocol amendments will be prepared by the sponsor. All protocol modifications must be submitted 
to competent authorities according to local requirements and to the IRB/IEC together with, if applicable, a 
revised model ICF in accordance with local requirements. Written documentation from competent 
authorities (according to local requirements) and from the IRB/IEC and required site approval must be 
obtained by the sponsor before changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects only (eg, change 
in medical monitor or contact information). 
Information on any change in risk and/or change in scope must be provided to patients already actively 
participating in the study, and they must read, understand, and sign each revised ICF confirming 
willingness to remain in the study. 
13.3. 
Informed Consent 
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a certified 
translation of the local language. The final IRB/IEC-approved ICFs must be provided to the sponsor for 
health authority submission purposes according to local requirements.  
The ICFs must be signed and dated by the patient or the patient’s legally authorized representative before 
his or her participation in the study. The case history or clinical records for each patient shall document 
the informed consent process and that written informed consent was obtained prior to participation in the 
study.  
The ICFs will be revised whenever there are changes to study procedures or when new information 
becomes available that may affect the willingness of the patient to participate. The final revised 
IRB-/IEC-approved consent forms must be provided to the sponsor for health authority submission 
purposes.  
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during their 
participation in the study. For any updated or revised ICFs, the case history or clinical records for each 
patient shall document the informed consent process and that written informed consent was obtained 
using the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site file and 
must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality 
The sponsor will maintain confidentiality and privacy standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This approach ensures that patients’ 
names are not included in any data set transmitted to any sponsor location.  


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Patient medical information obtained by this study is confidential and may be disclosed only to third 
parties as permitted by the signed ICF (or a separate authorization for the use and disclosure of personal 
health information that has been signed by the patient), unless permitted or required by law.  
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated by this study must be available for inspection upon request by representatives of the 
US FDA, the China FDA, and all other national and local health authorities; by sponsor monitors, 
representatives, and collaborators; and by the IRBs/IECs for each study site, as appropriate.  
The investigator must assure that patients’ anonymity will be strictly maintained and that their identities 
are protected from unauthorized parties. The investigator agrees that all information received from the 
sponsor, including but not limited to the IB, this protocol, eCRFs, the IND, and any other study 
information, remain the sole and exclusive property of the sponsor 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 the 
sponsor. 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. 
13.5. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient and accurate financial information, in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to the 
absence of certain financial interest of the clinical investigators and/or disclose those financial interests, 
as required, to the appropriate health authorities. This is intended to ensure financial interests and 
arrangements of the clinical investigators with BeiGene that could affect reliability of data submitted to 
health authorities are identified and disclosed by the sponsor. Investigators are responsible for providing 
information about their financial interests before participation in the study, and to update this information 
if any relevant changes occur during the study and for 1 year after completion of the study (ie, last patient, 
last visit). 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Collection and Management Responsibilities 
14.1.1. 
Data Collection 
Data required by the protocol will be entered into an electronic data capture (EDC) system.  
Data collection in the eCRF must follow the instructions described in the eCRF Completion Guidelines. 
The investigator has ultimate responsibility for the collection and reporting of all clinical data entered in 
the eCRF. The investigator must provide an e-signature in the EDC system to attest to its accuracy, 
authenticity, and completeness. 


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Data contained in the eCRFs are the sole property of BeiGene and should not be made available in any 
form to third parties without written permission from BeiGene, except for authorized representatives of 
BeiGene or appropriate regulatory authorities.  
14.1.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored by BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to produce 
queries, and maintenance of an audit file that includes all database modifications) will be followed to 
support accurate data collection. Data will be reviewed for outliers, logic, data inconsistencies, and 
completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the study is 
being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs for 
completeness, clarity, and cross checking with source documents is required to monitor the progress of 
the study. Direct access to source data is also required for inspections and audits and will be carried out 
giving due consideration to data protection and medical confidentiality. 
AEs will be coded using the MedDRA. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary. Concomitant diseases/medical history will be coded using the MedDRA. 
14.2. 
Study Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 
into at least 1 of the following categories: 1) investigator’s study file, and/or 2) patient clinical source 
documents. 
The investigator’s study file will contain the protocol/amendments, eCRF, IRB/IEC, and governmental 
approval with correspondence, informed consent, drug records, staff curriculum vitae and authorization 
forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key efficacy/safety 
parameters independent of the eCRFs) would include documents such as (although not be limited to) the 
following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, x-ray, pathology and special assessment reports, 
consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (eg, audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and personnel. Where permitted by local laws/regulations 


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or institutional policy, some or all these records can be maintained in a format other than hard copy (eg, 
microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The 
investigator must assure that all reproductions are legible, are a true and accurate copy of the original, and 
meet accessibility and retrieval standards, including regenerating a hard copy, if required. Furthermore, 
the investigator must ensure there is an acceptable backup of these reproductions and that an acceptable 
quality control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that study center for the study, as dictated by any institutional requirements or local laws or 
regulations, or the sponsor’s standards/procedures; otherwise, the retention period will default to the 
15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including but not 
limited to the following: archival at an off-site facility, or transfer of ownership of or responsibility for the 
records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store these in 
sealed containers outside of the site so that they can be returned sealed to the investigator in case of a 
regulatory audit. When source documents are required for the continued care of the patient, appropriate 
copies should be made for storage outside of the site. 
14.3. 
Protocol Deviations 
The investigator is responsible for ensuring that the study is conducted in accordance with the procedures 
and evaluations described in this protocol. Investigators assert they will apply due diligence to avoid 
protocol deviations. 
The investigator is to document and explain any deviations from the approved protocol. The investigator 
must promptly report any major deviations that might impact patient safety and/or data integrity to the 
Sponsor and to the IRB/IEC, in accordance with established IRB/IEC policies and procedures.  
14.4. 
Publication and Data Sharing Policy 
A clinical study report will be prepared. BeiGene will ensure that the report meets the standards set out in 
the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an 
abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, objective, and 
clinically meaningful manner that is consistent with good science, industry and regulatory guidance, and 
the need to protect the intellectual property of BeiGene (sponsor), regardless of the outcome of the study. 
The data generated in this clinical study are the exclusive property of the sponsor and are confidential. For 
multicenter studies, the first publication or disclosure of study results shall be a complete, joint 
multicenter publication or disclosure coordinated by the sponsor. Thereafter, any secondary publications 
will reference the original publication(s). Authorship will be determined by mutual agreement and all 


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authors must meet the criteria for authorship established by the International Committee of Medical 
Journal Editors Uniform Requirements for Manuscripts or stricter local criteria (International Committee 
of Medical Journal Editors 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and presentations 
(both oral and written) to the sponsor prior to submission or presentation in accordance with the clinical 
study agreement. This allows the sponsors to protect proprietary information, provide comments based on 
information from other studies that may not yet be available to the investigator, and ensure scientific and 
clinical accuracy. Each investigator agrees that, in accordance with the terms of clinical study agreement, 
a further delay of the publication/presentation may be requested by the sponsor to allow for patent filings 
in advance of the publication/presentation. 
14.5. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction with the 
investigator or study center personnel, as appropriate: 
• 
Return of all study data to the sponsor 
• 
Resolve and closure of all data queries 
• 
Accountability, reconciliation, and arrangements for unused study drug(s) 
• 
Review of study records for completeness 
• 
Return of treatment codes to the sponsor 
• 
Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue this study 
or suspend enrollment either at a single study center or at all study centers at any time for reasons 
including, but not limited to, safety or ethical issues or severe noncompliance. If the sponsor determines 
such action is needed, the sponsor will discuss this with the investigator (including the reasons for taking 
such action) at that time. When feasible, the sponsor will provide advance notification to the investigator 
of the impending action prior to it taking effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study if the 
study is suspended or terminated, and will also inform the regulatory authorities of the suspension or 
termination of the study and the reason(s) for the action. If required by applicable regulations, the 
investigator must inform the IEC/IRB promptly and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor. In addition, 
arrangements will be made for the return of all unused study drug(s) in accordance with the applicable 
sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the agreement 
established between the investigator and the sponsor. 


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14.6. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial property 
rights which are conceived or reduced to practice by the study center personnel during the course of or as 
a result of the study are the sole property of the sponsor, and are hereby assigned to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions inconsistent with 
this statement is executed between the sponsor and the study center, that contract’s ownership provisions 
shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study center as part 
of the study (other than a patient’s medical records) are the sole property of the sponsor and will be kept 
by the investigator and other study center personnel.  
This information and data will not be used by the investigator or other study center personnel for any 
purpose other than conducting the study.  
These restrictions do not apply to: 
• 
Information that becomes publicly available through no fault of the investigator or study center 
personnel 
• 
Information that is necessary to disclose in confidence to an IEC/IRB solely for the evaluation of 
the study 
• 
Information that is necessary to disclose to provide appropriate medical care to a patient 
• 
Study results that may be published as described in Section 14.4 
If a written contract for the conduct of the study (which includes confidentiality provisions inconsistent 
with this section) is executed, that contract’s provisions shall apply to the extent they are inconsistent with 
this section. 
 
 
 


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15. 
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16. 
APPENDICES 
 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety Follow-
up Phone Call5 
Survival Follow-up6 
Cycle 1 
Cycle 2  
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
1 
8 
(±1)2 
15 
(±2)2 
1 
(±1)  
8 
(±1) 2 
15 
(±2) 2 
1  
(±3) 3 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 (± 14) 
days after last 
dose of 
tislelizumab 
Approximately Every 
3 Months (± 14 days) 
Informed consent1 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/prior 
medications 
x 
 
 
 
 
 
 
 
 
 
 
Child-Pugh 
classification score 7 
x 
(-7 to -1) 
 
 
 
 
 
 
 
 
 
 
Height  
x 
 
 
 
 
 
 
 
 
 
 
Vital signs /weight8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Complete physical 
examination9 
x 
 
 
 
 
 
 
 
x 
 
 
Limited physical 
examination9 
 
x 
x 
x 
x 
 
 
x 
 
 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
 
 
x 
x 
 
 
12-Lead ECG10 
x 
x 
 
 
x 
 
 
x 
x 
 
 
Hematology11 
x 
(-7 to -1) 
x 
(Part 1) 
x 
(Part 1) 
x 
(Part 1) 
x 
(Part 1) 
x 
(Part 1) 
x 
(Part 1) 
x 
(Part 1) 
x 
 
 
x 
(Part 2) 
 
 
x 
(Part 2) 
 
 
x 
(Part 2) 
Clinical chemistry11 
x 
(-7 to -1) 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Coagulation 
parameters11 
x 
(-7 to -1) 
x 
 
 
x 
 
 
x 
x 
 
 


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Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety Follow-
up Phone Call5 
Survival Follow-up6 
Cycle 1 
Cycle 2  
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
1 
8 
(±1)2 
15 
(±2)2 
1 
(±1)  
8 
(±1) 2 
15 
(±2) 2 
1  
(±3) 3 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 (± 14) 
days after last 
dose of 
tislelizumab 
Approximately Every 
3 Months (± 14 days) 
Urinalysis11 
x 
(-7 to -1) 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AFP  
x 
x 
 
 
x 
 
 
x 
x 
 
 
Pregnancy test12 
x 
(-7 to -1) 
x 
 
 
x 
 
 
x 
x 
 
 
Thyroid function13 
x 
Cycles 4, 7, 10, and 
every 3 cycles thereafter 
x 
 
 
HBV/HCV tests14 
x 
Patients who have detectable HBV DNA at screening, the respective viral load test will be 
performed every 4 cycles starting at Cycle 5 (Day 1 of Cycles 5, 9, 13, etc), and EOT Visit. 
 
 
Tumor assessment15 
x 
In the first year, every 6 weeks (± 7 days) 
every 9 weeks (± 7 days) 
thereafter 
 
 
Pulmonary function 
test16 
x 
As clinically indicated 
 
 
MUGA (multigated 
acquisition)/echo-
cardiogram17 
x 
Every 12 weeks (±7 days) 
 
 
PK sampling for 
tislelizumab 18 
 
Patients enrolled in part 1 only, see Appendix 2 
 
 
PK sampling for 
lenvatinib 18 
 
 
 
ADA sampling for 
tislelizumab18 
 
 
 
Lenvatinib 
administration19 
 
Daily 
 
 
 
Tislelizumab 
administration 20 
 
x 
 
 
x 
 
 
x 
 
 
 
AEs21 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Assessment  
Screening1 
Treatment Period 
EOT Visit4 
Safety Follow-
up Phone Call5 
Survival Follow-up6 
Cycle 1 
Cycle 2  
Cycle 3 and 
Subsequent 
Cycles 
Days (window) 
-28 to -1 
1 
8 
(±1)2 
15 
(±2)2 
1 
(±1)  
8 
(±1) 2 
15 
(±2) 2 
1  
(±3) 3 
Within 30 Days 
After Last Dose 
of Study Drug(s) 
60 and 90 (± 14) 
days after last 
dose of 
tislelizumab 
Approximately Every 
3 Months (± 14 days) 
Concomitant 
medications22 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Patient diary 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Survival status6 
 
 
 
 
 
 
 
 
 
 
x 
Abbreviations: ADA, antidrug antibody, AE, adverse event; AFP, alpha fetoprotein; CR, complete response; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, end of treatment; HBV, hepatitis B virus; HCV, hepatitis C virus; MUGA, multigated acquisition; PD, progressive disease; 
PR, partial response; SAE, serious adverse event; x, to be performed. 
Note: On days when lenvatinib and tislelizumab dosing are both scheduled, the daily dose of lenvatinib should precede tislelizumab infusion. 
1. During Screening, written informed consent must be signed before performing any study-specific tests or procedures. Results of standard-of-care tests or 
examinations performed before obtaining informed consent and within 28 days before the first dose of study drug(s) may be used for screening assessments 
rather than repeating such tests.  
2. In Cycle 1 and cycle 2, besides Days 1 of both cycles, patients enrolled in Part 1 and part 2 will return to study sites for assessments on Days 8 and 15 of both 
cycles. On Days 1, 8 and 15 of Cycle 1 and Cycle 2, lenvatinib will be given in the clinic. 
3. A window of ± 3 days is allowed. 
4. The EOT Visit is conducted within 30 days after last dose of the study drugs or before initiation of a new anticancer treatment, whichever occurs first. If 
routine laboratory tests (eg, hematology, clinical chemistry) have been performed ≤ 7 days before the EOT Visit, these tests do not need to be repeated. A 
tumor assessment is not required at the EOT Visit if ≤ 6 weeks have passed since the last assessment. If the study drugs were initially interrupted due to AEs 
and then permanently discontinued, the EOT Visit may occur later, but no later than the permitted time of dose delay plus 7 days.  
5. The Safety Follow-up Phone calls. Telephone contacts with patients should be conducted to assess irAEs and concomitant medications (if appropriate, ie, 
associated with an irAE or is a subsequent anticancer therapy) at 60 and 90 days (± 14 days) after the last dose of tislelizu mab, regardless of whether or not 
the patient starts a new anticancer therapy.  
6. Survival follow-up information will be collected via telephone calls for all patients, patient medical records, and/or clinic visits approximately every 3 months 
(± 14 days) after the EOT Visit until death, loss to follow-up, withdrawal of consent, or study termination by sponsor. All patients will be followed for survival 
and subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
7. Child-Pugh classification for liver function is required to be assessed for HCC patients only within 7 days before the first dose of study drugs. 
8. Vital signs collected on study include temperature, pulse, and the assessment of blood pressure (systolic and diastolic) should follow Section 7.3.1. The 
patient’s vital signs are required to be recorded within 60 minutes before; during; and 30 minutes after the first infusion o f tislelizumab. For subsequent 
infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 30 minutes after the infusion. Vital signs 


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should also be recorded prior to administration of lenvatinib; recorded values may be used for pre-tislelizumab assessment if vital signs are collected within 
60 minutes before tislelizumab infusion.  
Vital should be collected at screening, weekly of first two cycles, on Day 1 of each subsequent cycle and at the EOT Visit for all patients. 
9. Complete physical examination including an evaluation of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 5) 
respiratory, 6) gastrointestinal, and 7) neurological systems is required to be performed at screening and EOT Visit. Limited physical examination: At 
subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations will be performed.  
10. 12-Lead ECG: The ECG recordings will be obtained during screening, C1D1, at the beginning of every subsequent cycle, EOT visit and as clinically 
indicated at other time points. Patients should be resting for at least 10 minutes before each ECG collection.  
11. Hematology, urinalysis and clinical chemistry (Appendix 3 clinical laboratory assessment) will be performed by the local laboratory at screening and 
within 7 days prior to the administration of study drugs on C1D1 in both Parts.  
Hematology, patients enrolled in part 1 will be assessed weekly during the first 2 cycles and then on Day 1 of each subsequent cycle. Patients enrolled in 
part 2 will be assessed on Day 1 of each cycle. In both Part 1 and Part 2, patients will be assessed at the EOT Visit.  
Coagulation tests includes international normalized ratio, prothrombin time, and activated partial thrombin time. Coagulation tests will be performed at 
screening, the beginning of every cycle, EOT visit.  
Clinical chemistry (Appendix 3 clinical laboratory assessment) will be performed by the local laboratory at screening and within 7 days prior to the 
administration of study drugs on C1D1 in both Parts. Patients enrolled in both part 1 and part 2 will be assessed weekly during the first 2 cycles, then on 
Day 1 of each subsequent cycle. In both Part 1 and Part 2, patients will be assessed at the EOT Visit.  
Urinalysis on routine urinalysis, if urine protein is ≥ 2+ (≥ 1+ in screening) by dipstick, then obtain a 24-hour urine sample for total protein and a random 
urine sample for total protein and creatinine to determine a protein to creatinine ratio. In 24-hour protein assessment, to achieve the result prior to study 
drugs administration on the day of each scheduled assessment, the urine sample may be collected 24 hours ahead of schedule in 24-hour protein assessment. 
Urinalysis will be performed by the local laboratory at screening and within 7 days prior to the administration of study drugs on C1D1 in both Parts. Patients 
enrolled in both part 1 and part 2 will be assessed weekly during the first 2 cycles, then on Day 1 of each subsequent cycle. In both Part 1 and Part 2, patients 
will be assessed at the EOT Visit. For CK and CK-MB tests and coagulation tests, refer to Appendix 3. 
12. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed by the local laboratory and 
documented as negative within 7 days before administration of study drugs. Urine or serum pregnancy tests will be performed during treatment before study 
drugs administration at each cycle, EOT visit. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. A negative 
pregnancy test (by urine or blood) must be completed and recorded before administration of study drugs at each cycle. 
13. TFTs (thyroid function test) by analysis of FT3, FT4, and TSH will be performed by the local laboratory at screening and every 3 cycles (ie, Day 1 of 
Cycles 4, 7, 10, etc), and EOT Visit. The test does not need to be repeated at the EOT Visit within 63 days after last test. 
14. HBV/HCV tests: Testing will be performed by the local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV 
antibody) and viral load assessment (HBV DNA and HCV RNA). Testing at screening is mandatory for patients. Additionally, for patients who have 
detectable HBV DNA at screening, the respective viral load test will be performed every 4 cycles starting at Cycle 5 (ie, Day  1 of Cycles 5, 9, 13, etc), and 
EOT Visit. 
15. Tumor imaging for tumor assessment should be performed based on Tumor and Response Evaluations (see Section 7.4.). Radiological images captured as 
standard of care before obtaining written informed consent and within 28 days before the first dose of study drugs may be used rather than repeating tests. 
All measurable and evaluable lesions are required to be assessed and documented. An MRI (or CT scan if MRI is contraindicated or not readily available) of 


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the head may be required at screening based on clinical judgement; bone scan or PET is required if clinically indicated. The same radiographic procedure 
must be used throughout the study for each patient. 
The investigator must review radiograph results before dosing at the next cycle. During the study, tumor imaging will be performed within 28 days prior to 
C1D1 and while on study approximately every 6 weeks ± 7 days in the first 12 months and approximately every 9 weeks ± 7 days thereafter. The 
investigator may perform additional scans or more frequent assessments if clinically indicated. Patients who discontinue study treatment early for reasons 
other than iCPD (eg, toxicity) will continue to undergo tumor assessments following the original plan until the patient withdraws consent, dies, or until the 
study terminates, whichever occurs first. Patients who continue tislelizumab treatment beyond radiographic investigator-assessed PD based on RECIST v1.1 
will be monitored with a follow-up scan no more than 8 weeks beyond the initial diagnosis of radiographic PD (repeated imaging on next scheduled tumor 
assessment visit date, around 6 weeks from the date of initial documentation of PD is recommended). 
16. Pulmonary function test only for patients treated with tislelizumab: Patients who are suspected or known to have serious/severe respiratory conditions or 
exhibit significant respiratory symptoms unrelated to the underlying cancer will have pulmonary function testing which may in clude, but is not limited to, 
spirometry and assessment of diffusion capacity done during the screening period to assist the determination of suitability on the study. 
17. MUGA/Echocardiogram: Evaluations of cardiac function will be performed at screening and every 12 weeks (±7 days). Investigator will decide the 
method (MUGA or echocardiograms) for evaluation of cardiac function. The method used for individual patients should be consistent throughout study 
participation.  
18. The PK sampling for tislelizumab, PK sampling for lenvatinib PK and ADA sampling for tislelizumab will be collected only in patients enrolled in part 1. 
See Appendix 2 Appendix 2for PK sampling for tislelizumab, PK sampling for lenvatinib and ADA sampling for tislelizumab while study treatment. Unless 
the events of DLT occurred frequently (defined as which leads to Part 1 discontinued. See Section 3.1.1 for details), the test of lenvatinib PK won’t be 
performed. 
19. Lenvatinib administration orally once daily with or without food in the morning. 
20. Tislelizumab administration on Day 1 of every cycle after lenvatinib administration.  
21. AEs will be graded and recorded throughout the study according to NCI-CTCAE, v5.0. During screening section just SAEs will be collected. After first dose 
AEs will be collected. 
22. All concomitant medications received within 30 days before the first dose of study drugs and 30 days after the last dose of study treatment should be 
recorded.


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APPENDIX 2. 
SCHEDULE OF PK ASSESSMENTS 
Collection 
Time and 
Allowable 
Window 
Patients Enrolled in Part 1 
C1D1, C5D1 
C2D1，C9D1, 
C17D1 
EOT visit 
PK-Tislea 
x 
Pre-Tisle dose 
-60 min 
X 
Post-Tisle infusion
+30 min 
x 
Pre-Tisle-dose 
-60 min 
 
x 
 
PK-Lenva b 
x 
Pre-Lenva dose 
-30 min 
X 
Post-Lenva dose 
2h ± 10min 
 
 
 
 
ADA-Tislec 
x 
pre-Tisle dose 
-60 min 
 
x 
Pre-Tisle dose 
-60 min 
 
x 
 
 
Abbreviations: PK, pharmacokinetic; Tisle, tislelizumab; Lenva, lenvatinib; x, to be performed 
a. 
PK sampling for tislelizumab: predose (within 60 min before the start of tislelizumab infusion) samples should 
be collected on Day 1 of Cycles 1, 2, 5, 9, and 17 (if achieved); two postdose (within 30 min after the end of 
tislelizumab infusion) samples should be collected at C1D1 and C5D1; and an additional PK sample should be 
collected at the EOT Visit. Should a patient present with DLT event or ≥ Grade 3 or above irAE, additional PK 
samples may be taken to determine the serum concentration of tislelizumab. 
b. 
PK sampling for lenvaitnib: predose (within 30 min before administration of lenvatinib) samples should be 
collected on Day 1 of Cycles 1, 5; two postdose samples at 2h (± 10min) should be collected at C1D1 and 
C5D1.Unless the events of DLT occurred frequently (defined as which leads to Part 1 discontinued. See Section 
3.3.1 for details), the test of lenvatinib PK won’t be performed. It’s highly recommended that perdose samples of 
lenvatinib and tislelizumab are drawn through once blood sampling on scheduled days if both in allowed windows, 
and postdose samples of lenvatinib and tislelizumab are drawn through once blood sampling on scheduled days 
as well if both in allowed windows. 
c. 
ADA sampling for tislelizumab: samples should be collected before start of Day 1 tislelizumab infusion of Cycles 
1, 2, 5, 9 and 17 (if achieved) and at the EOT Visit (See Appendix 1). All samples should be drawn at the same 
time as blood collection for predose PK samples. 
 


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APPENDIX 3. 
CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
 
Hematology 
Coagulationa 
Urinalysis 
Alkaline phosphatase 
Hematocrit 
Prothrombin time or INR 
Glucose  
Alanine aminotransferase 
Hemoglobin 
aPTT 
Protein 
Aspartate aminotransferase 
Platelet counts 
 
Blood 
Albumin 
WBC count 
 
Ketones 
Total protein 
Lymphocyte count  
24-hour proteinb 
Lactate dehydrogenase 
Neutrophil count 
 
 
Total bilirubin 
 
 
 
Direct bilirubin 
 
 
 
Blood urea nitrogen or urea 
 
 
 
Potassium 
 
 
 
Sodium  
 
 
 
Corrected calciumc 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
CKd 
 
 
 
CK-MBd, e 
 
 
 
Lipase 
 
 
 
Serum amylase 
 
 
 
Abbreviations: aPTT, activated partial thromboplastin time; CK, creatine kinase; CK-MB, creatine kinase cardiac 
muscle isoenzyme; INR, International Normalized Ratio; WBC, white blood cell. 
a. 
Coagulation tests are required at screening, the beginning of every cycle and EOT visit Visit.  
b. 
On routine urinalysis, if urine protein is ≥ 2+ (≥ 1+ in screening) by dipstick, then obtain a 24-hour urine sample 
for total protein and a random urine sample for total protein and creatinine to determine a protein to creatinine 
ratio. To achieve the result prior to study drugs administration on the day of each scheduled assessment, the 
urine sample may be collected 24 hours ahead of schedule in 24-hour protein assessment (see Section 7.3.5). 
c. 
If testing for corrected calcium is not feasible at the local laboratory, total calcium may be performed instead 
d. 
Patients receiving tislelizumab will receive CK and CK-MB testing. If tislelizumab has been permanently 
discontinued, CK and CK-MB testing is no longer required. Patients with a history of cardiological disease or 
after discontinuation of tislelizumab, may receive CK and CK-MB testing if clinically indicated. 
e. 
In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 
 
In addition, the following tests will be conducted in this study:  
• 
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal 
ligation) must be performed and documented as negative within 7 days prior to administration of study 
drug(s). Urine or serum pregnancy tests will be performed once every 3 weeks or monthly during treatment 
and at the EOT Visit. A serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal. A negative pregnancy test (by urine or blood) must be completed and recorded before 
administration of study drug(s) at each cycle 
• 
Thyroid function tests (thyroid-stimulating hormone [TSH], free T3, free T4) will be performed at 
Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and EOT Visit (see Section 7.3.4 for details). 
 


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APPENDIX 4. 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all predisease 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 et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 


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APPENDIX 5. 
CHILD-PUGH CLASSIFICATION SCORING SYSTEM 
The information presented here has been obtained from the Washington University Medical Center, with 
sources as follows: 
• 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list. Liver Transl Surg. 1997;3(6):628-37. 
• 
Pugh RNH, Murray-Lyon IN, Dawson DL, et al. Transection of the esophagus for bleeding 
esophageal varices. Brit J Surgery. 1973;60:646-64. 
• 
Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. N Engl J 
Med. 1966;274(9):473-81. 
Child-Pugh classification is either Grade A (mild: score 5 to 6 points), B (moderate: from 7 to 9 points), 
or C (severe: from 10 to 15 points) and is determined by both clinical and biochemical parameters (as 
shown below). 
Clinical/Biochemical Parameter 
Score (Anomaly Severity) 
1 
2 
3 
Hepatic encephalopathy (NCI-CTCAE grade)a 
0b 
1c or 2d 
3e or 4f 
Ascites (presence and severity) 
None 
Mild 
Moderate 
Total bilirubin (mg/dL) 
< 2.0 
2.0 to 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prolonged prothrombin time (seconds) 
or 
Activated partial thromboplastin time 
(INRg) 
< 4 
or 
< 1.7 
4 to 6 
or 
1.7 to 2.3 
> 6 
or 
> 2.3 
Abbreviations: INR, international normalized ratio; NCI-CTCAE, National Cancer Institute Common 
Terminology Criteria for Adverse Events. 
a. 
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma by exchange blood transfusion.  
N Engl J Med. 1996;274(9):473-481. 
b. 
Grade 0: Consciousness, personality, neurological examination, and electrocardiogram are all normal. 
c. 
Grade 1: Restlessness, sleep disorders, irritability/anxiety, hand tremor, writing disorders, 5CPS waves. 
d. 
Grade 2: Lethargy, time barrier, discomfort, asterixis, ataxia, three-phase slow wave. 
e. 
Grade 3: Drowsiness, coma, orientation disorder, over-reflection, stiff/slow wave. 
f. 
Grade 4: Cannot wake up from coma, no independent personality/behavior, irrational, slow 2-3CPS Delta 
activity. 
g. 
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of adults 
on the liver transplant waiting list. Liver Transl Surg. 1997;3(6):628-637. 
 


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APPENDIX 6. 
PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history of an 
acquired or congenital immune deficiency or autoimmune disease.  
Please contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
 


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APPENDIX 7. 
CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN OF 
CHILDBEARING POTENTIAL,” “NO CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy testing in clinical 
trials include the use of highly effective forms of birth control. These methods include the following: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with the inhibition of 
ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with the inhibition of ovulation (oral, injectable, or 
implantable) 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized male partner, provided that the vasectomized partner is the sole sexual partner of the woman of 
childbearing potential study participant and that the vasectomized partner has received medical assessment of 
surgical success. 
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of exposure 
associated with the study treatment) 
o Note: Total sexual abstinence should only be used as a contraceptive method if it is in line with 
the patient’s usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), declaration of abstinence for the duration of exposure to 
study drug, and withdrawal are not acceptable methods of contraception 
Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a 
highly effective method of contraception, and if used, this method must be combined with a highly effective form of 
birth control, listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are physiologically capable 
of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of the following 
criteria: 
• 
Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) 
• 
Postmenopausal, defined as: 
o ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 


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alternative medical causes for the lack of spontaneous menses for ≥ 12 months have been 
ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of hormonal contraception or 
hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG). 


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APPENDIX 8. 
NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity (eg, no shortness of breath when walking, climbing stairs, et 
cetera). 
II 
Mild symptoms (eg, mild shortness of breath and/or angina).  
Slight limitations during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, eg, walking short distances (20-100 meters). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound. 
Adapted from Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 
9th ed.  
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114.  


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APPENDIX 9. 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from serum 
creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the 
Modification of Diet in Renal Disease (MDRD) Study equation. NKDEP’s calculators rely on creatinine 
determinations which are isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be 
using creatinine methods calibrated to be IDMS traceable.  
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. This 
equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 body surface 
area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found on the National Institute of Diabetes and Digestive and 
Kidney Diseases webpage (https://www.niddk.nih.gov/health-information/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators) 
Classification of Renal Impairment Using FDA Guidance for Industry  
The renal impairment classification scale provided in the guidance document considers eGFR 
and Estimated Creatinine Clearance (CLcr). It allows for the fact that equations to calculate 
eGFR are evolving. In this study, eGFR will be calculated using the CKD-EPI equation.  
Classification of Renal Function Based on Estimated GFR or Estimated Creatinine Clearance 
Stage 
Description 
eGFR 
(mL/min/1.73m2) 
CLcr 
(mL/min) 
1 
Control (Normal) GFR 
≥ 90 
≥ 90 
2 
Mild Decrease in GFR 
60-89 
60-89 
3 
Moderate Decrease in 
GFR 
30-59 
30-59 
4 
Severe Decrease in GFR 
15-29 
15-29 
5 
End Stage Renal Disease 
<15 not on dialysis or requiring 
dialysis 
<15 not on dialysis or requiring 
dialysis 
 


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Page 139 of 177 
APPENDIX 10. 
IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT 
The recommendations below for the diagnosis and management of any irAE are intended as a guidance. 
This document should be used in conjunction with expert clinical judgement (by specialist physicians 
experienced in the treatment of cancer using immunological agents), and individual institutional 
guidelines or policies. 
Criteria used to diagnose irAEs include blood tests, diagnostic imaging, histopathology, and microbiology 
assessments to exclude alternative causes such as infection, PD, and adverse effects of concomitant drugs. 
In addition to the results of these tests, the following factors should be considered when making an irAE 
diagnosis:  
• 
What was the temporal relationship between initiation of tislelizumab and the adverse event? 
• 
How did the patient respond to withdrawal of tislelizumab? 
• 
Did the event recur when tislelizumab was reintroduced? 
• 
Was there a clinical response to corticosteroids? 
• 
Is the event an autoimmune endocrinopathy? 
• 
Is PD or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the irAE field associated with 
the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of Possible  
Immune-related Adverse Events 
Immune-Related Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  


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Recommended Diagnostic Tests in the Management of Possible  
Immune-related Adverse Events 
Immune-Related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a patient 
experiences bleeding, pain, or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.  
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a hepatologist. 
A liver biopsy is encouraged. 
Renal toxicity 
Review hydration status and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to nephrology for further management assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology 
referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK, CK-MB, troponin I and T analysis, and refer 
to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle isoenzyme; CNS, central nervous 
system; CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function testing; LKM, liver 
kidney microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic 
resonance imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; 
T4, thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and 
creatinine. 


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Page 141 of 177 
Treatment of Immune-Related AEs 
• 
An irAEs can escalate quickly; study treatment interruption, close monitoring, timely diagnostic 
work-up and treatment intervention, as appropriate, with patients is required 
• 
An irAEs should improve promptly after introduction of immunosuppressive therapy. If this does 
not occur, review the diagnosis, seek further specialist advice, and contact the medical monitor 
• 
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be considered 
if there is evidence of a clinical response to study treatment, after consultation with the medical 
monitor 
• 
Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. Equivalent 
dosages of other corticosteroids can be substituted. For steroid-refractory irAEs, consider use of 
steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• 
Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term 
immunosuppressive therapy 
 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker, and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
µg/kg/day). Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require treatment 
with a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month. If there is no improvement 
in 48 hours, treat as Grade 3-4. Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. Initiate 
pulse intravenous 
methylprednisolone 1 mg/kg for 
patients with headache/visual 
disturbance due to pituitary 
inflammation. Convert to oral 
prednisolone and taper over at least 1 
month. Maintain hormone 
replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen. 
Consider Pneumocystis infection 
prophylaxis. Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with intravenous 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 2 
months. Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 


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Page 143 of 177 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day. Taper over at least 4 
weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or intravenous 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms. Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids over 
2-4 weeks, consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate intravenous 
methylprednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no perforation, 
sepsis, TB, hepatitis, NYHA grade 
III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/ sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
medical monitor. 
 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 


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Page 144 of 177 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
2 
Rash covers 10%-30% 
of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch. Consider a 
short course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: intravenous 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the medical monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate intravenous 
methylprednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:  
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
intravenous (methyl)prednisolone 
2 mg/kg/day. When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
medical monitor. 
4 
ALT or AST > 20X 
ULN 
Initiate intravenous 
methylprednisolone 2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 6 weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed intravenous methylprednisolone 
• 
If on intravenous, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate 
intravenous (methyl)prednisolone 
1-2 mg/kg. Taper corticosteroids 
over at least 4 weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline. Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9- 
13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week. Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management. Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose value 
> 500 mg/dL; > 27.8 
mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment. Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the medical monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate intravenous 
(methyl)prednisolone 2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea, 
and vomiting 
Admit to hospital for urgent 
management. Initiate intravenous 
(methyl)prednisolone 1-2 mg/kg/day. 
Hold study treatment; 
reintroduce only after 
discussion with the 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments, and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management. Initiate intravenous 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider intravenous 
corticosteroids if not contraindicated 
by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
Hold study treatment 
until improved to Grade 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
with/without pain 
taper over at least 4 weeks 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg. Consider 
bolus intravenous 
(methyl)prednisolone and1-
2 mg/kg/day maintenance for severe 
activity restriction or dysphagia. If 
symptoms do not improve add 
immunosuppressant therapy. Taper 
oral steroids over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
1 
Asymptomatic but 
abnormal CK-MB, 
cardiac troponin, or 
intraventricular 
conduction delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac symptoms 
or any increase in cardiac serum 
markers to the coronary care unit. 
Initiate oral prednisolone or 
intravenous (methyl)prednisolone at 
1-2 mg/kg/day. Manage symptoms of 
cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
antithymocyte globulin 
Hold study treatment 
until completely 
resolved or myocarditis 
has been ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
has been excluded and 
symptoms have 
completely resolved 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac muscle 
isoenzyme; INR, international normalized ratio; LFT, liver function testing; MMF, mycophenolate mofetil; 
NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, 
thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 


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APPENDIX 11. 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following Eisenhauer et al 2009.  
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). Changes in only the 
largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria.  
Note: Lesions are either measurable or non-measurable using the criteria provided below. The term 
“evaluable” in reference to measurability will not be used because it does not provide additional meaning 
or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and 
a minimum of 10 mm). 
• 
10 mm caliper measurement by clinical exam (when superficial). 
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques are all non-measurable. 
Bone lesions: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 


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Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. Trial protocols should detail the conditions under which such lesions would be considered 
measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organ, but in addition 
should be those that lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by 
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be 
identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as 
2 dimensions in the plane in which the image is obtained (for CT scan, this is almost always the axial 
plane; for MRI the plane of acquisition may be axial, saggital, or coronal). The smaller of these measures 
is the short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a short 
axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as “present”, “absent”, or in rare cases “unequivocal progression” (more 
details to follow). In addition, it is possible to record multiple non-target lesions involving the same organ 


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as a single item on the case record form (eg, “multiple enlarged pelvic lymph node” or “multiple liver 
metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are accessible 
by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
P10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. As 
noted above, when lesions can be evaluated by both clinical examination and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the trial. 
• 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
• 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (eg, for body scans). 
• 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
• 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific guidelines for 


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both CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 
developed CA-125 progression criteria which are to be integrated with objective tumor assessment for 
use in first-line trials in ovarian cancer. 
• 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect 
of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or stable disease) and PD. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.  
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
• 
Target lesions that become “too small to measure”. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure”.  


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• 
When this occurs, it is important that a value be recorded on the eCRF. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
• 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and instead should 
be assessed only qualitatively at the time points specified in the protocol. 
• 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
• 
PD: Unequivocal progression (as detailed below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression.) 
• 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
• 
When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
 
• 
When the patient has only non-measurable disease: This circumstance arises in some Phase 3 
trials when it is not a criterion of trial entry to have measurable disease. The same general concept 


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applies here as noted above, however, in this instance there is no measurable disease assessment 
to factor into the interpretation of an increase in non-measurable disease burden. Because 
worsening in non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a measurable 
lesion).  
Examples include an increase in a pleural effusion from “trace” to “large”, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”. If “unequivocal progression” is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of new 
lesions are important. There are no specific criteria for the identification of new radiographic lesions; 
however, the finding of a new lesion should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than tumor (for 
example, some “new” bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate PD. An example of this is the patient who has visceral disease at 
baseline and while on trial has a CT or MRI brain ordered which reveals metastases. The patient’s brain 
metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible “new” disease). New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on a 
new lesion. 


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• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET 
at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are 
needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drugs until the end of treatment taking 
into account any requirement for confirmation. On occasion a response may not be documented until after 
the end of therapy so protocols should be clear if post-treatment assessments are to be considered in 
determination of BOR. Protocols must specify how any new therapy introduced before progression will 
affect best response designation. The patient’s BOR assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. Furthermore, 
depending on the nature of the trial and the protocol requirements, it may also require confirmatory 
measurement. Specifically, in nonrandomized trials where response is the primary endpoint, confirmation 
of PR or CR is needed to deem either one the “BOR”. 
The BOR is determined once all the data for the patient is known. Best response determination in trials 
where confirmation of complete or partial response IS NOT required: Best response in these trials is 
defined as the best response across all time points (for example, a patient who has SD at first assessment, 
PR at second assessment, and PD on last assessment has a BOR of PR). When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline. If the minimum time is 
not met when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second and does 
not meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-up 
after the first SD assessment would be considered inevaluable. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Any 
Any 
PD 
Any 
Yes or No 
Yes 
PD 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” size (< 
10 mm), they may still have a measurement reported on scans. This measurement should be recorded 
even though the nodes are normal in order not to overstate progression should it be based on increase in 
size of the nodes. As noted earlier, this means that patients with CR may not have a total sum of “zero” on 
the eCRF. 
 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in most 
trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed 
response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and should be 
clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific medical 
literature for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment, progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 
 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 


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In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is required 
to ensure responses identified are not the result of measurement error. This will also permit appropriate 
interpretation of results in the context of historical data where response has traditionally required 
confirmation in such trials. However, in all other circumstances, ie, in randomized trials (Phase 2 or 3) or 
trials where stable disease or progression are the primary endpoints, confirmation of response is not 
required since it will not add value to the interpretation of trial results. However, elimination of the 
requirement for response confirmation may increase the importance of central review to protect against 
bias, in particular in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a minimum 
interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, taking 
as reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving stable disease for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between 2 
measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are influenced 
by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define a 
standard follow-up frequency. The frequency should take into account many parameters including disease 
types and stages, treatment periodicity, and standard practice. However, these limitations of the precision 
of the measured endpoint should be taken into account if comparisons between trials are to be made. 
 


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APPENDIX 12. 
MODFIED RECIST (mRECIST) ASSESSMENT FOR 
HEPATOCELLULAR CARCINOMA 
The text below was obtained from the following Lencioni R et al 2010. 
DEFINITIONS 
The AASLD-JNCI (Journal of the National Cancer Institute) guidelines included for the first time a 
formal modification of the assessment of response based on the RECIST criteria, and aimed to translate 
the concept of viable tumor posed by the previous guidelines in a more updated framework. These 
amendments are referred to as modified RECIST assessment (mRECIST) for HCC. 
AASLD-JNCI GUIDELINES FOR Assessment of Standardizing Response 
Image acquisition 
Optimization of image acquisition protocols and consistency in the use of the same protocol throughout 
follow-up examinations are key for proper application of mRECIST. Patients can be followed with either 
contrast-enhanced spiral computed tomography (CT) preferably with use of multislice scanners or 
contrastenhanced dynamic magnetic resonance imaging (MRI). The administration of intravenous 
contrast is recommended for all CT or MRI studies if not medically contraindicated. In contrast-enhanced 
studies, it is mandatory to obtain a dual-phase imaging of the liver. Every effort should be made to time 
the contrast administration so that high-quality arterial-phase imaging is obtained throughout the liver on 
the first run, and high-quality portal venous-phase imaging is obtained throughout the liver on the second 
run. Delayed imaging obtained in the equilibrium phase may be useful, but it is not mandatory and should 
be done only if it is part of clinical practice. For multidetector CT scanners that are capable of acquiring 
very thin slices, it is necessary to keep in mind that it is mandatory to use contiguous slices for image read 
and interpretation, to avoid missing small lesions. For example, the analysis of contiguous slices with 
traditional 5 mm thickness and 5 mm reconstruction interval is acceptable; however, the analysis of 2.5 
mm thickness slices at 5 mm intervals is not acceptable. 
Image interpretation 
To properly use the proposed mRECIST for HCC to assess response rates and time to progression in HCC 
clinical trials and to ensure comparability across studies, uniform image acquisition parameters, rigorous 
quality control, and independent blinded multireader assessments are mandatory. Therefore, the expert 
panel recommended adopting a centralized radiologic review for image interpretation rather than base the 
assessment on the image evaluation performed by local investigators. Independent radiologists will be 
responsible for performing qualitative and quantitative assessments of imaging data. They will assess 
baseline imaging to determine the overall tumor burden and use this as a comparator for subsequent 
measurements. Tumor response will then be determined for each follow-up imaging time point. Overall 
response assessment includes, according to RECIST, evaluation of target lesions response, nontarget 
lesions response, and new lesions. 
Assessment of tumor lesions at baseline 
According to RECIST, tumor lesions are categorized at baseline as follows: measurable (lesions that can 
be accurately measured in at least one dimension as ≥1 cm with a spiral CT scan) or nonmeasurable [all 
other lesions, including small lesions (longest diameter <1 cm with spiral CT scan) and truly 


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nonmeasurable lesions]. The original RECIST publication states that all measurable lesions up to a 
maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. The recent 1.1 release of RECIST has 
reduced the number of lesions to select as target lesions to a maximum of two lesions per organ and five 
lesions in total. In fact, analyses on a large prospective database has shown that assessment of five versus 
10 lesions per patient did not affect the overall response rate, and that progression-free survival was only 
minimally affected. Target lesions should be selected on the basis of their size (those with the longest 
diameter) and their suitability for accurate repeated measurements. All other lesions (or sites of disease) 
should be identified as nontarget lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be noted throughout follow-up. 
It is our understanding that the measurement of the longest viable tumor diameter for the assessment of 
response according to mRECIST can be only applied in case of typical lesions. Conversely, for non- 
enhancing atypical lesions, as well as for any extrahepatic neoplastic niches, the measurements of the 
longest overall tumor diameter as per conventional RECIST should prevail. 
To be selected as a target lesion using mRECIST, an HCC lesion should meet all the following criteria: 
• 
The lesion can be classified as a RECIST measurable lesion (i.e., the lesion can be accurately 
measured in at least one dimension as 1 cm or more). 
• 
The lesion is suitable for repeat measurement. 
• 
The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
It is important to point out that only well-delineated, arterially enhancing lesions can be selected as target 
lesions for mRECIST. This may not be the case of infiltrative-type HCC. Infiltrative-type HCC should be 
considered as a nontarget lesion when the mass shows ill-defined borders and therefore does not appear to 
be suitable for accurate and repeat measurements. HCC lesions previously treated with locoregional or 
systemic treatments may or may not be considered as suitable to be selected as target lesions for 
mRECIST: if the lesion shows a well-delineated area of viable (contrast enhancement in the arterial 
phase) tumor that is at least 1 cm in longest diameter, then it can be selected as a target lesion. In contrast, 
if the lesion is poorly demarcated or exhibits atypical enhancement as a result of the previous 
intervention, then it cannot be selected as a target lesion for mRECIST. 
RESPONSE CRITERIA 
Evaluation of Target Lesions Response 
The mRECIST for HCC has introduced the following amendments to RECIST in the determination of 
tumor response for target lesions: 
• 
Complete response: the disappearance of any intratumoral arterial enhancement in all target lesions. 
• 
Partial response: at least a 30% decrease in the sum of diameters of viable (contrast enhancement in 
the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target 
lesions. 


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• 
Progressive disease: an increase of at least 20% in the sum of the diameters of viable (enhancing) 
target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target 
lesions recorded since the treatment started. 
• 
Stable disease: any cases that do not qualify for either partial response or progressive disease. 
The measurement of the longest diameter of the viable tumor may be challenging in lesions showing 
partial internal necrosis. The following points should be taken into account in such cases: 
• 
The measurement of the viable tumor should be performed on CT or MRI obtained in the arterial 
phase, when the contrast between viable vascularized tumor tissue and nonenhancing necrotic tissue 
is the highest. 
• 
The longest diameter of the viable tumor is not necessarily located in the same scan plane in which 
the baseline diameter was measured: a thorough careful evaluation of the CT or MRI scans is 
required. 
• 
The measurement of the viable tumor diameter should not include any major intervening areas of 
necrosis. 
It is important to point out that a reduction of at least 30% in the diameter of the viable tumor (the 
threshold required to declare partial response according to mRECIST) corresponds to a decrease of 65% 
in viable tumor volume. In contrast, an increase of at least 20% in the diameter of the viable tumor (the 
threshold required to declare progressive disease according to mRECIST) corresponds to an increase of at 
least 73% in viable tumor volume. The panel acknowledged that direct volumetric measurement to 
identify partial response and progression should be a priority in future clinical trial research. 
Evaluation of Nontarget lesions response 
The RECIST guideline provides the following definitions of the criteria used to determine the objective 
tumor response for nontarget lesions: complete response is the disappearance of all nontarget lesions; 
incomplete response/stable disease is the persistence of one or more nontarget lesions; and progressive 
disease is the appearance of one or more new lesions and/or unequivocal progression of existing nontarget 
lesions. 
According to mRECIST for HCC, tumor necrosis should be taken into account when assessing the 
response of nontarget lesions. The disappearance of intratumoral arterial enhancement in nontarget 
lesions should be considered equivalent to the disappearance of nontarget lesions, and therefore, should 
declare complete response of nontarget lesions. The persistence of intratumoral arterial enhancement in 
one or more nontarget lesions should be considered equivalent to persistence of one or more nontarget 
lesions, and therefore, should declare incomplete response / stable disease. The appearance of one or more 
new lesions and/or unequivocal progression of existing nontarget lesions should declare progressive 
disease. 
Special recommendations for the assessment of tumor response in nontarget lesions in patients with HCC 
and cirrhosis can be made regarding the following point: 
• 
Portal vein thrombosis. Malignant portal vein thrombosis should be considered a nonmeasurable 
lesion due to the difficulty in performing consistent measurements of the malignant thrombus during 


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the course of the treatment. Measurements of the extent of the malignant thrombus may be impaired 
by the possible presence of a bland component of the thrombosis. 
• 
Porta hepatis lymph node. Lymph nodes detected at the portal hepatis can be considered as malignant 
if the lymph node short axis is at least 20 mm. Evidence of reactive lymph nodes at the porta hepatis, 
in fact, is a common finding in patients with cirrhosis regardless of the presence of an HCC. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. 
• 
Pleural effusion and ascites. The original RECIST publication specifies that cytologic confirmation of 
the neoplastic nature of any effusion that appears or worsens during treatment is required when the 
measurable tumor has met criteria for response or stable disease. Under such circumstances, the 
cytologic examination of the fluid collected will permit differentiation between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease (if the neoplastic 
origin of the fluid is confirmed). The mRECIST for HCC panel of experts considered this issue to be 
of high importance in the setting of HCC in cirrhosis. The emergence or the increase in ascites is a 
common event during the course of treatment in a cirrhotic patient, which may be due to worsening of 
the underlying chronic liver disease and be unrelated to cancer progression. Other effusions, such as 
pleural effusion, may also be unrelated to cancer progression and be caused by the liver insufficiency. 
Thus, the mRECIST for HCC emphasizes that cytopathologic confirmation of the neoplastic nature of 
any effusion (particularly ascites) that appears or worsens during treatment is required when the 
measurable tumor has met criteria for response or stable disease. It has to be underlined that 
peritoneal carcinomatosis is a very rare event in HCC. 
New lesions 
The AASLD practice guideline for the clinical management of HCC has recommended strict criteria for 
the imaging diagnosis of HCC in cirrhosis. Noninvasive diagnostic criteria of HCC can be made without 
histology in lesions of at least 1 cm in diameter showing characteristic vascular features of HCC arterial 
hypervascularization with washout in the portal venous or the late phase at dynamic imaging studies. For 
diagnostic purposes, two imaging techniques CT and MRI are required for such a confirmation in tumors 
of 1 to 2 cm in diameter, and one imaging technique in tumors beyond 2 cm in cirrhotic patients. 
In the assessment of tumor progression, these concepts have been adopted by the mRECIST assessment 
proposal, considering some specificities for the frame of progression mode: 
• 
A newly detected hepatic nodule will be classified as HCC and therefore will be declared as evidence 
of progression when its longest diameter is at least 1 cm and the nodule shows the typical vascular 
pattern of HCC on dynamic imaging, that is, hypervascularization in the arterial phase with washout 
in the portal venous or late venous phase. 
• 
Liver lesions larger than 1 cm that do not show a typical vascular pattern can be diagnosed as HCC by 
evidence of at least 1-cm-interval growth in subsequent scans. 
• 
An individual radiologic event will be adjudicated in retrospect as progression at the time it was first 
detected by imaging techniques, even if strict criteria were fulfilled only on subsequent radiologic 
testing. 


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Overall Response Assessment 
In mRECIST for HCC, identical to conventional RECIST, overall patient response is a result of the 
combined assessment of target lesions, nontarget lesions, and new lesions. It is important to point out that 
appearance of one or more new lesions declares progression whatever the response of target and nontarget 
lesions. Overcalling of equivocal lesions as new HCC, therefore, has a major impact on the outcome of 
studies with a radiologic endpoint, such as tumor response or time to progression. Hence, any newly 
detected focal liver lesion that does not meet the criteria reported above should be considered equivocal 
and not conclusive for disease progression. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
PR 
SD 
PD 
Any 
Any 
CR 
IR/SD 
Non-PD 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
SD 
PD 
PD 
PD 
Abbreviations: CR, complete response; PR, partial response; IR, incomplete response; SD, stable disease; PD, 
progressive disease. 
VALIDATION 
The proposed mRECIST assessment is expected to provide a reliable method for assessing tumor 
response in HCC clinical trials. These new criteria need now to pass the same examination as other 
methods used before. 
• 
At one time point pathologic correlation with tumor measurements will be required. 
• 
The effect of specific antiangiogenic agents changing the tumor inflow of blood might also have 
impact in the response assessment. 
• 
Regulatory agencies have to be persuaded that the mRECIST based on the AASLD-JNCI guidelines 
is the needed step forward to align the response rates induced by molecular drugs and hard endpoints 
such as survival. 


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APPENDIX 13. 
iRECIST: GUIDELINES FOR RESPONSE CRITERIA FOR USE IN 
TRIALS TESTING IMMUNOTHERAPEUTICS 
The text below was obtained from the following Lesley Seymour et al 2017. 
DEFINITIONS 
iRECIST is a consensus guideline developed by the RECIST working group for the use of modified 
Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to 
ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate 
validation of the guideline. 
Note: iRECIST is based on RECIST 1.1. Responses assigned using iRECIST have a prefix of “I” (ie, 
immune) eg, “immune” complete response (iCR) or partial response (iPR), and unconfirmed progressive 
disease (iUPD) or confirmed progressive disease (iCPD) to differentiate them from responses assigned 
using RECIST 1.1. Similar nomenclature is used for stable disease (iSD). New lesions are assessed and 
subcategorised into those that qualify as target lesions (new lesion, target) or non-target lesions (new 
lesion, non-target). 
Tumor lesions 
The continued use of RECIST 1.1 is recommended to define whether tumour lesions, including lymph 
nodes, are measurable or non-measurable, as well as for the management of bone lesions, cystic lesions, 
and lesions with previous local treatment (eg, radiotherapy). Similarly, no changes have been made to the 
recommendations regarding the method of measurement, although clinical examination and chest 
radiograph are rarely used, with the availability of more modern imaging techniques (eg, CT scans and 
MRI). The principles used to establish objective tumour response are largely unchanged from RECIST 
1.1, but the major change for iRECIST is the concept of resetting the bar if RECIST 1.1 progression is 
followed at the next assessment by tumour shrinkage. 
Measurable Disease (RECIST 1.1) 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and 
a minimum of 10 mm). 
• 
10 mm caliper measurement by clinical exam (when superficial). 
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease (RECIST 1.1) 
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. 
Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast disease, 


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lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques are all non-measurable. 
Bone lesions: 
• 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. Trial protocols should detail the conditions under which such lesions would be considered 
measurable. 
iUPD 
iRECIST defines iUPD on the basis of RECIST 1.1 principles; however, iUPD requires confirmation, 
which is done on the basis of observing either a further increase in size (or in the number of new lesions) 
in the lesion category in which progression was first identified in (ie, target or non-target disease), or 
progression (defined by RECIST 1.1) in lesion categories that had not previously met RECIST 1.1 
progression criteria. However, if progression is not confirmed, but instead tumour shrinkage occurs 
(compared with baseline), which meets the criteria of iCR, iPR, or iSD, then the bar is reset so that iUPD 
needs to occur again (compared with nadir values) and then be confirmed (by further growth) at the next 
assessment for iCPD to be assigned. If no change in tumour size or extent from iUPD occurs, then the 
timepoint response would again be iUPD. This approach allows atypical responses, such as delayed 
responses that occur after pseudoprogression, to be identified, further understood, and better 
characterised. 
GUIDELINES FOR CONTINUED TREATMENT AFTER iUPD 
We recommend that clinical trials in which treatment beyond initial RECIST 1.1-defined progression (ie, 
iUPD) is permitted should only allow patients who are clinically stable to continue on treatment until the 
next assessment (≥4 weeks later); this next imaging assessment should be no longer than 8 weeks later, to 


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ensure that patients remain fit for salvage therapies. A longer timeframe before the next assessment might 
be reasonable if pseudoprogression is well described in the tumour type (eg, melanoma treated with a 
CTLA4 inhibitor), especially if no effective salvage therapies are available (eg, BRAF wild-type 
melanoma) but should be justified in the trial protocol. All decisions regarding continuation or 
discontinuation of therapy should be made by the patient and their health-care provider; iRECIST 
describes what data are to be collected, submitted, and analysed in clinical trials of immune-based 
therapies. 
An assignment of clinical stability requires that no worsening of performance status has occurred, that no 
clinically relevant increases in disease-related symptoms such as pain or dyspnoea occur that are thought 
to be associated with disease progression (these symptoms are generally understood to mean a 
requirement for increased palliative intervention), and that no requirement for intensified management of 
disease-related symptoms exists, including increased analgesia, radiotherapy, or other palliative care. 
The imaging findings and the recommendation to continue with treatment despite iUPD should be 
discussed with the patient before a decision is made about whether or not to continue therapy. Patients 
who have iUPD and are not clinically stable should be designated as not clinically stable in the case report 
form. This designation will allow the best overall response to be calculated and the date of iUPD to be 
used in estimates of progression-free survival. 
If the confirmatory scan confirms iCPD, but the investigator or patient believes that continued treatment 
is appropriate, imaging should continue and data should be collected to allow further elucidation of 
tumour growth dynamics with immune modulators. For the same reason, and if feasible, even patients 
who discontinue therapy for iCPD are recommended to continue to have disease assessments until they 
start other systemic or local therapies. 
RESPONSE CRITERIA 
Assessment of Target Lesions 
For target lesions, iCR, iPR, and iSD can all be assigned after iUPD has been documented, as long as 
iCPD was not confirmed. iUPD is defined by RECIST 1.1 criteria for progressive disease; iUPD can be 
assigned multiple times as long as iCPD is not confirmed at the next assessment. Progression is confirmed 
in the target lesion category if the next imaging assessment after iUPD (4-8 weeks later) confirms a 
further increase in sum of measures of target disease from iUPD, with an increase of at least 5 mm. 
However, the criteria for iCPD (after iUPD) are not considered to have been met if complete response, 
partial response, or stable disease criteria (compared with baseline and as defined by RECIST 1.1) are met 
at the next assessment after iUPD. The status is reset (unlike RECIST 1.1, in which any progression 
precludes later complete response, partial response, or stable disease). iCR, iPR, or iSD should then be 
assigned; and if no change is detected, then the timepoint response is iUPD. 
Assessment of Non-target Lesions 
The assessment of non-target lesions at each timepoint follows similar principles. iUPD (but not iCPD) 
can have been documented before iCR or when the criteria for neither CR nor PD have been met (referred 
to as non-iCPD/non-iUPD) and can be assigned several times, as long as iCPD was not confirmed. iUPD 
is defined by RECIST 1.1 criteria; however, iUPD can be assigned multiple times as long as iCPD is not 


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confirmed at the next assessment. Progressive disease in the non-target lesion category is confirmed if 
subsequent imaging, done 4–8 weeks after iUPD, shows a further increase from iUPD. The criteria for 
iCPD are not judged to have been met if RECIST 1.1 criteria for complete response or non-iCR/non-
iUPD are met after a previous iUPD. The status is reset (unlike RECIST 1.1) and iCR, or non-iCR/non-
iUPD is assigned; if no change is detected, the timepoint response is iUPD. 
New Lesions 
Many aspects of new lesion assessment are unique to iRECIST. If a new lesion is identified (thus meeting 
the criteria for iUPD) and the patient is clinically stable, treatment should be continued. New lesions 
should be assessed and categorised as measurable or non-measurable using RECIST 1.1 principles. Five 
lesions (no more than two per organ) should be measured and recorded as a new lesion target, but should 
not be included in the sum of measures of the original target lesions identified at baseline (appendix p 17). 
Other measurable and non-measurable lesions are recorded as new lesion non-target. Trialists might 
choose to measure and record more than five new lesions for research purposes, but this method is not 
believed to be practical for general use. New lesions do not need to meet the criteria for new lesion target 
to result in iUPD (or iCPD); new lesion non-target can also drive iUPD or iCPD. Progressive disease is 
confirmed (iCPD) in the new lesion category if the next imaging assessment, done at 4–8 weeks after 
iUPD, confirms additional new lesions or a further increase in new lesion size from iUPD (sum of 
measures increase in new lesion target ≥5 mm, any increase for new lesion non-target). 
Notably, if iUPD criteria were met on the basis of progression in the target or non-target disease, or the 
appearance of new lesions, then RECIST 1.1-assigned progression in another lesion category in the 
confirmatory scan also confirms iCPD. 
Assessment of Timepoint and Best Overall Response 
Although the principles of the assignment of the timepoint response and best overall response closely 
follow RECIST 1.1, and reflect assessment of target and non-target lesions as well as the presence of new 
lesions, the possibility of pseudoprogression adds complexity. The timepoint response is calculated using 
the response assigned for each category of lesion (as for RECIST 1.1), but takes into account the last 
timepoint response. 
If the criteria for iUPD have never been met, principles follow RECIST 1.1.However, if the criteria for 
iUPD have been met, the next timepoint response could be: 
• 
iUPD: no change noted in any category of lesion. 
• 
iSD, iPR, or iCR. Here, iUPD (followed by iCPD) should occur again. 
• 
iCPD, if the category in which iUPD was met at the last timepoint response shows a further increase 
in tumour burden as evidenced (as applicable) by a ≥5 mm increase in sum of measures of target or 
new target lesions, further increase in non-target or new non-target lesions, or an increase in the 
number of new lesions. 
Note: iCPD of a category which did not meet criteria for iUPD now meets the criteria for RECIST 1.1 
progression Prefix “i” indicates immune responses assigned using iRECIST. RECIST=Response 


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Evaluation Criteria in Solid Tumours. iCR=complete response. iCPD=complete progression. iPR=partial 
response. iSD=stable disease. iUPD=unconfirmed progression. 
The algorithm for patients with no previous iUPD is identical to RECIST 1.1. For patients with iUPD at 
the last timepoint response, the next timepoint response is dependent on the status of all lesions, including 
target, non-target, new lesion target, and new lesion non-target; on whether any increase in size has 
occurred (either a further increase in size or a sufficient increase to assign a new iUPD if the criteria were 
not previously met); or the appearance of additional new lesions. 
For iRECIST, the best overall response (iBOR) is the best timepoint response recorded from the start of 
the study treatment until the end of treatment, taking into account any requirement for confirmation. 
iUPD will not override a subsequent best overall response of iSD, iPR, or iCR, meaning that iPR or iSD 
can be assigned (timepoint response or iBOR) even if new lesions have not regressed, or if unequivocal 
progression (non-target lesions) remains unchanged, providing that the criteria for iCPD are not met. 
Confirmation of response is not required when using RECIST 1.1, except in non-randomised trials, and 
this approach is also recommended for iRECIST. The duration of iCR and iPR is from the timepoint 
when the criteria for iCR or iPR are first met, whereas the duration of iSD is still calculated from 
baseline. 
Assessments that are not done or are not evaluable should be disregarded. For example, an iUPD followed 
by an assessment that was not done or not evaluable, and then another unconfirmed progressive disease, 
would be indicative of iCPD. Protocols should clearly specify whether assessments done after protocol 
therapy is discontinued can be considered in identification of iBOR; it might be reasonable to include 
assessments done several weeks or months after protocol treatment has been discontinued if late 
responses are anticipated (such as with a CTLA4 inhibitor) and patients have not received other systemic 
or local therapies. Protocols should also specify how any new therapy introduced before progression (eg, 
radiotherapy or surgery) will affect iBOR designation. Other RECIST 1.1 recommendations, including 
the management of missing assessments, remain unchanged, including requiring that the statistical 
analysis plan should indicate how missing data or assessments will be addressed in the determination of 
response and progression. 
TUMOR REASSESSMENT/DISEASE PROGRESSION 
Tumor Reassessment 
In general, follow-up response assessment every 6-12 weeks is recommended for iRECIST, depending on 
the frequency of treatment visits, as recommended for RECIST 1.1. The protocol should specify which 
anatomical locations are assessed at baseline and follow-up, and whether bone scans should be repeated at 
each response assessment, only to confirm iPR or iCR, or when clinically indicated. For all trials, 
especially comparative ones, response assessments should be done on a calendar schedule and not be 
affected by delays in therapy or the requirement for earlier confirmatory scans, which might be done to 
confirm iUPD or in some trials, to confirm complete or partial response. 
Tumour reassessment can be done earlier than originally planned (but only between 4 and 8 weeks after 
iUPD) to confirm iUPD (or, in non-randomised trials, to confirm iCR or iPR 4 weeks after the scan 
showing complete or partial response). If progression is not confirmed, reassessment should continue as 


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originally planned (ie, if scans were to be done at 8, 16, and 24 weeks, and a scan was done at 12 weeks 
to confirm response, then the next scans should be done at 16 weeks and 24 weeks, as planned). If 
patients continue on treatment per protocol after iCPD, assessments should continue to be done, at the 
same planned schedule, until protocol treatment is discontinued. 
Ideally, all imaging done after protocol treatment has been discontinued should continue to be recorded 
on the case report form until subsequent therapies are initiated, as the protocol and informed consent 
document permit. These data will allow further refinement of iRECIST. 
Primary Criteria of Disease Progression 
The event date to be used for calculation of progression-free survival (iPFS) should be the first date at 
which progression criteria are met (ie, the date of iUPD) provided that iCPD is confirmed at the next 
assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that iUPD date should 
not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the iUPD date should 
still be used in the following scenarios: if the patient stops protocol treatment because they were not 
judged to be clinically stable, or no further response assessments are done (because of patient refusal, 
protocol noncompliance, or patient death); the next timepoint responses are all iUPD, and iCPD never 
occurs; or the patient dies from their cancer. The case report form collects the reason why confirmatory 
response assessment was not done at any timepoint, such as not clinically stable, centre error, patient 
refusal, or patient death. 
For protocols that permit crossover, or if intermittent schedules are being tested, the protocol should 
clearly specify whether iUPD or iCPD would be used for a treatment decision leading to crossover and 
how data subsequent to crossover will be managed and analysed. In general, we suggest that iCPD be 
used especially for scenarios with immunotherapy in both treatment groups and when pseudoprogression 
is anticipated. 
Adjuvant trials of immune modulators given after curative surgery for melanoma or lung cancer are 
ongoing (NCT 02437279, 02388906, 02595944, 02504372, and 02273375) but have yet to report their 
results. Suspected new lesions in the curative setting should always be investigated thoroughly and 
preferably have a biopsy taken before the designation of relapse is assigned. If taking a biopsy sample is 
not technically feasible, then it would seem to be reasonable to follow the principles of iRECIST, with a 
follow-up scan to confirm relapse in patients who are clinically stable. 
The collection of anonymised imaging (even if centralised blinded review of imaging studies is not 
planned) is recommended for all studies using an imaging-based endpoint (ie, response or progression-
free survival) if feasible. Although the iRECIST guideline requires the recording of the measurements of 
up to five new lesions, it might eventually be necessary to record additional lesions to obtain a more 
precise estimate of progression. Central collection of images will allow further assessment by an 
independent radiologist if necessary. If real-time central review is planned, the protocol should clearly 
explain how treatment decisions will be made. 
We recommend that phase 3 clinical trials continue to incorporate both RECIST 1.1 and iRECIST and 
that RECIST 1.1 should continue to be used to define the primary efficacy outcomes (progression-free 


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survival, disease progression, and best overall response). Exploratory analyses using the iPD date (ie, the 
first date of iUPD that is subsequently confirmed) can be defined in the statistical analysis plan. Early-
phase trials can consider using iRECIST as the primary criteria. The protocol should carefully explain 
which will be the primary criteria used to assess response, and which would be exploratory. This 
information is especially important for trials that compare an immune modulator treatment with a non-
immune modulator treatment. 
VALIDATION 
iRECIST requires the confirmation of progression to rule out or confirm pseudoprogression. Although 
this recommendation is in keeping with that of RECIST 1.1 to continue treatment and repeat imaging in 
the case of a mixed response or equivocal findings, if pseudoprogression is common, patients might be 
exposed to a higher risk (of continuing ineffective therapy or increasing exposure to radiotherapy) or cost 
(for the potentially ineffective therapy or the costs of imaging). We recommend that these criteria are 
used for clinical trial protocols rather than to guide clinical practice. Treatment beyond RECIST 1.1-based 
progression should be considered only in carefully selected scenarios in which the patient is stable (or 
improving) symptomatically and if there is just a short period remaining before reassessment. 
RECIST 1.1 and iRECIST should yield almost identical results for non-immunotherapy treatments, based 
on the RECIST warehouses; whereas an immune modulator warehouse and associated sensitivity analysis 
of endpoints will enable the quantification of potential added benefit for the immunotherapy component. 
Although comparison of iRECIST in such situations incorporates an element of bias by construction, 
confirmation and validation of the guideline by overall survival results might gain additional importance. 
Our recommendation for the design of randomised studies planned for licensing applications is to 
continue to use RECIST 1.1 as the primary criteria for response-based endpoints. iRECIST should be 
regarded as exploratory in such trials, although earlier phase trials might consider using primarily 
iRECIST. 
Comparison of RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definitions of measurable 
and non-measurable 
disease; numbers and site 
of target disease 
Measurable lesions are ≥10 mm 
in diameter (≥15 mm for nodal 
lesions); maximum of five 
lesions (two per organ); all other 
disease is considered non-target 
(must be ≥10 mm in short axis 
for nodal disease) 
No change from RECIST 1.1; 
however, new lesions are assessed as 
per RECIST 1.1 but are recorded 
separately on the case report form (but 
not included in the sum of lesions for 
target lesions identified at baseline) 
Complete response, 
partial response, or stable 
disease 
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease 
Can have had iUPD (one or more 
instances), but not iCPD, before iCR, 
iPR, or iSD 


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Confirmation of complete 
response or partial 
response 
Only required for non-
randomised trials 
As per RECIST 1.1 
Confirmation of stable 
disease 
Not required 
As per RECIST 1.1 
New lesions 
Result in progression; recorded 
but not measured 
Results in iUPD but iCPD is only 
assigned on the basis of this category if 
at next assessment additional new 
lesions appear or an increase in size of 
new lesions is seen (≥5 mm for sum of 
new lesion target or any increase in 
new lesion non-target); the appearance 
of new lesions when none have 
previously been recorded, can also 
confirm iCPD 
Independent blinded 
review and central 
collection of scans 
Recommended in some 
circumstances-eg, in some trials 
with progression-based 
endpoints planned for marketing 
approval 
Collection of scans (but not 
independent review) recommended for 
all trials 
Confirmation of 
progression 
Not required (unless equivocal) 
Required 
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is considered when 
deciding whether treatment is 
continued after iUPD 
“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation Criteria in Solid Tumours. 
iUPD=unconfirmed progression. iCPD=confirmed progression. iCR=complete response. iPR=partial response. 
iSD=stable disease. 
Assignment of timepoint response using iRECIST 
 
 
Timepoint response with 
no previous iUPD in any 
category 
Timepoint response with previous 
iUPD in any category* 
Target lesions: iCR; non-target 
lesions: iCR; new lesions: no 
iCR 
iCR 


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Target lesions: iCR; non-target 
lesions: noniCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target 
lesions: noniCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target 
lesions: noniCR/non-iUPD; new 
lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease from last 
timepoint; non-target lesions: iUPD 
with no change, or decrease from 
last timepoint; new lesions: yes 
Not applicable 
New lesions confirm iCPD if new 
lesions were previously identified and 
they have increased in size (≥5 mm in 
sum of measures for new lesion target 
or any increase for new lesion non-
target) or number; if no change is 
seen in new lesions (size or number) 
from last timepoint, assignment 
remains iUPD 
Target lesions: iSD, iPR, iCR; non-
target lesions: iUPD; new lesions: 
no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in the size of non-target 
disease (does not need to meet 
RECIST 1.1 criteria for unequivocal 
progression) 
 
 
 
Target lesions: iUPD; non-target 
lesions: noniCR/non-iUPD, or iCR; 
new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in sum of measures ≥5 mm; 
otherwise, assignment remains iUPD 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed based on a further increase 
in previously identified target lesion 
iUPD in sum of measures >5 mm or 
non-target lesion iUPD (previous 
assessment need not have shown 
unequivocal progression) 


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Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in previously identified 
target lesion iUPD sum of measures 
≥5 mm, previously identified non-
target lesion iUPD (does not need to 
be unequivocal), or an increase in the 
size or number of new lesions 
previously identified 
Target lesions: non-iUPD or 
progression; nontarget lesions: non-
iUPD or progression; new lesions: 
yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of an increase 
in the size or number of new lesions 
previously identified 
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no 
pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete response, partial response, and stable 
disease would be the same. 
 * Previously identified in assessment immediately before this timepoint.  
Abbreviation: “i” indicates immune responses assigned using iRECIST. iCR=complete response. iPR=partial 
response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither CR nor PD 
have been met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumors. 
Scenarios of assignments of best overall response using iRECIST 
 
Timepoint 
response 1 
Timepoint 
response 2 
Timepoint 
response 3 
Timepoint 
response 4 
Timepoint 
response 5 
iBOR 
Example 1 iCR 
iCR, iPR, 
iUPD, or NE 
iCR, iPR, 
iUPD, or NE 
iUPD 
iCPD 
iCR 
Example 2 iUPD 
iPR, iSD, or 
NE 
iCR 
iCR, iUPD, or 
NE 
iCR, iPR, 
iSD, iUPD, 
iCPD, or NE 
iCR 
Example 3 iUPD 
iPR 
iPR, iSD, 
iUPD, or NE 
iPR, iSD, 
iUPD, NE, or 
iCPD 
iPR, iSD, 
iUPD, NE, or 
iCPD 
iPR 
Example 4 iUPD 
iSD or NE 
iPR 
iPR, iSD, 
iUPD, or NE 
iPR, iSD, 
iUPD, iCPD, 
or NE 
iPR 


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Example 5 iUPD 
iSD 
iSD, iUPD, or 
NE 
iSD, iUPD, 
iCPD, or NE 
iSD, iUPD, 
iCPD, or NE 
iSD 
Example 6 iUPD 
iCPD 
Any 
Any 
Any 
iCPD 
Example 7 iUPD 
iUPD (no 
iCPD) 
iCPD 
Any 
Any 
iCPD 
Example 8 iUPD 
NE 
NE 
NE 
NE 
iCPD 
Eight examples are presented for patients with target disease at baseline, but many more scenarios exist following 
the same principles. Table assumes a randomised study in which confirmation of complete response or partial 
response is not required. For patients with non-target disease only at baseline, only iCR or non-complete response or 
non-progression of disease can be assigned at each timepoint (not shown in the table for ease of presentation).  
Abbreviation: “i” indicates immune responses assigned using iRECIST. iBOR=best overall response. iCR=complete 
response. iPR=partial response. NE=not evaluable. iUPD=unconfirmed progression. iCPD=confirmed progression. 
iSD=stable disease. RECIST=Response Evaluation Criteria in Solid Tumours. 


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APPENDIX 14. 
MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED WITH 
CAUTION DURING TREATMENT WITH LENVATINIB 
The text below was obtained from the followings https://crediblemeds.org/ and 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Bold font indicates medications or substances that might be relatively commonly used. 
Italic font indicates medications for indications that are exclusionary for the current study or would likely 
result in discontinuation from study treatment with lenvatinib for management of a concurrent illness. 
 
MEDICATIONS THAT SHOULD BE AVOIDED 
Drugs with a Known Risk of QT Prolongation/Torsades de Pointes 
Amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), azithromycin, bepridil (off US 
market), chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride (off US market), 
citalopram, clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on US market), 
donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin (off US market), grepafloxacin (not on US market), halofantrine (not on US market), 
haloperidol, ibogaine (not on US market), ibutilide, levofloxacin, levomepromazine / 
methotrimeprazine (not on US market), levomethadyl (off US market), levosulpiride (not on US 
market), mesoridazine (off US market), methadone, moxifloxacin, ondansetron, oxaliplatin, 
pentamidine, pimozide, probucol (off US market), procainamide, propofol, quinidine, roxithromycin 
(not on US market), sevoflurane, sotalol, sparfloxacin (off US market), sulpiride (not on US market), 
sultopride (non on US market), terfenadine (off US market), terlipressin (not on US market), terodiline 
(not on US market), thioridazine, vandetanib. 
 
CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS 
Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and BCRP 
Transporters 
Enzyme 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, 
fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, 
ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan. 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan. 
CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS (CONTINUED) 
Sensitive Substrates and Substrates With Narrow Therapeutic Index for the Indicated CYP 
Enzymes  
Enzyme 
CYP2B6 
Bupropion. 
CYP2C8 
Repaglinide.  
CYP2D6 
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, 
nortriptyline, perphenazine, tolterodine, venlafaxine.  
CYP3A 
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, 
ibrutinib, indinavir, lomitapide, lovastatin, lurasidone, maraviroc, midazolam, 


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naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, 
tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam, vardenafil.  
Drugs with Conditional Risk of Torsades de Pointes 
Amantadine, amisulpride (not on US market), amitriptyline, amphotericin B, atazanavir, 
bendroflumethiazide / bendrofluazide (not on US market), chloral hydrate, diphenhydramine, 
doxepin, esomeprazole, famotidine, fluoxetine, fluvoxamine, furosemide / frusemide, galantamine, 
garenoxacin (not on US market), hydrochlorothiazide, hydroxychloroquine, hydroxyzine, 
indapamide, itraconazole, ivabradine, ketoconazole, lansoprazole, loperamide, metoclopramide, 
metolazone, metronidazole, nelfinavir, olanzapine, omeprazole, pantoprazole, paroxetine, 
piperacillin/tazobactam, posaconazole, propafenone, quetiapine, quinine sulfate, ranolazine, sertraline, 
solifenacin, telaprevir, torsemide / torasemide, trazodone, voriconazole, ziprasidone. 
 


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APPENDIX 15. 
BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION    
The Barcelona Clinic Liver Cancer (BCLC) system has been widely validated and is the most commonly 
used staging system for HCC. It determines cancer stage and patient prognosis based on tumor burden, 
severity of liver disease, and the patient’s ECOG Performance Status.  
The staging according to the BCLC classification assigns prognoses based on clinical and tumor 
parameters and is summarized as follows: 
BCLC Stagea, b 
Very early stage 
(0) 
Early stage (A) 
Intermediate stage 
(B) 
Advanced stage 
(C) 
Terminal stage 
(D) 
Single nodule <2 
cm Carcinoma in 
situ Child–Pugh 
A, ECOG PS 0 
Single or 3 
nodules <3 cm 
Child–Pugh A-B, 
ECOG PS 0 
Multinodular, 
Child–Pugh A-B, 
ECOG PS 0 
Portal invasion, 
Extrahepatic 
spread, Child–
Pugh A-B, ECOG 
PS 1-2 
Child–Pugh C 
ECOG PS 3-4 
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status.  
a. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with 
hepatocellular carcinoma. Gastroenterology. 2016;150:835-53.  
b. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. 
Semin Liver Dis 1999;19:329–38. 

SAP_001.pdf: 
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CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-A317-211 
Study Protocol 
Title: 
A Phase 2 Study to Investigate the Preliminary Antitumor Activity, 
Safety and Tolerability of Tislelizumab in Combination with Lenvatinib 
in Patients with Unresectable Locally Advanced or Metastatic 
Hepatocellular Carcinoma 
Date: 
Apr 27, 2021 
Version: 
1.0 
NCT Number:
NCT04401800


 
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SIGNATURE PAGE 
Author:
              
              
 
 
 
 
 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, China 
 
 


 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
2.1 
Study Design 
7 
2.2 
Study Schema 
9 
2.3 
Study Assessments 
9 
3 
STUDY OBJECTIVES 
10 
3.1 
Primary Objectives 
10 
3.2 
Secondary Objectives 
10 
3.3 
Exploratory Objectives 
11 
4 
STUDY ENDPOINTS 
11 
4.1 
Primary Endpoints 
11 
4.2 
Secondary Endpoints 
11 
4.3 
Exploratory Endpoints 
11 
5 
SAMPLE SIZE CONSIDERATION 
11 
6 
STATISTICAL METHODS 
12 
6.1 
Analysis Populations 
12 
6.2 
Data Analysis General Considerations 
12 
6.2.1 
Definitions and Computations 
12 
6.2.2 
Conventions 
13 
6.2.3 
Handling of Missing Data 
13 
6.2.4 
Adjustment for Covariates 
13 
6.2.5 
Multiplicity Adjustment 
13 
6.2.6 
Data Integrity 
14 
6.3 
Subject Characteristics 
14 
6.3.1 
Patient Disposition 
14 
6.3.2 
Protocol Deviations 
14 
6.3.3 
Demographic and Other Baseline Characteristics 
14 
6.3.4 
Disease History and Characteristics 
14 
6.3.5 
Prior Anti-Cancer Treatment 
15 
6.3.6 
Prior and Concomitant Medications 
15 
6.3.7 
Medical History 
16 
6.4 
Efficacy Analysis 
16 
6.4.1 
Primary Efficacy Endpoints 
16 
6.4.2 
Secondary Efficacy Endpoints 
17 
6.4.3 
Subgroup Analyses 
18 
6.5 
Safety Analyses 
19 
6.5.1 
Dose-Limiting Toxicity Analysis 
19 
6.5.2 
Extent of Exposure 
20 
6.5.3 
Adverse Events 
21 
6.5.4 
Immune-related TEAEs 
22 
6.5.5 
Laboratory Values 
22 


 
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6.5.6 
Alpha-fetoprotein 
23 
6.5.7 
HBV DNA 
23 
6.5.8 
Vital Signs 
23 
6.5.9 
Physical Examination 
24 
6.5.10 
Electrocardiograms (ECG) 
24 
6.5.11 
Eastern Cooperative Oncology Group (ECOG) 
24 
6.6 
Pharmacokinetic Analyses 
24 
6.7 
Immunogenic Analyses 
24 
6.8 
Exploratory Efficacy Endpoint 
25 
6.9 
Biomarker Analyses 
25 
7 
INTERIM ANALYSIS 
25 
8 
CHANGES IN THE PLANNED ANALYSIS 
26 
9 
REFERENCES 
27 
10 
APPENDIX 
28 
10.1 
Imputation of Missing/Partially Missing Dates 
28 
10.2 
handling of censoring time to event data 
30 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug Antibody 
AEs 
Adverse Events  
ATC 
Anatomical Therapeutic Chemical  
BCLC 
Barcelona Clinic Liver Cancer  
BOR 
Best Overall Response 
CI 
Confidence Interval  
CK 
Creatine Kinase 
CK-MB 
Creatine Kinase Mb 
Cmax 
Maximum Plasma Concentration  
CP-A 
Child–Pugh Classes A  
CP-B 
Child–Pugh Classes B 
CR 
Complete Response  
CSR 
Clinical Study Report 
DCR 
Disease Control Rate  
DLT 
Dose Limiting Toxicity 
DOR 
Duration Of Response  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF  
Electronic Case Report Form  
EFF 
Efficacy Evaluable Analysis Set 
FDA 
US Food And Drug Administration  
GFR 
Glomerular Filtration Rate 
HBV 
Hepatitis B Virus  
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus  
ICH 
International Council For Harmonization 
irAE 
Immune-Related Adverse Event 
iRECIST 
Immune-Related Response Evaluation Criteria In Solid 
Tumors 
IV 
Intravenous Injection  
KIT 
KIT Proto-Oncogenes  
KM 
Kaplan-Meier  
MedDRA® 
Medical Dictionary For Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria In Solid Tumors 


 
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Abbreviation 
Definition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria 
For Adverse Events  
ORR 
Overall Response Rate  
OS 
Overall Survival  
PD  
Progressive Disease 
PD-1 
Programmed Cell Death Protein-1 
PD-L1 
Programmed Cell Death Protein Ligand-1 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic  
PO 
Orally 
PR 
Partial Response  
PT 
Preferred Term 
PT 
Prothrombin Time 
Q3W 
Every 3 Weeks   
QD 
Once A Day 
RECIST  
Response Evaluation Criteria In Solid Tumors 
RP2D  
Recommended Phase 2 Dose/Doses 
SAEs 
Serious Adverse Events 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan  
SD 
Stable Disease  
SMC 
Safety Monitoring Committee  
SOC 
System Organ Class  
TACE 
Transarterial Chemoembolization 
 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze, and report results for BGB Protocol A317-211 a “A Phase 2 
Study to Investigate the Preliminary Antitumor Activity, Safety and Tolerability of Tislelizumab 
in Combination with Lenvatinib in Patients with Unresectable Locally Advanced or Metastatic 
Hepatocellular Carcinoma”. The focus of this SAP is for the planned analyses specified in the 
study protocol amendment version 1.0 dated 25 December 2019. If the protocol is amended or 
updated, then appropriate adjustments to the SAP may be made if they are related to the planned 
analyses or sample size. 
The SAP described hereafter is an a priori plan. This is an open label study with a planned interim 
analysis (using Simon 2 stage design). The SAP will be finalized and approved before interim 
analysis. Statistical programming may occur as study data accumulate in order to have analysis 
programs ready at the time the study finishes. 
All statistical analyses will be conducted using SAS® (SAS Institute, Inc., Cary, NC, USA), 
Version 9.3 or higher. 
2 
STUDY OVERVIEW 
2.1 
STUDY DESIGN 
This is an open-label, multicenter Phase 2 clinical study for patients with histologically or 
cytologically confirmed unresectable locally advanced or metastatic HCC. All patients will receive 
study treatments until confirmed progressive disease assessed by investigator (iCPD)  based on 
iRECIST, unacceptable toxicity, 12-months treatment duration completion, death, withdrawal of 
consent, study termination by sponsor or patients meet any discontinuation criterion (see protocol 
Section 3.6 and Section 3.7 for details), whichever comes first. Patients will be closely monitored 
for safety and tolerability throughout the study. This study consists of the following two parts: 
Part 1 (Safety run-in part [21-day DLT assessment] for lenvatinib in combination with 
tislelizumab): Approximately 6-12 patients with unresectable locally advanced or metastatic HCC 
will be enrolled in this part.  
 The safety and tolerability of starting dose for lenvatinib in combination with tislelizumab 
will be evaluated. 3 patients with baseline body weight≥60 kg and 3 patients with baseline 
body weight＜60 kg will be enrolled. These patients will be administered with lenvatinib 
orally once a day and tislelizumab (200mg) by intravenous injection (IV), on Day 1 of each 
21-day cycle (once every 3 weeks, Q3W). The starting dose for lenvatinib in safety run-in 
part will be based on baseline body weight. 12 mg lenvatinib will be administered once 
daily if baseline body weight of patient≥60 kg. 8 mg lenvatinib will be administered once 
daily if baseline body weight of patient＜60 kg. 
 If ≤1 of 6 patients experience a dose limiting toxicity (DLT) in lenvatinib starting dose 
cohort, this dose level is determined as RP2D (Recommended Phase 2 Dose). The part 2 
will be started to enroll at RP2D. 


 
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 If ＞1 of 6 patients experience a DLT in this cohort, sponsor will decide to terminate the 
study or to start a new cohort to investigate lenvatinib at a reduced dose. Lenvatinib dose 
in the dose reduced cohort may be set as 8 mg or 4 mg once daily based on baseline body 
weight≥60 kg or＜60 kg, respectively. 6 eligible patients, 3≥60 kg and 3＜60 kg will be 
enrolled in this cohort. Tislelizumab dose is the same, 200 mg IV Q3W. 
 If≤1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, this dose level is 
determined as RP2D. The part 2 will start to enroll at RP2D. 
 If＞1 of 6 patients experience a DLT in lenvatinib dose reduced cohort, the part 1 will be 
stopped, and part 2 won’t be proceeded. 
The Safety Monitoring Committee (SMC) will determine RP2D of combination treatment based 
on all available safety data. 
Part 2: The planned 54 patients will be enrolled in this part. Each eligible patient will be 
administered by lenvatinib in combination with tislelizumab. Lenvatinib in accordance with 
recommended dose determined in part 1 will be administered orally, once daily continuously, 
tislelizumab will be administered sequentially starting on Cycle 1 Day 1 and every 21 days 
thereafter. 
The planned 60-66 patients will be enrolled in whole study, including 6-12 patients in part 1 and 
54 patients in part 2. A Simon’s 2 stage design will be used to test the superiority of studied 
combination treatment vs. the historical control. When 30 patients dosed at RP2D level (including 
patients from both part 1 and part 2) are enrolled and all reach their best overall response (BOR) 
assessed by central site imaging facility for tumor assessment based on RECIST v1.1, the 
preliminary efficiency and safety of those 30 patients will be assessed as interim analysis. 
 If within these 30 patients, ≤6 patients achieve response including complete response (CR) 
and partial response (PR) as their BOR assessed by central site imaging facility for tumor 
assessment based on RECIST v1.1, the study will be terminated. 
 If within these 30 patients, ＞6 patients achieve response including CR and PR as their 
BOR assessed by central site imaging facility for tumor assessment based on RECIST v1.1, 
the study will continue. 
 The enrollment won’t be interrupted after 30 patients were enrolled. 
 If patients don’t meet any discontinuation criterion, such as iCPD based on iRECIST, 
unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor, 
lenvatinib and tislelizumab will be administered until patient completes his/her 12-month 
treatment duration of study drugs. After 12-month treatment duration completion, if the 
patients are still under the response (CR, PR) or stable disease (SD) assessed by 
investigator based on RECIST v1.1 or under the response (complete response [iCR], partial 
response [iPR]), stable disease (iSD) and unconfirmed progression (iUPD) assessed by 
investigator based on iRECIST, and may continue receiving benefit based on investigator’s 
assessment, tislelizumab could be further provided by sponsor, this decision must be agreed 


 
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with medical monitor and documented in the study records, patients are also required to be 
reconsented. 
2.2 
STUDY SCHEMA 
 
Abbreviations: QD, once a day; Q3W, every 3 weeks; PO, orally; IV, intravenous injection; LEN, Lenvatinib; 
TIS, Tislelizumab. 
Note: The dose level of tislelizumab is fixed in the entire study. In part 1 whether to proceed to the lenvatinib 
dose reduced cohort will depend on safety observations in lenvatinib starting dose cohort and sponsor’s decision. 
 
2.3 
STUDY ASSESSMENTS 
Patients will be closely monitored for safety and tolerability throughout the study. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the 
first dose administration of lenvatinib plus tislelizumab at each dose level. For DLT assessment 
decision, only DLTs occurring within 21 days will be evaluated. The following patients will not 
be considered evaluable for DLT, and will be replaced if needed to meet the minimum patient 
number required for safety evaluation: 
 Patients who withdraw or are withdrawn from the study before completing the DLT 
assessment window for reasons other than a DLT. 
 Patients receiving combination therapy who do not receive ≥ 75% of scheduled lenvatinib 
and ≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT 
assessment window unless they experience a DLT. 
Tumor Assessments 
Radiological assessment of tumor-response status will be performed approximately every 6 weeks 
(± 7 days) in the first year, then every 9 weeks (± 7 days) thereafter.  
Tumor response will be assessed by investigators and central site imaging facility for tumor 
assessment respectively based on RECIST v1.1, mRECIST and iRECIST.  


 
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After first documentation of response (CR or PR), confirmation of tumor response should occur at 
4 weeks or later after the first response or at the next scheduled assessment time point.   
If radiographic initial PD is observed by the investigator based on RECIST 1.1, patients should 
continue treatment with tislelizumab until iCPD (investigator assessed based on iRECIST) is 
confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 8 weeks from the date of initial 
documentation of PD, repeated imaging on next scheduled tumor assessment visit date, around 6 
weeks from the date of initial documentation of PD is recommended). The criteria which must be 
met in order to treat patients to continue study drugs beyond initial PD via investigator assessed 
based on RECIST v1.1 will be described in protocol (see protocol Section 7.4 for details). 
The decision to continue study drug(s) beyond investigator-assessed progression must be agreed 
with the medical monitor and documented in the study records. In such cases, patients are also 
required to be reconsented. 
Central site imaging facility for tumor assessment 
Central site imaging facility for tumor assessment is composed of 3 radiology experts at the leading 
site or the site where the leading PI is located, specialized in tumor radiological assessment. The 
selection of these experts will be confirmed by leading PI and medical monitor, documented in 
study records. The executive plan will be described in protocol (see protocol Section 7.4.2 for 
details). 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
 
To assess the preliminary antitumor activity as indicated by overall response rate (ORR) 
assessed by central site imaging facility for tumor assessment per Response Evaluation 
Criteria in Solid Tumors (RECIST) version (v)1.1 of tislelizumab in combination with 
lenvatinib in patients with unresectable locally advanced or metastatic hepatocellular 
carcinoma 
3.2 
SECONDARY OBJECTIVES 
 
To characterize the safety and tolerability of tislelizumab in combination with lenvatinib 
in patients with unresectable locally advanced or metastatic hepatocellular carcinoma 
 To assess the preliminary antitumor activity as indicated by ORR assessed by investigators 
per RECIST v1.1 of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma  
 To assess the preliminary antitumor activity as indicated by ORR assessed by investigators 
and central site imaging facility for tumor assessment per modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) and Immune-related Response Evaluation Criteria in 
Solid Tumors(iRECIST) respectively of tislelizumab in combination with lenvatinib in 
patients with unresectable locally advanced or metastatic hepatocellular carcinoma  


 
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 To assess the preliminary antitumor activity as indicated by duration of response (DOR), 
disease control rate (DCR), and progression-free survival (PFS) assessed by investigators 
and central site imaging facility for tumor assessment per RECIST v1.1, mRECIST and 
iRECIST respectively of tislelizumab in combination with lenvatinib in patients with 
unresectable locally advanced or metastatic hepatocellular carcinoma 
3.3 
EXPLORATORY OBJECTIVES 
 
To characterize the pharmacokinetic (PK) and immunogenicity of tislelizumab when given 
in combination with lenvatinib in Part I 
 To assess OS 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
 
ORR assessed by central site imaging facility for tumor assessment based on RECIST v1.1 
4.2 
SECONDARY ENDPOINTS 
 
The safety and tolerability of tislelizumab in combination with lenvatinib will be evaluated 
by the incidence, nature, and severity of adverse events (AEs) and serious AEs (SAEs) per 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v5.0, clinical laboratory abnormalities, relevant physical exam, ECGs, vital signs 
and DLTs. 
 ORR assessed by investigators based on RECIST v1.1 
 ORR assessed by investigators and central site imaging facility respectively based on 
mRECIST and iRECIST 
 DOR, DCR, and PFS assessed by investigators and central site imaging facility 
respectively based on RECIST v1.1, mRECIST and iRECIST 
4.3 
EXPLORATORY ENDPOINTS  
 
Serum concentrations of tislelizumab and incidences of anti-tislelizumab-antibodies 
(ADA) in Part I 
 
OS 
5 
SAMPLE SIZE CONSIDERATION 
The planned 60-66 patients will be enrolled in whole study, including 6-12 patients in part 1 and 
54 patients in part 2.  
Part 1 (lenvatinib in combination with tislelizumab safety run-in): Approximately 6 to 12 patients 
with unresectable locally advanced will be enrolled.  


 
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With total of 60 patients at RP2D from both part 1 and part 2, based on Simon’s 2 stage design 
(Simon, 1989), we have about 95% power to detect a statistical significant difference between 
ORR (assessed based on RECIST v1.1) in studied combination treatment (assumed to be around 
40%) to a historical of 18.8% with 1-sided alpha as 0.025. Within first 30 pts (including the 6 
patients from part 1 and 24 patients from part 2) in the efficacy analysis set, if we observe≤6 
responders, study will be terminated. Otherwise, study will continue. If within the final 60 patients 
in the efficacy analysis set, we observe≥18 responders, we will claim we are statistically superior 
than a historical control of 18.8% under the settings. Participants withdraw due to personal reason 
or AE before first assessment will be replaced, which might need 4-6 extra participants. 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
 The safety analysis set (SAF) includes all patients who received at least 1 dose of any study 
drug (any component for the combination therapy). 
 The efficacy evaluable analysis set (EFF) includes all dosed patients with measurable 
disease at baseline per RECIST v1.1 and who had at least one evaluable post-baseline 
tumor assessment unless treatment was discontinued due to clinical disease progression or 
death before the first post treatment tumor assessment. 
 DLT evaluable analysis set for lenvatinib and tislelizumab combination includes patients 
who received at least 75% of the assigned total dose of lenvatinib and ≥ 67% 
(approximately two-thirds) of the assigned total dose of tislelizumab for the DLT 
assessment window. Additionally, patients who had a DLT event will also be considered 
evaluable. 
 The PK analysis set includes patients who received at least 1 dose of tislelizumab 
(lenvatinib) study drug and contributed at least 1 post-baseline quantifiable tislelizumab 
(lenvatinib) PK sample.  
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 Definitions and Computations 
Study day: Study days will be calculated in reference to the date of the first dose of study treatment.  
For assessments conducted on or after the date of the first dose of study treatment, study day will 
be calculated as (assessment date – date of first dose of study treatment + 1).  For assessments 
conducted before the date of the first dose of study treatment, study day is calculated as 
(assessment date – date of first dose of study treatment). There is no study day 0.  
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings; Study day and any corresponding durations will be presented based on the imputation 
rules specified in Appendix. 
Treatment duration: The treatment duration will be calculated as (date of last dose of study 
treatment – date of first dose of study treatment + 1) for lenvatinib; and calculated as (date of last 


 
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dose of study treatment – date of first dose of study treatment + 21) for Q3W dose regimens 
(Tislelizumab). 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the time of first dose date. 
All calculations and analyses will be conducted using SAS version 9.3 or higher. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal digit. 
 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up to 
1 decimal digit. 
 Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
 P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’. 
 Missing efficacy or safety data will not be imputed unless otherwise specified. 
 For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
 For discrete endpoints, summary statistics will include frequencies and percentages. 
Percentages will be presented to one decimal place. 
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures.  Specific rules for handling of missing or partially missing dates for 
adverse events and prior/concomitant medications/procedures are provided in Appendix 10.1. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For observed 
data analyses, missing data will not be imputed and only the observed records will be included. 
6.2.4 Adjustment for Covariates 
Not applicable. 
6.2.5 Multiplicity Adjustment 
Not applicable.  


 
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6.2.6 Data Integrity 
Before pre-specified interim or final statistical analysis begins, the integrity of the data should be 
reviewed to assure fit-for-purpose.  The data set for analysis should be an accurate and complete 
representation of the patients' 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 Patient Disposition 
The number (percentage) of patients with treatment/study ongoing, discontinued from study 
drug(s) and/or study, and reasons for study drug(s) or study discontinuation will be summarized in 
the SAF. The end of study status (alive, dead, withdrew consent, or lost to follow-up) at the data 
cut-off date and study follow-up duration (months) will be summarized using the data from the 
eCRF.  
6.3.2 Protocol Deviations 
Protocol deviation criteria will be established; patients with protocol deviations will be identified 
and documented before the database lock for the interim and primary analyses. 
Major protocol deviations will be summarized by each category. A data listing of protocol 
deviations will be provided. 
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the SAF. Continuous variables include age, BMI (in kg/m2), weight (in kg), height (in cm); 
categorical variables include gender, age group (<65 vs. ≥65), ECOG status, country, race, child-
bearing potential, tobacco use status, alcohol consumption, and HBsAg (positive vs. negative), 
HCVAb (positive vs. negative), Hepatitis B, and Hepatitis C. 
6.3.4 Disease History and Characteristics 
The number (percentage) of patients reporting a history of disease and characteristics, as recorded 
on the CRF, will be summarized. 
HCC history and characteristics such as BCLC initial staging, time from initial diagnosis to the 
first study dose, method of initial HCC diagnosis, histological type of cancer , BCLC staging at 
study entry, time from BCLC staging at study entry to the first study dose, macrovascular invasion, 
extrahepatic spread, distant metastases, location of metastases and number of metastatic sites will 
also be summarized. 
Alpha-fetoprotein at baseline (descriptively as well as by category >= 200 ng/mL and >= 400 
ng/mL) will be summarized as part of disease history. 


 
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HCC relevant medical history (Hepatitis B, Hepatitis C, Cirrhosis, Non-alcoholic 
steatohepatitis/Fatty Liver, etc.) and ongoing status will be summarized in descriptive statistics. 
Total Child-Pugh Score at baseline will be summarized by category (frequency and percentages). 
HBV and HCV infection status at baseline based on screening HBV (Hepatitis B Surface Antigen, 
Hepatitis B Surface Antibody and Hepatitis B Core Antibody) and HCV (Hepatitis C Virus 
Antibody). Test results will be summarized with HBsAg (Positive vs. Negative), and HCVAb 
status (Positive vs. Negative). 
The number (percentage) of patients reporting clinically significant symptoms at baseline will be 
summarized by System Organ Class and MedDRA preferred term. Severity of the symptoms 
according to NCI-CTCAE will be summarized by maximum grade. 
Relevant data listings of disease history will be provided. 
6.3.5 Prior Anti-Cancer Treatment 
Number of regimens of prior anti-cancer drug therapies will be summarized in frequencies and 
percentages. Regimen names, best response to the last therapy, duration of the last therapy, time 
from last disease progression to first study dose and reasons of the last therapy discontinued will 
be summarized. 
Total number (percentage) of patients who received any prior liver local regional therapies will be 
summarized, and the number of types of prior liver local regional therapies will be summarized, 
and number of patients who received any type of liver local regional therapies will also be 
summarized by therapy type. Prior liver local regional therapy TACE will be summarized by 
chemotherapeutic drug names in frequencies and percentages, prior liver local regional therapy 
HAIC (Hepatic Artery Infusion Chemotherapy) will be summarized by chemotherapeutic drug 
names in frequencies and percentages, prior liver local regional radiation therapy (EBRT or SIRT) 
will also be summarized by radiation therapy type. Treatment intention of the above liver local 
regional therapies will also be summarized in frequencies and percentages (curative or palliative).  
Prior systemic radiotherapies (therapy type, treatment intention, sites etc.) and prior 
surgeries/procedures (name, intention, and anatomic location) will be summarized similarly as 
prior liver local therapy. Relevant detail listings will be provided for potential narratives use. 
6.3.6 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using current version of 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 patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name. 
Prior medications will be defined as medications that stopped before the day of first dose of study 


 
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drugs. Concomitant medications will be defined as medications that 1) started before the first dose 
of study drugs and were continuing at the time of the first dose of study drugs, or 2) started on or 
after the date of the first dose of study drugs up to 30 days after the patient’s last dose. A listing of 
prior and concomitant medications will be included in the clinical study report (CSR) for this trial. 
In addition, telephone contacts with patients should be conducted to assess irAEs and concomitant 
medications (if appropriate, eg, associated with an irAE or is a new anticancer therapy) at 60 and 
90 days (±14 days) after the last dose of tislelizumab regardless of whether or not the patient starts 
a new anticancer therapy.   
6.3.7 Medical History  
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
codes of the version currently in effect at BeiGene at the time of databased lock. The number 
(percentage) of patients reporting a history of any medical condition, as recorded on the eCRF, 
will be summarized by MedDRA system organ class (SOC) and preferred term (PT) based on the 
safety analysis set. A listing of medical history will be provided.  
6.4 
EFFICACY ANALYSIS 
Since this study may start a new cohort with Lenvatinib at a reduced dose (Tis 200mg Q3W IV+ 
Len 8mg or 4mg QD PO), if so, we need to specify the dose level for all below efficacy analyses 
and the analyses will be conducted by dose (high vs.  low) and combined. High dose refers to Tis 
200mg Q3W IV + Len 12mg or 8mg OD PO, low dose refers to Tis 200mg Q3W IV + Len 8mg 
or 4mg OD PO. 
6.4.1 Primary Efficacy Endpoints 
Primary endpoint for Part 1 is safety endpoint (DLT), no hypothesis testing will be done for Part 
1 safety run-in. 
Objective Response Rate (ORR) at RP2D 
ORR is defined as the proportion of subjects achieving a best overall response (BOR) of CR or 
PR.  
For part 2, hypothesis testing of confirmed ORR in the EFF evaluated based on RECIST v1.1 by 
central site imaging facility for tumor assessment will be the primary efficacy analysis.  
The ORR in studied BGB-A317 combination treatment is assumed as 40% in patients with 
previously treated unresectable HCC. The historical rate in a similar population is estimated as 
18.8% for mono Lenvatinib (Kudo, 2018). The null and alternative hypotheses are set as follows:  
H0: ORR = 18.8% 
Ha: ORR > 18.8% 
A Simon’s 2 stage design will be used to test the superiority of studied combination treatment vs. 
the historical control. If the obtained 1-sided p-value is less than 0.025, it will be concluded that 


 
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the combination treatment statistically significantly increases ORR compared to the historical 
control. Therefore, the superiority of the combination treatment will be demonstrated.  
As stated in Section 2, if ≤6 responses are observed within the first 30 patients, the study will be 
terminated. 
The number and proportion of ORR will be summarized by dose and combined. The precision of 
the estimators will be assessed by two-sided Clopper-Pearson 95% confidence intervals (CI). 
Patients without post-baseline tumor assessment will not be included into EFF, and patients 
discontinued treatment due to early clinical PD or death before the first post treatment tumor 
assessment will be included into EFF and considered as 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 also be presented. 
The primary efficacy analysis will be conducted when mature response rate data have been 
observed, estimated as no more than 6 months after the last subject received the first dose of study 
drug. Additional efficacy analysis will be conducted approximately 12 months after the last subject 
received the first dose of study drug. 
6.4.2 Secondary Efficacy Endpoints 
Below analyses are all based on EFF population and will be analyzed by dose and combined. 
6.4.2.1 Response Rate 
 ORR assessed by investigators based on RECIST v1.1 
 ORR assessed by investigators and central site imaging facility for tumor assessment 
respectively based on mRECIST and iRECIST.  
 DCR assessed by investigators and central site imaging facility based on RECIST v1.1, 
mRECIST, and iRECIST 
ORR is defined as the proportion of subjects achieving a best overall response (BOR) of CR or 
PR.  
DCR is defined as the proportion of patients with BOR of CR, PR or SD. Patients without post-
baseline tumor assessment will be considered as failure in DCR.  
A point estimate and a 2-sided Clopper-Pearson 95% confident interval (CI) will be provided for 
ORR or DCR by dose and combined, respectively. 
6.4.2.2 Duration of Response (DOR) 
DOR is defined as the time interval between the date of the earliest qualifying response (CR or 
PR) and the date of PD or death (whichever occurs earlier). DOR analysis will only include 
responders.  


 
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DOR = (The earlier of PD or death date − The earlier of PR or CR date + 1) / 7 in weeks. 
The KM method will be used to estimate the key secondary endpoint DOR assessed by 
investigators and central site imaging facility based on RECIST v1.1, mRECIST, and iRECIST, 
and corresponding quantiles (including the medians), if estimable, in the responders. A two-sided 
95% CIs of median, if estimable, will be constructed with a generalized Brookmeyer and Crowley 
method (Brookmeyer and Crowley, 1982).  
The DOR censoring rule will follow the FDA Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics (FDA, 2018) with some modifications (See Appendix 
10.2).   
6.4.2.3 Progression Free Survival (PFS) 
PFS is defined as the time from the date of the first dose of study drug(s) to the date of the 
confirmed documentation of PD or death, whichever occurs first.  
PFS = (The earlier of PD or death date − Date of treatment initiation + 1) / 30.4375 in =months. 
PFS, assessed by investigators and central site imaging facility based on RECIST v1.1, mRECIST, 
and iRECIST, will be similarly analyzed in the efficacy evaluable population using the Kaplan-
Meier (KM) method as described above. KM method along with the corresponding 95% CI based 
on Greenwood’s formula (Greenwood, 1926) will be used to construct the PFS time point estimates 
which are defined as the percentages of patients in the analysis population who remain alive and 
progression-free at the specified time points (ie, 3, 6, or 12 month). KM curves will be constructed 
to provide a visual description of the PFS rate versus time.  
Censoring rule for PFS will follow DOR censoring rule (see Appendix 10.2). 
In addition, number of patients who received post-treatment anti-cancer therapies 
(surgery/procedure, radiation, or systemic therapies) and regiment names will be summarized. 
6.4.3 Subgroup Analyses 
Subgroup analysis on key efficacy endpoints (ORR, DOR, DCR, PFS) will be conducted to explore 
the consistence of efficacy across variety of subgroups, as appropriate (ie. when there is sufficient 
number of patients in the subgroup, otherwise relevant subgroups may be combined).  Subgroup 
analyses will be performed per RECIST v1.1 by both investigator and central site imaging facility. 
Subgroup variables may include, but not limited to,  
 age (< 65 vs. ≥ 65 years) 
 gender (female vs. male) 
 macrovascular invasion and/or extrahepatic spread (present vs. absent) 
 macrovascular invasion (present vs. absent) 
 extrahepatic spread (present vs. absent) 


 
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 hepatitis virus infection (HBV vs. HCV vs. uninfected) 
 ECOG PS (0 vs. 1) 
 Child-Pugh Classification Score (5 vs. 6) 
 alpha-fetoprotein (< 400 ng/mL vs. >= 400 ng/mL) 
 BCLC stage (Stage B vs. Stage C) 
 Prior liver loco-regional therapy (yes vs. no) 
 # of prior TACE loco-regional therapy (1 vs. 2+) 
Subgroup results in proportions will also be presented in forest plots. The subgroup variables and 
their respective categories are subject to change if warranted to better represent the data. 
6.5 
SAFETY ANALYSES 
The sponsor, leading investigator and maybe other investigators will establish a SMC for ongoing 
safety assessment throughout the study. The SMC charter will define the organization members 
and procedures. The SMC will evaluate safety data from Part 1 and decide the dose level for next 
group or if enroll more eligible patients, based on the safety data from the former dose level. The 
SMC will continue monitoring safety data during Part 2 periodically as needed. 
Since this study may start a new cohort with Lenvatinib at a reduced dose (Tis 200mg Q3W IV+ 
Len 8mg or 4mg QD PO), if so, we need to specify the dose level for all below safety analyses and 
the analyses will be conducted by dose (high vs.  low) and combined. High dose refers to Tis 
200mg Q3W IV + Len 12mg or 8mg OD PO, low dose refers to Tis 200mg Q3W IV + Len 8mg 
or 4mg OD PO. 
All subjects who are exposed to (or started receiving) any study drug (any component for the 
combination therapy) will be evaluated for safety by dose. Safety will be determined by the 
spontaneous reporting of AEs and by laboratory values (hematology, clinical chemistry, 
coagulation, and urinalysis). Vital signs, physical examinations, ECOG and ECGs findings will 
also be used in determining the safety profile. The severity of AEs will be graded according to the 
CTCAE v5.0. The incidence of DLT events and TEAEs will be reported as the number 
(percentage) of patients with DLT/TEAEs by system organ class (SOC) and preferred term (PT). 
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables), and changes from baseline will be 
determined for laboratory parameters and vital signs by dose. 
Patients who have an AE leading to treatment discontinuation will be followed until the event 
resolves, the investigator assesses the event as stable, the patient is lost to follow-up, or the patient 
starts a different antitumor therapy. 
6.5.1 Dose-Limiting Toxicity Analysis 
Dose-limiting toxicity (DLT) will be assessed among evaluable patients within 21 days after the 
first dose administration of lenvatinib plus tislelizumab at each dose level. For DLT assessment 


 
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decision, only DLTs occurring within 21 days will be evaluated. The following patients will not 
be considered evaluable for DLT, and will be replaced if needed to meet the minimum patient 
number required for safety evaluation: 
 Patients who withdraw or are withdrawn from the study before completing the DLT 
assessment window for reasons other than a DLT. 
 Patients receiving combination therapy who do not receive ≥ 75% of scheduled lenvatinib 
and ≥ 67% (approximately two-thirds) of scheduled tislelizumab during the DLT 
assessment window unless they experience a DLT. 
The DLT events will be summarized descriptively for each combination dosing level in the DLT 
evaluable analysis set. 
6.5.2 Extent of Exposure 
Extent of exposure to the study drug will be summarized descriptively by study drug, and by dose 
level with respect to the following: 
 
Number of treatment cycles received: defined as the total number of treatment cycles in which 
at least one dose of the study drug is administered  
 
Duration of exposure (months): defined as the duration (in month) from the date of the first 
dose to the last exposure of the study drug 
 
Total dose received per patient (mg): defined as the cumulative dose of the study drug during 
the treatment period of the study  
 Actual dose intensity (ADI) per patient (mg/day for Lenvatinib; mg/cycle for 
Tislelizumab): defined as sum of actual dose received by a patient divided by duration of 
treatment  
 Relative dose intensity (RDI) per patient (%): defined as the ratio of actual dose 
intensity(mg/day) and planned dose intensity  
The number (percentage) of patients requiring dose reduction will be summarized for Lenvatinib. 
The number (percentage) of patients requiring dose delay, dose interruption, and overdose will be 
summarized for Tislelizumab. Frequency of does delay and frequency of dose interruption will be 
summarized by categories (0, 1, ≥2). The cycle in which the first dose delay/interruption occurred 
will be summarized for Tislelizumab using descriptive statistics. The cycle in which the first dose 
reduction/interruption occurred will be summarized for Lenvatinib using descriptive statistics. 
Frequency of dose delay and interruption as well as reason for dose delay and interruption will be 
summarized descriptively for Tislelizumab. Frequency of dose reduction and interruption as well 
as reason for dose reduction and interruption will be summarized descriptively for Lenvatinib. 
Dose interruption is defined as any dose temporary discontinuation due to AE or held for 
procedure. Dose reduction for Lenvatinib is defined as any planned dose reduced from the 
original planned dose, regardless of reasons.  Dose missing is defined as any dose temporary 
discontinuation due to reasons other than AE or held for procedure. Overdose for Lenvatinib is 
defined as any dose excess compare with original planned dose based on RP2D determined in 


 
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part 1. Overdose for Tislelizumab is defined as any dose administered more than 200mg in each 
treatment cycle. If the patient misses any once dose of Lenvatinib and is able to take it within 12 
hours, this case should not belong to dose interruption or dose missing.  
6.5.3 Adverse Events  
AEs will be graded by the investigators using CTCAE v5.0. 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 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 had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug(s) and up to 30 days following study drug(s) 
discontinuation or initiation of new anticancer therapy, whichever occurs first. TEAE classification 
also applies to irAEs recorded up to 90 days after the last dose of tislelizumab, regardless of 
whether the patient starts a new anticancer therapy. Only those AEs that were treatment-emergent 
will be included in summary tables. All AEs, treatment emergent or otherwise, will be presented 
in patient data listings. 
An overview table, including the incidence of and the number of patients 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, 
TEAEs that led to Tislelizumab dose delay, dose interruption, overdose, and dose modification 
(dose delay or dose interruption), TEAEs that led to Lenvatinib dose interruption, dose missed, 
dose reduction, overdose, and dose modification (dose reduction or dose interruption), adjudicated 
immune-related TEAEs, and infusion related reactions will be provided. Treatment-related AEs 
include those events considered by the investigator to be related to study treatment or with missing 
assessment of the causal relationship.   
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT.  A patient will be counted only once by the highest severity grade according to 
CTCAE v.5.0 within an SOC and PT, even if the patient experienced more than 1 TEAE within a 
specific SOC and PT.  
The number (percentage) of patients with treatment-emergent SAEs, treatment-related TEAEs, 
TEAEs with grade 3 or above, treatment-related TEAE with grade 3 or above, treatment-related 
SAEs, TEAEs that led to death, Tislelizumab treatment-related TEAE leading to death,  Lenvatinib 
treatment-related TEAE leading to death, TEAEs that led to treatment discontinuation, TEAEs that 
led to Tislelizumab dose delay, dose interruption, overdose, and dose modification (dose delay or 
dose interruption), TEAEs that led to Lenvatinib dose interruption, dose missed, dose reduction, 
overdose, and dose modification (dose reduction or dose interruption), Tislelizumab treatment-
related TEAE leading to treatment discontinuation, Lenvatinib treatment-related TEAE leading to 
treatment discontinuation, Tislelizumab treatment-related TEAE leading to dose delay,  dose 
interruption, overdose, and dose modification (dose delay or dose interruption), Lenvatinib 
treatment-related TEAE leading to dose interruption, dose missed, dose reduction, overdose, and 


 
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dose modification (dose reduction or dose interruption), most frequently reported (incidence ≥5%) 
treatment-related TEAE for Tislelizumab,  most frequently reported (incidence ≥5% ) treatment-
related TEAE for Lenvatinib, most frequently reported (incidence ≥ 2 %) treatment-related TEAE 
with grade 3 or above for Tislelizumab, most frequently reported (incidence ≥ 2 %) treatment-
related TEAE with grade 3 or above for Lenvatinib, infusion related reactions (IRRs), IRRs with 
grade 3 or above, and IRRs leading to treatment discontinuation will be summarized by SOC and 
PT.  
6.5.4 Immune-related TEAEs 
 Immune-related TEAEs (  irTEAEs) will be summarized by irTEAE category.  
 irTEAEs with grade 3 or above by irTEAE category 
 irTEAEs leading to treatment discontinuation by category 
 irTEAEs leading to death by category 
 irTEAEs leading to dose delay and dose interruption by category 
 irTEAEs treated with glucocorticoids by category 
 irTEAEs treated with high dose glucocorticoids by category 
Patient data listings of all AEs, SAEs, AEs that led to death and AEs that led to treatment 
discontinuation will be provided. 
All deaths and causes of death will be reported, including those occurred during the study treatment 
period and those reported during the survival follow-up period after treatment 
completion/discontinuation. 
6.5.5 Laboratory Values 
Clinical laboratory (e.g., hematology, serum chemistry, coagulation, thyroid function and 
urinalysis) values will be evaluated for each laboratory parameter as appropriate. Abnormal 
laboratory values will be flagged and identified as those outside (above or below) the normal range. 
For all quantitative parameters listed in Table 1, the actual value and the change from baseline to 
each post-baseline visit and to the end of treatment will be summarized by visit using descriptive 
statistics (n, mean, standard deviation, median, minimum, maximum for continuous variables; n 
[%] for categorical variables).  
Laboratory parameters (Alkaline phosphatase, Alanine aminotransferase, Aspartate etc.) that are 
graded in NCI CTCAE (v. 5.0) will be summarized by shifts from baseline CTCAE grades to worst 
post-baseline grades. In the summary of laboratory parameters by CTCAE grade, parameters with 
CTCAE grading in both high and low directions will be summarized separately. Shift tables will 
be used to summarize the grade change from baseline to worst post baseline value with counts and 
percentages. 
Table1 Clinical Laboratory Assessments 


 
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Clinical Chemistry 
 
Hematology 
Coagulation 
Thyroid function  
Urinalysis 
Alkaline phosphatase* 
Hematocrit 
Prothrombin time 
or INR 
TSH 
Free T3 
Free T4 
Glucose  
Alanine 
aminotransferase* 
Hemoglobin* 
aPTT 
 
Protein* 
Aspartate 
aminotransferase* 
Platelet counts* 
 
 
Blood 
Albumin* 
WBC count* 
 
 
Ketones 
Total protein* 
Lymphocyte 
count* 
 
 
24-hour protein* 
Lactate dehydrogenase* Neutrophil 
count* 
 
 
Random 
protein/creatinine 
ratio* 
Total bilirubin* 
 
 
 
 
Direct bilirubin* 
 
 
 
 
Blood urea nitrogen or 
urea 
 
 
 
 
Potassium 
 
 
 
 
Sodium  
 
 
 
 
Corrected calcium 
 
 
 
 
Creatinine* 
 
 
 
 
Glucose 
 
 
 
 
CK 
 
 
 
 
CK-MB 
 
 
 
 
Lipase 
 
 
 
 
Serum amylase 
 
 
 
 
Note: parameters with * are our primary interests.  
Furthermore, to evaluate liver injury, potential Hy’s Law cases will also be summarized. 
6.5.6 Alpha-fetoprotein  
The actual value and change from baseline in alpha-fetoprotein will be summarized descriptively 
over time by visit. 
6.5.7 HBV DNA 
The actual value and change from baseline in HBV DNA will be summarized descriptively over 
time by visit. 
6.5.8 Vital Signs 
The change from baseline and Potentially Clinically Significant (PCS) vital signs in blood 
pressure, pulse rate, weight, temperature in Celsius will be summarized in descriptive statistics. 
Vital signs will be listed by patient and visit. 


 
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Blood pressure that are graded in NCI CTCAE (v. 5.0) will be summarized by shifts from baseline 
CTCAE grades to worst post-baseline grades.  
6.5.9 Physical Examination 
Physical examination will be assessed during screening and study visits. Physical examination 
findings prior to first dose of study treatment will be collected in medical history, clinically 
significant abnormalities found in physical examination will be reported in adverse events.  No 
separate physical examination data will be collected and reported in this study. 
6.5.10 Electrocardiograms (ECG) 
ECG will be performed at the baseline and multiple time points (refer the time points to the 
protocol study assessments and procedures schedule) after the start of treatment. Observed and 
change from baseline in ECG will be summarized descriptively over time by visit. Observed post-
baseline QTc interval measurement and increase from baseline by pre-specified thresholds will be 
summarized by category.  
6.5.11  Eastern Cooperative Oncology Group (ECOG) 
A shift table from baseline to worst post-baseline in ECOG performance status will be 
summarized.  
6.6 
 PHARMACOKINETIC ANALYSES 
Blood samples for PK analysis of tislelizumab will be collected at specified time points (refer to 
Appendix 2 of protocol). The actual collection date and time of each blood sample will be recorded. 
The timing of PK samples may be altered and/or PK samples may be obtained at additional time 
points upon sponsor approval to ensure thorough PK monitoring.  
The tislelizumab concentration data collected sparsely at predose and around Tmax will be tabulated 
and summarized by visit/cycle and dose level. Descriptive statistics will include means, standard 
deviations, medians, and ranges as appropriate. 
Additional PK, including population PK analyses, may be conducted as appropriate, and the results 
of such analysis may be reported separately from the CSR. 
6.7 
IMMUNOGENIC ANALYSES 
Human anti-drug antibodies (ADA) to tislelizumab will be assessed during the study as defined in 
the protocol. 
ADA attributes: 
 
Treatment boosted ADA is defined as ADA positive at baseline that was boosted to a 4-
fold or higher level following drug administration.  
 
Treatment-induced ADA is defined as ADA negative at baseline and ADA positive post-
baseline.  


 
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 
Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more time 
points during treatment or follow-up, where the first and last ADA positive samples are 
separated by 16 weeks or longer; or detected in the last time point. 
 
Transient ADA response is defined as a treatment-induced response that is not considered 
persistent. 
 
Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological activity. 
ADA response endpoints: 
 ADA incidence is defined as sum of treatment-emergent ADA, which include both 
treatment-induced and treatment-boosted ADA-positive patients, as a proportion of the 
ADA evaluable population.  
 ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point. 
Samples to assess anti-tislelizumab-antibodies will be collected. The immunogenicity results will 
be summarized using descriptive statistics by the number and percentage of patients who develop 
detectable ADA.  The incidence of positive ADA and neutralizing ADA will be reported for 
evaluable patients.  The effect of immunogenicity on PK, efficacy, and safety may be evaluated if 
data allow. 
6.8 
EXPLORATORY EFFICACY ENDPOINT 
Overall Survival (OS) 
OS is defined as the time (in month) from the date of the first dose of study drug(s) to the date of 
death. Patients who remained alive at data cutoff or discontinuation of the study (discontinued 
study due to reasons other than “Death”) will be censored at the time of the last date the patient 
was known to be alive.  
The OS time point estimates, defined as the percentages of patients in the analysis population who 
remain alive at the specified time points (e.g., 3, 6 or 12 month), will be estimated using the KM 
method along with the corresponding 95% CI constructed using Greenwood’s formula. The KM 
estimates of OS will be plotted over time. 
6.9 
BIOMARKER ANALYSES 
Not applicable. 
 
7 
INTERIM ANALYSIS 
For Part 2, one futility interim analysis will be conducted based on the Simon’s 2-stage design (see 
Section 6.4.1 for details). 
 


 
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8 
 CHANGES IN THE PLANNED ANALYSIS 
NA 


 
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9 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time, Biometrics 1982; 38(1): 29-
41. 
Clopper, C. and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of the binomial, 
Biometrika 1934; 26: 404-413. 
Collett D. Modelling survival data in medical research. New York: Chapman & Hall; 1994. 
Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. United States Department of 
Health and Human Services, National Institutes of Health, National Cancer Institute, Washington, DC, 
USA, Nov 27, 2017. 
Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al.  New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 2009; 45:228-47. 
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).  
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical Patients (London: 
Her Majesty’s Stationery Office). 1926; 33:1-26. 
International Conference on Harmonization Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95). July 1996.  
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of American 
Statistical Association. 1958; 53:457-81. 
Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Piscaglia, F., ... & Blanc, J. F. (2018). Lenvatinib 
versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised 
phase 3 non-inferiority trial. The Lancet, 391(10126), 1163-1173.Lencioni, Riccardo, and Josep M. Llovet. 
"Modified RECIST (mRECIST) assessment for hepatocellular carcinoma." Seminars in liver disease. Vol. 
30. No. 01. © Thieme Medical Publishers, 2010.Shankar, G., Arkin, S., Cocea, L. et al. Assessment and 
Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized 
Terminology and Tactical Recommendations. AAPS J (2014) 16: 658. 
Seymour, Lesley, et al. "iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics." The Lancet Oncology 18.3 (2017): e143-e152. 
Simon, R. (1989). Optimal Two-stage Design for Phase II Clinical Trials. Controlled Clinical Trials, 10, 1-
10. 
 
 
 
 
 
 
 


 
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10 APPENDIX 
10.1 
IMPUTATION OF MISSING/PARTIALLY MISSING DATES 
Missing data will not be imputed unless otherwise specified. The imputation rule for the safety 
analyses will be used to address the issues with partial dates.  
 
i) 
When the start date or end date of an adverse event is partially missing, the date will be 
imputed to determine whether the adverse event is treatment-emergent. When in doubt, the 
adverse event will be considered treatment emergent by default. The following rules will 
be applied to impute partial dates for adverse events: 
 
If start date of an adverse event is partially missing, impute as follows: 
 If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
 If both month and day are missing and year ≠ year of treatment start date, then set to January 
01 
 If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date 
 If day is missing and month and year ≠ month and year of treatment start date, the set to 
first of the month 
If year of the start date is missing, or start date is completely missing, do not impute. 
If end date of an adverse event is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
If year of the end date is missing, end date is completely missing, do not impute 
ii) 
When the start date or end date of a medical or disease history/medication/therapy 
(systematic or radiotherapy)/surgery or procedure is partially missing, the date will be 
imputed to determine whether the medical or disease history/medication/therapy 
(systematic or radiotherapy)/surgery or procedure is prior or concomitant or post. The 
following rules will be applied to impute partial dates: 
If the start date is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
If the end date is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 


 
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If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
 If the date is known to be prior study treatment, e.g. for medical history, disease history, or prior 
therapies etc., the imputed date should be compared against the first dose date. If it is after the first 
dose date, then replace the imputed date with the first dose date – 1. 
If the date is known to be post study treatment, e.g. for post-treatment subsequent therapies, the 
imputed date should be compared against the last dose date. If it is before the last dose date, then 
replace the imputed date with the last dose date + 1. 
iii) 
Deaths 
If death date is partial, impute death date as the first day of the month, and JAN as the month. if 
month is missing, then take the max of (the imputed date and the last known alive date +1); if death 
date is completely missing, set as the last known alive date +1. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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10.2 HANDLING OF CENSORING TIME TO EVENT DATA 
Table 2 shows the primary censoring rules for the derivation of PFS using RECIST v1.1 criteria.  
The censoring rule for time to event data (DOR, PFS)  using RECIST v1.1 will follow FDA 
Guidance for Industry Clinical Study Endpoints for the Approval of Cancer Drugs and Biologics 
(Food and Drug Administration Center for Drug Evaluation and Research ; Center for Biologics 
Evaluation and Research, 2018); see the following table.  
 
Table 2 Censoring Rules for Analysis of Progression-Free Survival Per RECIST v1.1 
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of the first dose  
Censored 
2 
Progression documented on scheduled visit or 
between scheduled visits 
Date of first radiologic PD assessment  
Progressed 
3 
No progression at the time of data cut-off or 
withdrawal from study 
Date 
of 
last 
adequate 
radiologic 
assessment prior to or on date of data cut-
off or withdrawal from study 
Censored 
 
4 
New anticancer treatment started 
Date 
of 
last 
adequate 
radiologic 
assessment prior to or on date of new 
anticancer treatment 
Censored 
5 
Death before first PD assessment 
Date of death 
Progressed 
6 
Death between adequate assessment visits* 
Date of death 
Progressed 
7 
Death or progression after more than one 
missed visit** 
Date 
of 
last 
adequate 
radiologic 
assessment prior to missing occurred 
Censored 
Abbreviations: CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease, 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined by 
investigators. 
** More than one missed visit is defined as the duration between the last tumor assessment and death or PD is longer 
than 13 weeks week in the first 18 weeks, and longer than 19 weeks thereafter. 
 
Details of censoring rules for time to event data (DOR, PFS) using iRECIST and mRECIST, please 
see Supplemental Data Definition.