Conditions: Triple Negative Breast Cancer Endometrial Cancer Solid Tumor, Unspecified, Adult Colorectal Cancer
Keywords: Breast cancer Triple negative Her2- HR- ER- PR- Her2 negative HR negative ER negative PR negative TNBC VEGF VEGFR Endometrial cancer Colon Rectal mCRC Colorectal
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 52
Healthy volunteers: no

Brief summary:
This is an open-label, multi-center, non-randomized, Phase 1b/2 study to assess the safety and efficacy of fruquintinib in combination with tislelizumab in patients with locally advanced or metastatic solid tumors. This study will be conducted in 2 parts; a Safety Lead-in Phase (Part 1) and a Dose Expansion Phase (Part 2).

The Safety Lead-in Phase, open to any-comer solid tumors, will determine the RP2D. The RP2D will be administered to 3 cohorts of patients in the Dose Expansion Phase.

* Cohort A: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-treated)
* Cohort B: Advanced or Metastatic Triple Negative Breast Cancer (TNBC) (IO-Naïve)
* Cohort C: Advanced or Metastatic Endometrial Cancer (EC) (IO-Naïve)
* Cohort D: Advanced or Metastatic Colorectal Cancer (mCRC) (IO-Naïve)

Detailed description:

Arms:
arm 1: Approximately 6-12 patients with locally advanced or metastatic solid tumors will be enrolled to receive fruquintinib in combination with tislelizumab and assessed for DLTs during the 28-day DLT observation period arm 2: Patients will be enrolled to one of the following expansion cohorts:

* Cohort A: TNBC (immuno-oncology \[IO\]-treated in the metastatic setting)
* Cohort B: TNBC (IO-Naïve in the metastatic setting)
* Cohort C: EC
* Cohort D: MSS CRC

Interventions: intervention 1: Fruquintinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: Oral VEGFR inhibitor intervention 2: PD-1 inhibitor

Protocol document:
Prot_000.pdf: 
Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
 
P a ge 1  
 
C O N FI D E N TI A L  
 
 
 
Cli nic al St u d y Pr ot oc ol  
A N O P E N -L A B E L , P H A S E 1 b/ 2  S T U D Y T O E V A L U A T E T H E S A F E T Y A N D 
E F FI C A C Y O F F R U Q UI N TI NI B I N C O M BI N A TI O N WI T H TI S L E LI Z U M A B I N 
P A TI E N T S  WI T H A D V A N C E D S O LI D T U M O R S   
 
S h ort Title  
A P hase 1 b/ 2 St u d y of Fr u q ui nti ni b i n C o m bi nati o n wit h 
Tisleliz u ma b i n A d va nce d S oli d T u m ors  
I n vesti g ati o n al Pr o d uct(s): 
Fr u q ui nti ni b ( H M P L -0 1 3) a n d Tisleliz u ma b ( B G B -A 3 1 7)  
Pr ot oc ol N u m ber:  
2 0 2 0 -0 1 3 -0 0 U S 3  
Cli nic al P h ase:  
1 b/ 2  
D ate of Iss ue:  
0 6 Dece m b er  2 0 2 3  
A me n d me nt:  
5  
Versi o n:  
1  
S p o ns or:  
H U T C H M E D Li mite d  
B uil di n g 4, 7 2 0 Cail u n R oa d, C hi na  
( S ha n g hai) Pil ot Free Tra de Z o ne  
S ha n g hai, C hi na, 2 0 1 2 0 3  
 
htt p:// w w w. h utc h -me d.c o m  
Re g ul at or y A ge nc y I de ntifier 
N u m ber(s):  
 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is t he c o nfi de ntial a n d pr o priet ar y i nf or mati o n of 
H U T C H M E D Li mite d a n d e xce pt as ma y b e re q uire d b y a p plica ble l a ws or re g ulati o n, ma y 
n ot be discl ose d t o ot hers wit h o ut pri or writte n pe r missi o n of H U T C H M E D  Li mite d . 
 
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STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by ICH E6(R2), and all applicable local and national regulatory 
requirements.  Enrollment at any clinical study site may not begin prior to that site receiving 
approval from the ethics committee of record for the protocol and all materials provided to 
potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The principal investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard 
to the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
 
P a ge 3  
 
C O N FI D E N TI A L  
 
 
S P O N S O R’ S A P P R O V A L   
Title  
A n O pe n -La b el, P hase 1 b/ 2 St u d y t o E val uate t he Safet y a n d Efficac y of Fr u q ui nti ni b 
i n C o m bi nati o n wit h Tisleliz u ma b i n Patie nts wit h A d va nce d S oli d T u m ors  
Pr ot oc ol N u m ber  
2 0 2 0 -0 1 3 -0 0 U S 3  
D ate of Iss ue  
0 6 Dece m ber  2 0 2 3  
A m e n d m e nt  
5  
Versi o n  
1  
T he desi g n of t his st u d y as o utli ne d b y t his pr ot oc ol has bee n re vie we d a n d a p pr o ve d b y t he 
sp o ns or’s res p o nsi ble pers o n nel as i n dicate d i n t he si g nat ure ta ble bel o w.  
N a m e:  
Title:  
 
 
 
H U T C H M E D  I nter nati o nal C or p . 
Si g n at ure:  
See a p pe n de d si g n at ure p a ge   
D ate:  [ D D M o nt h Y Y Y Y] 
 
P P D
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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2020-013-00US3 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6(R2) 
• To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site 
• To obtain informed consent, and updated consent in the event of new information or 
amendments, from all participants enrolled at my study site prior to initiating any 
study -specific procedures or administering investigational products to those participants 
• To maintain records of each subject’s participation and all data required by the protocol 
 
Name: 
Title:  
Institution:  
 
 
 
Signature:  
Date [DD Month YYYY]:   
 
 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
 
P a ge 5  
 
C O N FI D E N TI A L  
 
 
A M E N D M E N T S U M M A R Y   
T his Cli nical St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3 A me n d me nt 5 re places Cli nical St u d y Pr ot oc ol 
2 0 2 0 -0 1 3 -0 0 U S 3  A me n d me nt 4 .  T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he 
criteria set f ort h i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia m e nt a n d t he 
C o u ncil of t he E ur o pea n U ni o n.  
T he pri mar y p ur p ose of A me n d me nt 5 is t o pr o vi de n otificati o n of ter mi nati o n of t his st u d y u p o n 
t he strate gic e v al uati o n of t he cli nical de vel o p m e nt of fr u q ui nti ni b i n t he U nite d States .  T his 
c ha n ge is n ot base d o n a n y c o ncer n f or p atie nt safet y or efficac y relati ve t o fr u q ui nti ni b a n d/ or 
tisleliz u ma b treat me nt.  
 
  T he maj or  c ha n ges i n c or p orate d i n A me n d me nt 5  relati ve 
t o A me n d me nt 4  are s u m marize d bel o w.  E dit orial a n d f or matti n g c ha n ges are n ot i ncl u de d i n t his 
s u m mar y.  S u m maries of pri or a me n d me nts are a v aila ble i n A p pe n di x 1 4 . 
Secti o n N u m ber  
S u m m ar y of C h a n ge  
R ati o n ale f or C h a n ge  
C o ver Pa ge, S p o ns or’s A p pr o val, 
D oc u me nt Hist or y, a n d Hea der  
A d mi nistrati ve u p dates were ma de t o 
reflect A me n d me nt 5 . 
A d mi nistrati ve u p dates were ma d e 
t o reflect A me n d me nt  5 . 
Secti o n 1. 2  –  Sc he d ule of E ve nts , 
Ta ble 1 ; Secti o n 6. 1. 4 –  Treat me nt 
Peri o d; Secti o n 6. 1. 2 2 –  S ur vi val 
F oll o w -u p Peri o d ; a n d 
Secti o n  6. 3  –  St u d y Ter mi nati o n.  
La n g ua ge was a d de d detaili n g t he 
u p date d  ti meli ne f or t he last da y t o 
i nitiate a ne w treat me nt c ycle, 
treat me nt disc o nti n uati o n, e n d of 
treat me nt visit, a n d Safet y F oll o w -u p 
visit.  
T hese u p dates were ma de t o 
acc o m m o date  t he pr ocess of st u d y 
ter mi nati o n. 
Secti o n 1. 2  –  Sc he d ule of E ve nts , 
Ta ble 2  a n d Secti o n  6. 1. 1 9 –  P K 
Assess me nts  
La n g ua ge was a d de d t o i n dicate 
ter mi nati o n of P K a n d 
im m u n o ge nicit y sa m ple c ollecti o n 
after 3 1 Dece m ber 2 0 2 3.  
T his u p date was ma de t o 
acc o m m o date t he pr ocess of st u d y 
ter mi nati o n. 
 
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DOCUMENT HISTORY  
Amendment 
Version 
Date of Issue 
Original 
1 
12 Oct 2020 
Amendment 1 
1 
16 Dec 2020 
Amendment 2 
1 
01 Sep 2021 
Amendment 3 
1 
07 Feb 2022 
Amendment 4 
1 
02 Feb 2023 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
AMENDMENT SUMMARY ........................................................................................................ 5 
DOCUMENT HISTORY............................................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................... 7 
LIST OF TABLES ....................................................................................................................... 12 
LIST OF FIGURES ..................................................................................................................... 13 
LIST OF APPENDICES .............................................................................................................. 13 
LIST OF ABBREVIATIONS ...................................................................................................... 15 
1 
SYNOPSIS ....................................................................................................................... 19 
1.1 
Study Schematic............................................................................................................ 23 
1.2 
Schedule of Events ........................................................................................................ 23 
2 
INTRODUCTION ........................................................................................................... 29 
2.1 
Study Rationale ............................................................................................................. 29 
2.2 
Background ................................................................................................................... 30 
2.2.1 
Target Indications and Populations ............................................................................ 30 
2.2.1.1 
Triple Negative Breast Cancer ................................................................................ 30 
2.2.1.2 
Endometrial Cancer ................................................................................................ 30 
2.2.1.3 
Colorectal Cancer.................................................................................................... 31 
2.2.2 
Description of Fruquintinib........................................................................................ 31 
2.2.2.1 
Fruquintinib Administration Regimen .................................................................... 31 
2.2.2.2 
Fruquintinib Justification for Dosing Strategy ....................................................... 31 
2.2.3 
Description of Tislelizumab ....................................................................................... 32 
2.2.3.1 
Tislelizumab Administration Regimen ................................................................... 32 
2.2.3.2 
Tislelizumab Justification for Dosing Strategy....................................................... 32 
2.2.4 
Rationale for the Starting Combination Doses .......................................................... 33 
2.2.5 
Supportive Nonclinical Data ...................................................................................... 34 
2.2.5.1 
Fruquintinib............................................................................................................. 34 
2.2.5.2 
Tislelizumab ............................................................................................................ 35 
2.2.6 
Supportive Clinical Data ............................................................................................ 36 


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2.2.6.1 
Fruquintinib............................................................................................................. 36 
2.2.6.2 
Tislelizumab ............................................................................................................ 40 
2.2.7 
Rationale for Fruquintinib and Tislelizumab in Combination ................................... 43 
2.2.7.1 
Triple Negative Breast Cancer ................................................................................ 43 
2.2.7.2 
Endometrial Cancer ................................................................................................ 45 
2.2.7.3 
Colorectal Cancer.................................................................................................... 45 
2.2.8 
Rationale for Biomarker Strategy .............................................................................. 46 
2.3 
Benefit:Risk Assessment .............................................................................................. 48 
2.3.1.1 
Risk Assessment ..................................................................................................... 48 
2.3.1.2 
Benefit Assessment ................................................................................................. 54 
2.3.1.3 
Overall Benefit:Risk Conclusion ............................................................................ 55 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 56 
4 
STUDY PLAN ................................................................................................................. 58 
4.1 
Study Design ................................................................................................................. 58 
4.1.1 
Part 1: Safety Lead-in Phase ...................................................................................... 58 
4.1.2 
Part 2: Dose Expansion Phase.................................................................................... 59 
4.1.3 
Assessment of Dose-Limiting Toxicity ..................................................................... 61 
4.1.4 
Dose-Limiting Toxicity Definition ............................................................................ 61 
4.2 
Design Rationale ........................................................................................................... 62 
5 
POPULATION ................................................................................................................ 63 
5.1 
Definitions..................................................................................................................... 63 
5.2 
Inclusion Criteria .......................................................................................................... 63 
5.3 
Exclusion Criteria ......................................................................................................... 66 
6 
STUDY CONDUCT ........................................................................................................ 70 
6.1 
Study Procedures .......................................................................................................... 70 
6.1.1 
Informed Consent....................................................................................................... 70 
6.1.2 
Screening Period ........................................................................................................ 70 
6.1.3 
Enrollment.................................................................................................................. 70 
6.1.4 
Treatment Period ........................................................................................................ 70 
6.1.5 
Medical History ......................................................................................................... 71 
6.1.6 
Tumor Diagnosis and Treatment History .................................................................. 71 
6.1.7 
Demographics ............................................................................................................ 71 
6.1.8 
Concomitant Medication and Procedures .................................................................. 71 


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6.1.9 
Comprehensive Physical Examination ...................................................................... 71 
6.1.10 
Limited Physical Examination ................................................................................... 71 
6.1.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........................ 72 
6.1.12 
Vital Signs .................................................................................................................. 72 
6.1.13 
Laboratory Evaluations .............................................................................................. 72 
6.1.13.1 
Hematology ............................................................................................................. 72 
6.1.13.2 
Blood Chemistry ..................................................................................................... 72 
6.1.13.3 
Blood Amylase and Lipase ..................................................................................... 73 
6.1.13.4 
Fasting Lipid Panel ................................................................................................. 73 
6.1.13.5 
Coagulation Indicators ............................................................................................ 73 
6.1.13.6 
Thyroid Function .................................................................................................... 73 
6.1.13.7 
Urinalysis ................................................................................................................ 73 
6.1.13.8 
Pregnancy Test ........................................................................................................ 73 
6.1.13.9 
Virological Screening ............................................................................................. 73 
6.1.14 
Electrocardiograms Monitoring ................................................................................. 74 
6.1.15 
Echocardiogram/Multigated Acquisition Scan .......................................................... 74 
6.1.16 
Anti-Tislelizumab Antibody Test .............................................................................. 74 
6.1.17 
Tumor Sample Collection .......................................................................................... 75 
6.1.17.1 
Archived Tumor Sample ......................................................................................... 75 
6.1.18 
Tumor Evaluation/Imaging ........................................................................................ 75 
6.1.19 
Pharmacokinetics Assessments .................................................................................. 76 
6.1.20 
End of Treatment Visit............................................................................................... 76 
6.1.21 
Safety Follow-up Period ............................................................................................ 76 
6.1.22 
Survival Follow-up Period ......................................................................................... 77 
6.1.23 
End of Study .............................................................................................................. 77 
6.2 
Discontinuation or Withdrawal ..................................................................................... 77 
6.2.1 
Individual Subjects..................................................................................................... 77 
6.2.1.1 
Permanent Discontinuation of Treatment ............................................................... 77 
6.2.1.2 
Withdrawal From Study .......................................................................................... 78 
6.2.1.3 
Replacement of Subjects ......................................................................................... 78 
6.2.1.4 
Subjects Lost to Follow-up ..................................................................................... 78 
6.2.2 
Stopping Rules ........................................................................................................... 78 
6.2.2.1 
Part 1 (Safety Lead-in) ............................................................................................ 78 


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6.2.2.2 
Part 2 (Dose Expansion) ......................................................................................... 79 
6.3 
Study Termination ........................................................................................................ 79 
7 
STUDY INTERVENTIONS ........................................................................................... 80 
7.1 
Description of Products................................................................................................. 80 
7.1.1 
Fruquintinib................................................................................................................ 80 
7.1.1.1 
Formulation, Packaging, Storage, and Handling .................................................... 80 
7.1.1.2 
Dosing and Administration ..................................................................................... 80 
7.1.2 
Tislelizumab ............................................................................................................... 81 
7.1.2.1 
Formulation, Packaging, Storage, and Handling .................................................... 81 
7.1.2.2 
Dosing and Administration ..................................................................................... 82 
7.2 
Drug Accountability...................................................................................................... 82 
7.2.1 
Assignment/Disposal (Study Site) ............................................................................. 82 
7.2.2 
Assignment/Return (Subject) ..................................................................................... 83 
7.3 
Assessment and Verification of Compliance ................................................................ 83 
7.4 
Prior and Concomitant Therapies ................................................................................. 83 
7.4.1 
Prohibited Therapies .................................................................................................. 83 
7.4.2 
Medications to Be Used With Caution ...................................................................... 84 
7.4.3 
Permitted Therapies ................................................................................................... 84 
7.4.4 
Drug-Drug Interactions .............................................................................................. 85 
7.4.5 
Rescue Therapies ....................................................................................................... 86 
7.5 
Dose Delay, Interruption, or Modification ................................................................... 86 
7.5.1 
Dose Modification for Tislelizumab .......................................................................... 87 
7.5.2 
Dose Modification for Fruquintinib ........................................................................... 87 
7.5.3 
Fruquintinib Dose Modification Guidance ................................................................ 87 
7.5.3.1 
Fruquintinib Dose Modification Sequence for General Hematologic and Non-
Hematologic Toxicity ............................................................................................. 87 
7.5.3.2 
Fruquintinib Dose Modifications for Potential Risks and Important Identified Risks
 ................................................................................................................................ 88 
7.5.4 
Dose Management for Tislelizumab .......................................................................... 92 
8 
SAFETY MONITORING .............................................................................................. 100 
8.1 
Definitions................................................................................................................... 100 
8.1.1 
Adverse Event .......................................................................................................... 100 
8.1.2 
Serious Adverse Event ............................................................................................. 100 


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8.2 
Adverse Event Reporting ............................................................................................ 101 
8.2.1 
Adverse Event Reporting Period ............................................................................. 101 
8.2.2 
Expedited Reporting ................................................................................................ 101 
8.3 
Definition of a Suspected Unexpected Serious Adverse Reaction ............................. 102 
8.4 
Definition of Immune-Mediated Adverse Events ....................................................... 102 
8.5 
Eliciting Adverse Events............................................................................................. 103 
8.6 
Assessment of Severity ............................................................................................... 103 
8.7 
Causality Assessment.................................................................................................. 104 
8.8 
Documenting Adverse Events..................................................................................... 104 
8.8.1 
Diagnosis versus Symptoms and Signs.................................................................... 105 
8.8.2 
Adverse Events Occurring Secondary to Other Events ........................................... 105 
8.8.3 
Persistent or Recurrent Adverse Events ................................................................... 105 
8.8.4 
Abnormal Laboratory Values or Abnormal Vital Signs .......................................... 105 
8.8.5 
Preexisting Medical Conditions ............................................................................... 106 
8.8.6 
Pregnancy ................................................................................................................. 106 
8.8.7 
Worsening of Solid Tumor ...................................................................................... 106 
8.8.8 
Death ........................................................................................................................ 106 
8.9 
Duration of Follow-up for Adverse Events ................................................................ 107 
8.10 
Overdose ..................................................................................................................... 107 
9 
STATISTICAL ANALYSIS ......................................................................................... 108 
9.1 
Statistics and Analysis Method ................................................................................... 108 
9.1.1 
Statistical Hypothesis ............................................................................................... 108 
9.1.2 
Sample Size Rationale ............................................................................................. 108 
9.1.2.1 
Safety Lead-In Phase ............................................................................................ 108 
9.1.2.2 
Dose Expansion Phase .......................................................................................... 108 
9.1.3 
Analysis Sets ............................................................................................................ 109 
9.2 
Statistical Analyses ..................................................................................................... 110 
9.2.1 
Subject Disposition .................................................................................................. 110 
9.2.2 
Demographic and Other Baseline Characteristics ................................................... 110 
9.2.3 
Prior and Concomitant Medications ........................................................................ 110 
9.2.4 
Efficacy Analysis ..................................................................................................... 111 
9.2.4.1 
Primary Efficacy Analysis .................................................................................... 111 
9.2.4.2 
Secondary Efficacy Analysis ................................................................................ 111 


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9.2.5 
Safety Analysis ........................................................................................................ 112 
9.3 
Pharmacokinetics Analysis ......................................................................................... 113 
9.4 
Immunogenicity Analysis ........................................................................................... 113 
9.5 
Other Exploratory Analyses ........................................................................................ 113 
9.6 
Interim Analyses ......................................................................................................... 113 
10 
ETHICAL CONSIDERATIONS ................................................................................... 114 
10.1 
Good Clinical Practice ................................................................................................ 114 
10.2 
Ethics Review ............................................................................................................. 114 
10.3 
Informed Consent........................................................................................................ 114 
10.4 
Data Privacy ................................................................................................................ 115 
10.5 
Disclosure ................................................................................................................... 116 
10.6 
Data Quality Assurance .............................................................................................. 116 
10.7 
Biological Specimens and Data .................................................................................. 116 
11 
OVERSIGHT ................................................................................................................. 117 
11.1 
Independent Monitoring.............................................................................................. 117 
11.1.1 
Safety Review Committee ....................................................................................... 117 
11.2 
Quality Control and Assurance ................................................................................... 117 
11.2.1 
Monitoring ............................................................................................................... 117 
11.2.2 
Audits ....................................................................................................................... 118 
11.2.3 
Records .................................................................................................................... 118 
11.2.3.1 
Data Capture and Management ............................................................................. 118 
11.2.3.2 
Source Documentation .......................................................................................... 119 
11.2.3.3 
Records Retention ................................................................................................. 119 
11.3 
Study Termination or Study Site Closure ................................................................... 119 
12 
PUBLICATION POLICY ............................................................................................. 121 
13 
FINANCING AND INSURANCE ................................................................................ 122 
14 
REFERENCES .............................................................................................................. 123 
15 
APPENDICES ............................................................................................................... 130 
 
LIST OF TABLES  
Table 1 
Schedule of Events for Study 2020-013-00US3 .................................................. 24 
Table 2 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments ......................................................................................................... 28 


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Table 3 
Risk Assessment (List of Risks as per Current IB [Edition 13.0]) ...................... 48 
Table 4 
Objectives and Endpoints for Study 2020-013-00US3 ........................................ 56 
Table 5 
Investigational Treatments Used in This Study ................................................... 80 
Table 6 
Fruquintinib Starting Dose Reductions ................................................................ 87 
Table 7 
Fruquintinib Dose Modifications for Hematologic and Non-Hematologic Toxicity
.............................................................................................................................. 88 
Table 8 
Fruquintinib Dose Modifications for Potential Risks .......................................... 88 
Table 9 
Fruquintinib Dose Modifications for Dermatological Toxicities ........................ 89 
Table 10 
Fruquintinib Dose Modifications for Proteinuriaa ............................................... 89 
Table 11 
Fruquintinib Dose Modifications for Hypertension ............................................. 90 
Table 12 
Fruquintinib Dose Modifications for Decreased Platelet Count .......................... 91 
Table 13 
Fruquintinib Dose Modifications for Hemorrhage at Any Site ........................... 91 
Table 14 
Fruquintinib Dose Modifications for Abnormal Liver Function ......................... 92 
Table 15 
Examples of Immune-Mediated Adverse Events .............................................. 102 
Table 16 
Estimated ORR and 2-Sided 95% Confidence Intervals ................................... 109 
Table 17 
Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions) .............................................................................................................. 140 
Table 18 
Time Point Response: Patients with Non-Target Lesions Only ........................ 141 
Table 19 
Best Overall Response When Confirmation of Complete Response and Partial 
Response is Required ......................................................................................... 142 
Table 20 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab ....................................................................................................... 157 
 
LIST OF FIGURES  
Figure 1 
Study Schematic................................................................................................... 23 
Figure 2 
Severe or Serious Hemorrhagic Events Management Flow Chart .................... 150 
Figure 3 
Schema From American Heart Association/American College of Cardiology for 
Controlling Hypertension in Adults ................................................................... 152 
 
LIST OF APPENDICES  
Appendix 1 
COVID-19 Risk Assessment ............................................................................. 131 
Appendix 2 
Eastern Cooperative Oncology Group Performance Status ............................... 133 
Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ........................ 134 
Appendix 4 
Medications to Be Used With Caution During Treatment With fruquintinib ... 145 


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Appendix 5 
Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) .................. 146 
Appendix 6 
Clinical Management of Severe or Serious Hemorrhagic Events ..................... 148 
Appendix 7 
Management of Hypertension in Patients Receiving Fruquintinib .................... 151 
Appendix 8 
Conversion Tables for Urinalysis Results.......................................................... 154 
Appendix 9 
Immune-Mediated Adverse Event Evaluation and Management ...................... 155 
Appendix 10 Management of Adverse Events of Special Interest for Tislelizumab .............. 157 
Appendix 11 Cockcroft-Gault Formulas ................................................................................. 160 
Appendix 12 New York Heart Association Function Classification ....................................... 161 
Appendix 13 Prohibited Concomitant Medications that Have a Known Risk of QT prolongation 
and/or Torsades de Pointes (TdP) ...................................................................... 162 
Appendix 14 Amendment History ........................................................................................... 165 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-PD-1 
anti-programmed cell death protein-1 antibody 
anti-PD-L1 
anti-programmed cell death protein-L1 checkpoint pathway 
anti-VEGF  
anti-vascular endothelial growth factor 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society for Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCinf  
area under the curve from time 0 extrapolated to infinite time  
BCRP 
breast cancer resistant protein 
BOR 
best overall response 
BP 
blood pressure 
CAP 
College of American Pathologists 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CK-MB 
creatine kinase-MB 
CI 
confidence interval 
CL 
Clearance 
Cmax  
maximum observed concentration 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
CYP3A 
cytochrome P450, family 3, subfamily A 
CYP3A4 
cytochrome P450, family 3, subfamily A4 
DCR 
disease control rate  
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response  


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Abbreviation 
Definition 
EC 
endometrial cancer 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
endothelial growth factor receptor 
ER 
estrogen receptor 
ER/PGR 
estrogen receptor/progesterone receptor (abbreviated ER/PR in ASCO-CAP guidelines) 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEP 
gene expression profile 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
IC50 
inhibitory concentration 
ICF 
informed consent form  
ICH 
International Council for Harmonisation 
ICI 
immune checkpoint inhibitor 
IEC 
institutional ethics committee 
IgG 
immunoglobulin G 
imAE 
immune-mediated adverse event 
INR 
international normalized ratio 
IO 
immuno-oncology 
IRB 
institutional review board 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LVEF 
left ventricular ejection fraction 
M11 
desmethylation product, HM5025423 
MATE 
multidrug and toxin extrusion 
mBC 
metastatic breast cancer 
mCRC 
metastatic colorectal cancer 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
mismatch repair 
MSI 
microsatellite instability 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
no observed adverse effect level 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
OAT 
organic anion transporter 
OATP1B 
organic anion transporting polypeptide 1b 
OCT2 
organic cation transporter 2 
ORR 
objective response rate  
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PFS 
progression-free survival 
PGR 
progesterone receptor (abbreviated PR in ASCO-CAP guidelines) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s)  
PO 
oral 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
every day, once daily  
QTcF 
QT interval corrected by the method of Fridericia 
RCC 
renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
System organ class 
SOE 
Schedule of Events  


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Abbreviation 
Definition 
SRC 
safety review committee 
t½  
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrated lymphocyte 
TKI 
tyrosine kinase inhibitor 
TLF 
tables, listings, and figures 
TMB 
tumor mutation burden 
TMB-H 
tumor mutation burden-high 
TNBC 
triple negative breast cancer 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
Vc 
central volume 
VEGF 
vascular endothelial growth factor  
VEGFR 
vascular endothelial growth factor receptor 
 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
 
P a ge 1 9  
 
C O N FI D E N TI A L  
 
 
1  
S Y N O P SI S   
Title  
A n O pe n -La b el, P hase 1 b/ 2 St u d y t o E val uate t he Safet y a n d Efficac y of Fr u q ui nti ni b i n 
C o m bi nati o n wit h Tisleliz u ma b i n Patie nts wit h A d va nce d S oli d T u m ors  
S h ort Title  
A P hase 1 b/ 2 St u d y of Fr u q ui nti ni b i n C o m bi nati o n wit h Tisleliz u ma b i n A d va nce d S oli d 
T u m ors  
Pr ot oc ol 
N u m ber  
2 0 2 0 -0 1 3 -0 0 U S 3  
P h ase  
1 b/ 2  
Pr ot oc ol 
A m e n d m e nt 5  
T he pri mar y p ur p ose of t he A me n d me nt 5 is t o pr o vi de n otificati o n of ter mi nati o n of t his 
st u d y u p o n t he strate gic e val uati o n of t he cli nical de vel o p me nt of fr u q ui nti ni b i n t he U nite d 
States.   T his c h a n ge is n ot base d o n a n y c o ncer n f or patie nt safet y or efficac y relati ve t o 
fr u q ui nti ni b a n d/ or tisleliz u ma b treat me nt.  
 
  
R at i o n ale 
A n gi o ge n esis is a critical ste p i n t he i nce pti o n a n d de vel o p me nt of mali g na nt t u m ors .  O ne of 
t he maj or gr o wt h fact ors relate d t o t u m or a n gi o ge nesis is vasc ular e n d ot helial cell gr o wt h 
fact or ( V E G F), w hic h is secrete d b y t u m ors a n d acti vates t he vasc ular e n d ot helial gr o wt h 
fact or rece pt or ( V E G F R) si g nali n g pat h wa y lea di n g t o e n d ot helial cell pr oliferati o n.  Bl oc ki n g 
of t he V E G F/ V E G F R si g nali n g pat h wa y ca n i n hi bit t u m or a n gi o ge nesis a n d c ut off t he 
n utrie nts a n d o x y ge n s u p pl y t o t he t u m or.  
T u m or i m m u n e s ur veilla nce is als o ke y t o detect, kill, a n d eli mi nate ca ncer cells .  Ke y 
i m m u ne c h ec k p oi nt m olec ules are t he pr o gra m me d cell deat h pr otei n 1 ( P D-1) a n d its li ga n d 
( P D-L 1) .  W he n u pre g ulate d, t he P D 1/ P D‑ L 1 pat h wa y pr otects ca ncer cells fr o m i m m u ne 
s ur veilla nce. 
T h us, c o m bi nati o n t hera p y wit h a s mall -m olec ule i n hi bit or of t he V E G F R pat h wa y ma y 
i m pr o ve t he cli nical efficac y of P D-1/ P D -L 1 i m m u n ot hera pies b y pr o m oti n g i n hi biti o n of 
a n gi o ge nesis i n t he t u m or re gi o n, w hic h ca n s u p press t he gr o wt h of t u m or cell s a n d re d uce t he 
i nci de n ce of metastasis.  T he c o m bi nati o n of i m m u n ot hera pies a n d a nti -a n gi o ge nic a ge nts has 
bee n s h o w n precli nicall y t o ge nerate m ore p ote nt a nti -t u m or effects t ha n eit her a ge nt al o ne 
a n d has s h o w n be n efit i n vari o us t hera pe utic setti n gs.  
Fr u q ui nti ni b is a s mall -m olec ule a nti -t u m or q ui naz oli ne class t yr osi ne ki nase i n hi bit or ( T KI) 
t hat selecti vel y i n hi bits V E G F rece pt ors 1, 2, a n d 3. 
Tisleliz u ma b (als o k n o w n as B G B -A 3 1 7) is a h u ma nize d, i m m u n o gl o b uli n G 4 -varia nt 
m o n ocl o nal a nti b o d y a gai nst P D -1.  
I n t his st u d y, fr u q ui nti ni b i n c o m bi nati o n wit h tisleliz u ma b will be e val uate d i n patie nts wit h 
l ocall y a d va n ce d or metastatic s oli d t u m ors wit h e x pa n de d c o h orts i n tri ple ne gati ve breast 
ca ncer ( T N B C) , e n d o metrial ca ncer ( E C) , a n d micr osatellite sta ble ( M S S ) metastatic 
c ol orectal ca ncer ( m C R C) . 
T ar g et 
P o p ul ati o n  
A d ult male a n d fe male patie nts ≥1 8 years of a ge wit h l ocall y a d va nce d or metastatic s oli d 
t u m ors.  
Part 1 ( Safet y Lea d -i n P hase ): P atie nts wit h hist ol o gicall y  or c yt ol o gicall y d oc u me nte d 
a d va n ce d  or  metastatic s oli d t u m ors of a n y t y pe w h o ha ve  pr o gresse d o n sta n dar d s yste mic 
t hera p y a n d f or w hic h n o effecti ve t hera p y or sta ndar d of care e xists.  Patie nts wit h T N B C i n 
t he Safet y Lea d -i n m ust meet eli gi bilit y criteria defi ne d i n C o h orts A or B, a n d t h ose wit h E C 
i n t he Safet y Lea d -i n m ust meet eli gi bilit y criteria defi ne d i n C o h ort C.    
Part 2 ( D ose E x pa nsi o n P hase):  
•  
C o h ort A:  T N B C (i m m u n o -o nc ol o g y [I O] -treate d i n t he metastatic setti n g) 
•  
C o h ort B: T N B C (I O -Naï ve  i n the metastatic setti n g ) 
•  
C o h ort C: E C  (I O N aï ve)  
•  
C o h ort D: M S S m C R C (I O Naï ve ) 
I nter v e nti o n 
Part 1 ( Safet y Lea d -i n P hase):  
C CI


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• 
Dose level 1: Fruquintinib 5 mg oral (PO) once daily (QD) 3 weeks on/ 1 week off + 
tislelizumab 300 mg intravenously (IV) every 4 weeks (Q4W) 
OR 
• 
Dose level -1: Fruquintinib 4 mg PO QD 3 weeks on/1 week off + tislelizumab 
300 mg Q4W 
Part 2 (Dose Expansion Phase): Recommended Phase 2 dose (RP2D) from Part 1 
Objectives and Endpoints 
Part 
Tier 
Objectives 
Corresponding Endpoints 
Part 1: Safety 
Lead-in Phase 
Primary 
To assess the safety and tolerability of 
fruquintinib in combination with 
tislelizumab in patients with advanced 
solid tumors 
AEs characterized by type, 
frequency, severity per NCI CTCAE 
v5.0, timing, seriousness, 
relationship to study drug(s), and 
discontinuation of study drug(s) due 
to AEs 
To confirm the RP2D of fruquintinib 
in combination with tislelizumab 
RP2D 
Secondary 
To evaluate the efficacy of 
fruquintinib in combination with 
tislelizumab per investigator 
assessment 
ORR, PFS, DCR, CBR, DoR, and 
OS 
To characterize the PK profile of 
fruquintinib and metabolite M11 when 
combined with tislelizumab 
Plasma concentrations of fruquintinib 
and M11 
To evaluate the PK and 
immunogenicity of fruquintinib in 
combination with tislelizumab 
Serum concentrations of tislelizumab 
and incidence of ADA to 
tislelizumab 
Part 2: Dose 
Expansion 
Phase 
Primary 
To evaluate the ORR assessed by the 
investigator in patients with advanced 
or metastatic TNBC, EC, or MSS 
mCRC when treated with fruquintinib 
in combination with tislelizumab 
ORR per RECIST v1.1 
Secondary 
To further evaluate efficacy of 
fruquintinib in combination with 
tislelizumab in patients with advanced 
or metastatic TNBC, EC, or MSS 
mCRC per investigator assessment 
PFS, DCR, CBR, DoR, and OS 
 
 
To characterize the safety of 
fruquintinib in combination with 
tislelizumab 
AEs characterized by type, 
frequency, severity per NCI CTCAE 
v5.0, timing, seriousness, 
relationship to study drug(s), and 
discontinuation of study drug(s) due 
to AEs. 
To assess the PK profile of 
fruquintinib and metabolite M11 when 
combined with tislelizumab 
Plasma concentrations and derived 
PK parameters of fruquintinib and 
M11 
To characterize the PK and 
immunogenicity of fruquintinib when 
combined with tislelizumab 
Serum concentrations of tislelizumab 
and incidence of ADA to 
tislelizumab 
To detect the expression of PD-L1, 
MSS/microsatellite instability status, 
Changes from baseline in tumor 
markers, correlation with drug 


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and other biomarkers in tumor tissues 
of patients, and to perform relevant 
efficacy analysis to provide reference 
for the determination of dominant 
population 
exposure, and association with 
efficacy and safety parameters 
Exploratory 
To explore potential biomarkers 
associated with anti-tumor effects of 
fruquintinib in combination with 
tislelizumab 
Changes from baseline in 
biomarkers, correlation with drug 
exposure, and association with 
efficacy and safety parameters 
Brief Summary: This is an open-label, multicenter, non-randomized, phase 1b/2 study to assess the safety and 
efficacy of fruquintinib in combination with tislelizumab in patients with locally advanced or metastatic solid 
tumors.  This study will be conducted in 2 parts: a Safety Lead-in Phase (Part 1) and a Dose Expansion Phase 
(Part 2).  The Safety Lead-in Phase will determine the RP2D.  The RP2D will be administered to 4 cohorts of 
patients in the Dose Expansion Phase: 
• Cohort A: TNBC (IO-Treated in the metastatic setting) 
• Cohort B: TNBC (IO-Naïve in the metastatic setting) 
• Cohort C: EC (IO Naïve) 
• Cohort D: MSS mCRC (IO Naïve)  
Condition/ 
Disease 
Locally advanced or metastatic solid tumors 
Study 
Duration 
Approximately 30 months 
Treatment 
Duration 
28-day cycles 
Health 
Measurement/ 
Observation 
This study will determine the RP2D, as well as safety assessments including dose-limiting 
toxicities, treatment-emergent AEs, serious AEs, deaths, electrocardiograms, and clinical 
laboratory abnormalities.  During the Dose Expansion Phase, patients will receive fruquintinib 
and tislelizumab at RP2D for 28 days in each cycle until progressive disease (PD), intolerable 
toxicity, death, withdrawal of consent, or until the study terminates.  Patients may continue to 
receive fruquintinib and tislelizumab or either of the study drugs beyond the initial 
investigator-assessed PD, as defined by RECIST v1.1, provided that the patient has 
investigator-assessed clinical benefit and is tolerating study drug(s).  Patients who, at time of 
progression, have an ongoing AE that leads to treatment discontinuation and has completed the 
scheduled Safety Follow-up visit 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 new 
anticancer therapy.  If a patient discontinues study drug(s) due to reasons other than P140 D or 
death, tumor assessments should continue to be performed following the scheduled assessment 
plan until the start of new anticancer therapy, PD, death, lost to follow-up, or withdrawal of 
consent. 
Visit 
Frequency 
Cycle 1: every week (±1 day, except Day 1) 
Cycle 2: every 2 weeks (±1 day) 
Cycle 3 and onward: Day 1 (±3 days) 
End of Treatment: within 7 days (±3 days) after the last dose 
Number of 
Participants 
Part 1: approximately 6 to 12 patients will be enrolled 
Part 2: approximately 140 patients: 30 patients each in Cohorts A and B, 40 patients in 
Cohort C, and 40 patients in Cohort D 
Of note, based upon the strategic evaluation of the clinical development of fruquintinib, patient 
enrollment has been permanently discontinued for Cohorts A, B, and C in the Dose Expansion 
Phase, hence, the final actual total number of patients will reflect this strategic decision. 
Data 
Yes 


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Monitoring/ 
Other 
Committee 
 
 




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Table 1 
Schedule of Events for Study 2020-013-00US3  
Cycle/Period 
 
C1 
C2 
C3+ 
EOTw 
Safety 
Follow-
upx 
Survival 
Follow-
up 
Visit 
Screening 
D1 
D8 
D15 
D21 
D1 
D15 
D1 
≤7 Days 
After 
Last 
Dose 
30 Days 
After 
EOT 
Visit 
Every 
8 Weeks 
After 
EOT 
Visit 
Visit Window (days) 
-28 to -1 
-7 to -1 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 expression 
confirmationb 
X 
 
 
 
 
 
 
 
 
 
 
 
MSS/MSI status 
confirmationc  
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history, disease 
historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographicse 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications and 
concomitant proceduresf 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive physical 
examinationg 
X 
 
X 
 
 
 
 
 
 
 
 
 
Limited physical 
examinationh 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signsi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance statusi 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Laboratory evaluations: 
 
X 
 
 
 
 
 
 
 
 
 
 
Hematologyj 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistryk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood amylase and lipase 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Fasting lipid panell 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Coagulation indicatorsm 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum pregnancy testn 
 
X 
 
 
 
 
 
 
 
 
X 
 


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Table 1 
Schedule of Events for Study 2020-013-00US3  
Cycle/Period 
 
C1 
C2 
C3+ 
EOTw 
Safety 
Follow-
upx 
Survival 
Follow-
up 
Visit 
Screening 
D1 
D8 
D15 
D21 
D1 
D15 
D1 
≤7 Days 
After 
Last 
Dose 
30 Days 
After 
EOT 
Visit 
Every 
8 Weeks 
After 
EOT 
Visit 
Visit Window (days) 
-28 to -1 
-7 to -1 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±7 
±14 
Urine pregnancy testn 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
Thyroid function testo 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
Urinalysisp 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
Virological screeningq 
X 
 
 
 
 
 
 
 
X 
X 
 
 
PK assessments 
 
 
 
Refer to Table 2 
 
 
Tislelizumab 
immunogenicity 
 
 
 
Refer to Table 2 
 
 
12-Lead ECGr 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
ECHO/MUGA scan 
X 
 
Every 12 weeks from C1D1 (±1 week) until progression of disease 
 
 
Tumor evaluation/imagings 
Screening and every 8 weeks (±1 week) from C1D1 until disease progression 
X 
 
 
Fruquintinib drug 
administration 
 
 
PO QD, Days 1 to 21 of each cycle 
 
 
 
Tislelizumab drug 
administrationt 
 
 
X 
 
 
 
X 
 
X 
 
 
 
AEs/SAEsu 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall survivalv 
 
 
 
 
 
 
 
 
 
 
 
X 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; C=cycle; 
CK=creatine kinase; CKMB=creatine kinase-MB; CrCl=creatinine clearance;  D=day; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EOT=end of treatment; HBV=hepatitis B virus; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; ICF=informed consent form; INR=international normalized ratio; IV=intravenous; MSI=microsatellite 
instability; MSS=microsatellite stability stable; MUGA=multigated acquisition; PCR=polymerase chain reaction; PD=progressive disease; PD-L1=programmed death-ligand 
1; PK=pharmacokinetics; PO=orally; QD=once daily; Q3W=every 3 weeks; Q4W=every 4 weeks; QTcF=QT interval corrected by the method of Fredericia; 
RNA=ribonucleic acid; RP2D=recommended Phase 2 dose; SAE=serious adverse event; SOP=standard operating procedure. 
a 
Written informed consent must be obtained before any study-related examinations or procedures are performed.  However, before informed consent is obtained, if the 
examinations for standard treatment are performed within 28 days before the planned C1D1, they can be used to replace the examinations during the screening period without 
repeating the examinations, except for examinations that need to be performed 7 days before the start of the study drug administration.   


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b 
PD-L1 expression as determined locally, for Cohorts A, B, and C.  The results should be available in the source documents and be those used to make treatment decisions for 
the patient.  A redacted copy of the local results should accompany the archival tumor samples submitted as part of the protocol. 
c 
MSS/MSI status as determined locally, for Cohorts C and D only.  The results should be available in the source documents and be those used to make treatment decisions for 
the patient.  A redacted copy of the local results should accompany the archival tumor samples submitted as part of the protocol. 
d 
Medical history and disease history data include significant clinical disease or symptom, surgical history, history of malignancy (including date of diagnosis, classification and 
prognosis evaluation of the study disease, and the treatment performed and the outcome; the tumor species and outcomes of any other previous malignancies), smoking 
history, history of alcohol consumption, history of drug abuse, and other medical-related history.  
e 
Demographic information includes sex, race, and in some countries, year of birth. 
f 
Concomitant medications include any prescription and over-the-counter medications started after signing of ICF.  During the screening period, all drugs used for the patient 
within 28 days prior to the start of study drug should be recorded.  In subsequent visits, the drugs used in the patient after the last record, as well as drugs 30 days after the last 
dose of study drug(s), should be recorded in eCRF.  Subsequent new anti-tumor treatment regimens during the Safety and Survival Follow-up Periods will also be recorded. 
g 
A comprehensive physical examination includes patient height, weight, and general condition, as well as an examination of the head, heart, chest (including the lungs), 
abdomen, extremities, skin, lymph nodes, nervous system, and additional areas/systems as clinically indicated. 
h 
Limited physical examination includes vital signs and any change from baseline; any new abnormalities; examination of weight, thorax, abdomen; and additional 
areas/systems as clinically indicated.  In order to assess changes from baseline and to evaluate for new abnormalities, the limited physical examination should assess for new 
or changed skin lesions, enlarged lymph nodes, palpable masses, and appropriate examination to address any patient-reported symptoms. 
i 
Assessments can be performed up to and including C1D1.  Details for ECOG assessment can be found in Section 6.1.11 and for vital sign collection in Section 6.1.12. 
j 
Hematology includes red blood cell count, hemoglobin, hematocrit, absolute reticulocyte count, white blood cell count and classifications (neutrophils, lymphocytes, 
eosinophils, monocytes, and basophils), and platelet count.  If abnormal or primitive immature cells are seen, they must also be recorded.  Any additional routine blood tests 
during the study shall be arranged by the investigator as needed.  
k 
Blood chemistry includes ALT, AST, alkaline phosphatase (ALP), bicarbonate, bilirubin/total bilirubin, lactic dehydrogenase, non-fasting total cholesterol, triglycerides, uric 
acid, total protein, albumin, blood urea nitrogen or urea, creatinine, CrCl rate, sodium, potassium, magnesium, chloride, corrected calcium (for patients with 
hypoproteinemia), phosphorus, blood glucose, creatine phosphokinase, and creatine kinase-MB (CK-MB).  If CK-MB fractionation is not available, troponin I and/or troponin 
T should be tested instead.  Serum troponins may be substituted per local guidelines if used consistently throughout the study.  If tislelizumab has been permanently 
discontinued, CK and CK-MB testing will be done as clinically indicated.  
l 
Fasting lipid panel includes total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides.  
m 
Coagulation indicators include prothrombin time, aPTT, and INR. 
n 
Female patients of childbearing potential (including those who have undergone tubal ligation) must undergo a serum pregnancy test ≤7 days before the first dose and record a 
negative result.  If serum pregnancy test was drawn within 72 hours of C1D1, then urine pregnancy test is not required on C1D1.  After enrollment, urine pregnancy test 
should be conducted on Day 1 of every treatment cycle starting from Cycle 1, and at the EOT visit.  A serum pregnancy test should be performed at the Safety Follow-up 
Visit.  If the result of urine pregnancy testing is equivocal, a serum test should be performed.  Unscheduled testing via either method can be performed if there is an indication, 
however, any equivocal urine pregnancy tests should be repeated via serum pregnancy testing. 
o 
Thyroid function tests include serum free tri-iodothyronine, serum free thyroxine, and thyroid stimulating hormone. 
p 
Urinalysis includes urine pH, protein, glucose, blood and ketones; microscopic for white blood cell and red blood cell count.  A 24-hour urine for quantitative protein must be 
collected from all patients with 1+ proteinuria. 
q 
Testing will be performed by the local laboratory at screening and will include HBV/HCV serology (HBsAg and HCV antibody) and viral load assessment (HBV DNA and 
HCV RNA), which will be assessed only when HBsAg or HCV antibody is positive, respectively.  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 at the EOT visit. 
r 
ECG indicators include PR interval, QRS interval, RR interval, QT/QTcF interval and heart rate.  Unscheduled ECG or other cardiac examinations can be performed if 
clinically indicated.  All ECGs should be done prior to dosing of study drugs. 
s 
If a patient discontinues study drug(s) due to reasons other than PD or death, tumor assessments should continue to be performed following the scheduled assessment plan 
until the start of new anticancer therapy, PD, death, lost to follow-up, or withdrawal of consent. 
t 
Tislelizumab 300 mg IV will be administered on Day 1 of each 28-day cycle (once every 4 weeks).  Every 3 weeks (Q3W) dosing of tislelizumab may be explored depending 
on the tolerability of the Q4W dosing schedule. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
 
P a ge 2 7  
 
C O N FI D E N TI A L  
 
 
u 
After si g ni n g t h e i nf or me d c o nse nt f or m, all A Es i ncl u di n g S A Es re gar dless of attri b uti o n will be c ollecte d u ntil 3 0 da ys after t he last d ose of st u d y dr u g or i nitiati o n of a ne w 
treat me nt t h era p y, w hic he ver is earlier.  After t his peri o d, i n vesti gat ors s h o ul d re p ort o nl y S A Es t h at are c o nsi dere d t o be relate d t o t h e s t u d y dr u g.  I m m u ne-me diate d A Es 
(seri o us or n o nseri o us) s h o ul d be re p orte d u ntil 9 0 da ys after t he last d ose of tisleliz u ma b re gar dless of w het h er or n ot t h e  patie nt starts a ne w a ntica ncer t h era p y.  
v 
F oll o wi n g E O T , patie nts will be f oll o we d e ver y 8  wee ks  ( ± 1 4 da ys) via tele p h o ne or i n ma n ner t h at f oll o ws l ocal site S O Ps.  0 6  Ma y  2 0 2 4 will be t h e fi n al da y f or s ur vi val 
f oll o w u p. A n y patie nt w h o has n ot ha d c o ntact wit h t h e site wit hi n 3 0 da ys of t his d ate  (a n d n ot pre vi o usl y re p orte d as decease d or wit h dra w n c o nse nt f or f ut ure f oll o w -u p) 
s h o ul d ha ve a fi nal s ur vi v al f oll o w-u p c o n d ucte d via tele p h o ne or i n a ma n ner t hat f oll o ws l ocal site S O Ps.  
w  
All patie nts o n acti ve treat me nt at t h e ti me of A me n d me nt 5 are re q uire d t o ha ve a n E O T visit .  
 
  All E O T assess me nts 
descri b e d i n t h e  a b o ve ta ble s h o ul d be f oll o we d, i ncl u di n g t he fi n al c ollecti o n of patie nt dr u g diaries/fi n al dr u g acc o u nta bilit y re vie w. 
x  
A ll patie nts will be re q uire d t o ha ve a Safet y F oll o w -u p visit.
C CI




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2 
INTRODUCTION  
2.1 
Study Rationale  
Angiogenesis is a critical step in the inception and development of malignant tumors.  Tumor 
cells growing rapidly in a state of hypoxia can secrete a variety of pro-angiogenic growth factors 
that stimulate endothelial cell proliferation leading to the formation of excessive new blood 
vessels around the tumor.  These rapidly formed vasculatures are often coarsely packed and 
leaky, resulting in an exudation of tumors cells into the circulation initiating tumor metastasis.  
One of the major growth factors related to tumor angiogenesis is vascular endothelial cell growth 
factor (VEGF), which is secreted by tumors and activates the vascular endothelial growth factor 
receptor (VEGFR) signaling pathway leading to endothelial cell proliferation.  Blocking of the 
VEGF/VEGFR signaling pathway can inhibit tumor angiogenesis and cut off the nutrients and 
oxygen supply to the tumor (Duda 2007). 
Tumor immune surveillance is also key to detect, kill, and eliminate cancer cells.  The 
programmed cell death protein-1 (PD-1) pathway plays a critical role in regulating the immune 
response.  PD-1, an inhibitory immune checkpoint receptor expressed on activated T cells, 
B cells, natural killer cells, activated monocytes, dendritic cells, myeloid cells, and a subset of 
thymocytes (Pardoll 2012, Keir 2008) limits autoimmunity by regulating the activity of effector 
T cells in the periphery in response to an inflammatory stimulus (Pardoll 2012, Topalian 2012).  
Programmed death-ligand 1 (PD-L1), a PD-1 ligand, is an immunosuppressive signal that is 
upregulated in response to proinflammatory signals such as interferon-g (Keir 2008, 
Topalian 2012, Taube 2012).  PD-L1 is expressed in multiple solid tumor including breast 
cancer, with expression relatively higher in triple negative breast cancer (TNBC) 
(Mittendorf 2014).  The combination of immunotherapies and anti-angiogenic agents has been 
shown preclinically to generate more potent anti-tumor effects than either agent alone 
(Khan 2018) and has shown benefit in various therapeutic settings (Georganaki 2018).  Thus, 
therapy with a small-molecule inhibitor of the VEGFR pathway may improve the clinical 
efficacy of PD-1/PD-L1 immunotherapies in tumors including TNBC by promoting inhibition of 
angiogenesis in the tumor region, which can suppress the growth of tumor cells and reduce the 
incidence of metastasis. 
Fruquintinib, a potent, oral VEGFR tyrosine kinase inhibitor (TKI) with good kinase selectivity 
was approved for the treatment of metastatic colorectal cancer (mCRC) in patients who have 
failed at least 2 prior systemic antineoplastic therapies in China (FRESCO phase 3 study) 
(Li 2018).  Safety and preliminary efficacy of fruquintinib have been demonstrated in metastatic 
breast cancer (mBC), including TNBC, in a phase 1 study conducted in China (Study 2009-013-
00CH1) and in an ongoing phase 1/1b study conducted in the United States (US) (Study 2015-
013-00US1).  Expansion cohorts in TNBC and hormone receptor-positive, human epidermal 
growth factor receptor 2 (HER2)-mBC are currently enrolling.  Fruquintinib is in clinical 
development for a number of other cancer indications, including gastric cancer (GC) and 
advanced non-small-cell lung cancer (NSCLC).  A phase 3 study (FRESCO-2) of fruquintinib in 
combination with best supportive care is also ongoing in advanced colorectal cancer (CRC) 
patients in the US. 
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G (IgG)4-variant 
monoclonal antibody against the immune checkpoint PD-1 that was approved in China for the 
treatment of patients with relapsed or refractory classical Hodgkin lymphoma who received at 


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least 2 lines of systemic chemotherapy regimens and for the treatment of patients with locally 
advanced or metastatic urothelial carcinoma with PD-L1 high expression whose disease 
progressed during or following or within 12 months of platinum-containing chemotherapy. 
In this study, fruquintinib in combination with tislelizumab will be evaluated in patients with 
locally advanced or metastatic solid tumors with expanded cohorts in triple negative breast 
cancer (TNBC), endometrial cancer (EC), and microsatellite stable (MSS) mCRC. 
2.2 
Background  
2.2.1 
Target Indications and Populations  
2.2.1.1 
Triple Negative Breast Cancer  
Triple negative breast cancer is characterized by a lack of expression of estrogen receptor (ER), 
progesterone receptor (PGR), and the HER2 (Ryu 2011).  TNBC accounts for approximately 
15% of breast cancers diagnosed worldwide with an estimated 1 million cases diagnosed 
annually.  Patients diagnosed with TNBC have a worse prognosis compared to other types of 
breast cancer, with a 3-year overall survival (OS) rate of 14.7% (Leone 2019).  Factors 
contributing to the poor prognosis are, in part, related to short disease-free survival and increased 
risk for lung, liver, and brain metastasis contributing to shortened OS.  The combination of 
atezolizumab, a humanized engineered anti-programmed cell death protein-L1 checkpoint 
pathway (anti-PD-L1) monoclonal antibody, and nab-paclitaxel chemotherapy has been 
approved for the treatment of patients with unresectable locally advanced or metastatic TNBC 
whose tumors express PD-L1 (Schmid 2018).  However, treatment options following progression 
on the combination remain limited and prognosis remains poor.  Thus, there is a high unmet need 
to investigate new therapies in patients with refractory TNBC and to explore potential 
mechanisms to overcome resistance to anti-PD-L1 therapy.  Likewise, treatment options for 
TNBC patients whose tumors do not express PD-L1 are limited, and novel strategies to 
overcome potential intrinsic resistance to immunotherapy are also needed.  
2.2.1.2 
Endometrial Cancer  
Endometrial cancer is the fourth most common cancer in women and the incidence is increasing 
with a lifetime risk of approximately 3% (Leslie 2012).  There was an estimated 382,069 new 
cases and 89,929 deaths attributed to EC worldwide in 2018 (Zhang 2019).  For patients with 
advanced EC and lymph node metastasis, the 5-year survival rate is less than 50%.  For those 
with distant metastases, the survival rate falls to less than 20% (Ott 2017).  Most ECs are 
identified at an early stage and are treated surgically with or without the addition of chemo- or 
radio-therapy.  Common first-line treatment of advanced or recurrent EC consist of 
platinum-based chemotherapy regimens and may include biologics.  Hormonal therapy (HT) can 
also be considered for those tumors that express hormone receptors, but few long-term responses 
are observed and generally result in relative short progression-free survival (Miller 2020).  For a 
small number of patients whose tumors are microsatellite instability (MSI)-high (MSI-H) and 
mismatch repair deficient (dMMR), single-agent therapy with pembrolizumab is approved, but 
this represents only approximately 16% of recurrent EC tumors (Makker 2020).  Considering the 
poor prognosis and increased incidence and mortality of endometrial cancer, there remains a high 
unmet need for effective therapies in advanced, metastatic, or recurrent ECs. 


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2.2.1.3 
Colorectal Cancer  
CRC is a major global health issue, with an estimated 1.9 million new cases and 935,000 deaths 
in 2020 worldwide (Bray 2020).  The established initial and second-line systemic therapy for 
mCRC consists of fluoropyrimidine-, oxaliplatin-, and irinotecan-based cytotoxic chemotherapy 
(eg, FOLFOX: [5-Fluorouracil, leucovorin, and oxaliplatin] and FOLFIRI [5-fluorouracil, 
leucovorin, and irinotecan]).  In addition, a biologic anti-vascular endothelial growth factor 
(anti-VEGF) therapy is typically given with chemotherapy (eg, bevacizumab), and if the tumor is 
RAS wild-type, an anti-endothelial growth factor receptor (EGFR) therapy (eg, cetuximab) is 
administered.  When there is disease progression after the first 2 lines of chemotherapy, the 
established options are either regorafenib or TAS-102.  There is no standard of care for patients 
who have progressed on chemotherapy, relevant biologics, and TAS‑102 and/or regorafenib.  
Accordingly, there is an unmet medical need for new medications that are safe and effective in 
patients with refractory mCRC who have progressed on, or had intolerable toxicity from, 
available standard systemic therapies, and for whom no effective therapy or standard of care 
exists. 
Immune checkpoint inhibitors have demonstrated activity in patients with CRC and other solid 
tumors that are MSI‐H/dMMR, and nivolumab and pembrolizumab are currently approved by 
the Food and Drug Administration (FDA) for the 10% to 15% of patients with MSI‐H/dMMR 
mCRC (Morse 2019). However, PD-1 blockade is particularly ineffective in patients with MSS 
or mismatch repair (MMR)–proficient CRC which makes up the majority (95%) of mCRC 
patients (Ali 2018). This can be explained by the lower antigenicity due to the presence of fewer 
neoantigens, regardless of tumor mutation burden, resulting in fewer infiltrating CD8+ T cells in 
general and fewer strongly positive for PD‐1 (Morse 2019).  Recently, several strategies to turn a 
“cold” CRC tumor into an immunoreactive “hot” tumor were being tested in clinical trials, and a 
growing body of evidence supports the potentially synergistic effect of the combination of 
PD-L1 inhibitors and VEGFR TKIs in patients with MSS mCRC (Fukuoka 2020). 
2.2.2 
Description of Fruquintinib  
Fruquintinib is a small-molecule anti-tumor quinazoline class tyrosine kinase inhibitor (TKI) that 
selectively inhibits vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. 
2.2.2.1 
Fruquintinib Administration Regimen  
Fruquintinib (HMPL-013) capsule 5 mg will be administered orally (PO) once daily (QD), 3 weeks 
on/1 week off (4-week cycles).  Doses may be given either in the fasting state or after meals.  If 
dose adjustment is required, 1-mg capsules will be used. 
2.2.2.2 
Fruquintinib Justification for Dosing Strategy  
The optimal fruquintinib dose and dosing regimen were determined in 2 Chinese phase 1 studies, 
2009-013-00CH1 and 2012-013-00CH3, as well as 1 US phase 1/1b study, 2015-013-00US1.  
During dose escalation, Study 2009-013-00CH1 investigated continuous daily doses of 1 mg, 
2 mg, 4 mg, 5 mg, and 6 mg; in addition, 5 mg QD and 6 mg QD were studied on a regimen of 
3 weeks on, 1 week off (4-week cycles).  The maximum-tolerated dose (MTD)/recommended 
Phase 2 dose (RP2D) was 4 mg QD (continuous) or 5 mg QD (3 weeks on/1 week off). 


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In Study 2012-013-00CH3, the safety and tolerability of these 2 dosing regimens (4 mg QD 
continuously versus 5 mg QD, 3 weeks on/1 week off) were compared in patients with mCRC.  
The safety profile was better in the 5 mg QD (3 weeks on/1 week off) group than the 4 mg QD 
(continuous) group.  In addition, there was accumulation of drug over time in the 4 mg QD 
(continuous) group.  Thus, the 5 mg PO QD (3 weeks on/1 week off) dose and regimen was 
selected as the RP2D and the dosing regimen to be used in subsequent clinical development in 
China.  
The RP2D and dosing regimen were tested in the phase 2 (2012-013-00CH1) and phase 3 (2013-
013-00CH1 [FRESCO]) studies, which confirmed that the dose and dosing regimen were safe 
and effective in patients with refractory mCRC.  The 5 mg PO QD (3 weeks on/1 week off) dose 
and regimen is the standard dose and dosing regimen in all other completed, ongoing, and 
planned studies in patients with advanced cancer. 
In the US phase 1/1b study (2015-013-00US1), there were 2 dose cohorts in the dose escalation 
phase, 3 mg PO QD (n=7) and 5 mg PO QD (n=7).  Fruquintinib was well tolerated in both dose 
cohorts.  Therefore, 5 mg PO QD (3 weeks on/1 week off) was confirmed as the RP2D for global 
studies, as well. 
2.2.3 
Description of Tislelizumab  
Tislelizumab (also known as BGB-A317) is a humanized, IgG4-variant monoclonal antibody 
against PD-1. 
2.2.3.1 
Tislelizumab Administration Regimen  
Tislelizumab 300 mg will be administered intravenously on Day 1 of each 28-day cycle (once 
every 4 weeks).  Every 3 weeks (Q3W) dosing of tislelizumab may be explored depending on the 
tolerability of the every 4 weeks (Q4W) dosing schedule. 
2.2.3.2 
Tislelizumab Justification for Dosing Strategy  
The pharmacokinetics (PK), safety, and efficacy data obtained from the first-in-human 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.  Tislelizumab has a wide safety 
margin (the dose ranged from 0.5 mg/kg to 10 mg/kg every 2 weeks in BGB-A317 Study_001), 
with no MTD identified in BGB-A317 Study_001.  The flat dose of 200 mg intravenously once 
every 3 weeks was selected for further evaluation. 
Rates of treatment-related adverse events (AEs) and serious AEs (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.  Additionally, PK data also show no 
relationship between exposure and treatment-emergent immune-mediated AEs (imAEs).  
Similarly, confirmed objective response rates (ORRs) in patients treated with tislelizumab 2 
mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared with 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 clearance (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). 


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In addition, 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 best overall response (BOR) of partial 
response (PR), 4 patients (31%) had a BOR of stable disease (SD), and 5 patients (39%) had a 
BOR of progressive disease (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.  
The observed clinical activity in patients with advanced tumors, coupled with a manageable 
safety profile and supportive data, supports the proposed tislelizumab dose of 200 mg 
intravenously once every 3 weeks as the recommended dose for pivotal studies.  This dose 
regimen has been approved for treating patients with classical Hodgkin lymphoma and urothelial 
bladder cancer.  The dosage of 200 mg Q3W was also used in other pivotal studies under the 
development; for more information refer to the tislelizumab Investigator’s Brochure (IB). 
The alternative regimen of 300 mg once every 4 weeks is selected by matching dosing and 
exposure (area under the curve [AUC]) with the exposure of 200 mg once every 3 weeks 
regimen.  Exposure-response assessment of available clinical data from studies including BGB-
A317 Study_001, BGBA317-102, and BGB-A317-203 suggest no clinically significant 
relationships observed between tislelizumab exposure and efficacy (ORR) or safety across tumor 
types.  Thus, 300 mg once every 4 weeks regimen is not expected to be clinically different from 
the 200 mg once every 3 weeks in terms of safety or efficacy outcomes.  The higher maximum 
observed concentrations (Cmax) of 300 mg once every 4 weeks regimen compared with the 200 
mg once every 3 weeks is well covered by the available safety data at higher doses (up to 10 
mg/kg once every 2 weeks were used in BGB-A317 Study_001).  Moreover, the alternative 4-
weekly dose administration is expected to increase patient compliance when in combination with 
fruquintinib and offer additional convenience for care providers. 
2.2.4 
Rationale for the Starting Combination Doses  
The full dose of fruquintinib (5 mg daily, 3 weeks on followed by 1 week off, 4-week cycles) in 
combination with tislelizumab (300 mg once every 4 weeks) were selected as the starting doses 
for this study due to the well-established safety profiles of fruquintinib and tislelizumab, the non-
overlapping mechanisms of action, and the desire to treat patients at doses shown to be effective 
in previous studies.  Starting treatment with the full dose of each agent in an immunotherapy plus 
a TKI combination therapy is consistent with other studies.  Axitinib, like fruquintinib, targets 
VEGFR 1, 2, and 3 in addition to other pathways and has been evaluated in combination with an 
immunotherapy (pembrolizumab) for advanced renal cell carcinoma (RCC).  The phase 1b study 
enrolled 52 patients (11 in dose-finding phase, 41 in Dose Expansion Phase), and treatment was 
initiated with the full dose of both agents.  No unexpected toxicities were observed.  Three 
dose-limiting toxicities (DLTs) were reported in the 11 patients treated during the dose-finding 
phase: 1 patient had a transient ischemic attack, and 2 patients were only able to complete less 
than 75% of the planned axitinib dose because of treatment-related toxicity.  The maximum 
tolerated dose of this regimen was estimated to be the full doses of each agent.  Overall, patients 
received almost the full protocol-planned doses of both drugs.  Thirty-two (62%) patients had 
their axitinib dose reduced (ie, to <5 mg twice per day for 2 consecutive doses) because of 
axitinib-related toxicities.  Overall, 30 (58%) patients discontinued axitinib because of 
AEs (n=16) and disease progression (n=9); 27 (52%) patients discontinued pembrolizumab early 


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because of AEs (n=12) and disease progression (n=12).  Unprecedented anti-tumor activity and 
tolerability of this combination treatment led to breakthrough status designation from the US 
FDA; subsequent FDA approval of this combination at full dosages for each agent for RCC was 
based on data from the phase 3 KEYNOTE-426 study (Atkins 2018). 
2.2.5 
Supportive Nonclinical Data  
2.2.5.1 
Fruquintinib  
2.2.5.1.1 
Pharmacology  
Fruquintinib primarily targets the VEGFR family, VEGFR 1, 2, and 3 with 50% inhibitory 
concentration (IC50) of 33 nM, 35 nM, and 0.5 nM, respectively.  In multiple human tumor 
xenograft models in Nu/Nu mice, fruquintinib demonstrated a dose-dependent anti-tumor 
activity accompanied by strong anti-angiogenesis effect in tumor tissues.  In all tested tumor 
models, fruquintinib showed statistically significant tumor growth inhibition at doses as low as 
2 mg/kg/day. 
Refer to the fruquintinib IB for detailed information regarding pharmacology studies. 
2.2.5.1.2 
Toxicology  
Fruquintinib has been evaluated in repeat-dose toxicology studies for up to 6 months (26 weeks) 
in rats and 9 months (39 weeks) in dogs.  Other completed studies included single-dose studies, 
in vitro and in vivo genetic toxicology studies, a fertility and early embryonic 
development/implantation study in rats, and an embryo-fetal development study. 
Key findings from the toxicology studies are summarized below:  
• Safety pharmacology: No adverse effects were observed in dog cardiovascular and 
respiratory systems at the highest dose tested (0.34 mg/kg) and in the central nervous 
system at the highest dose tested (10 mg/kg).  
• General toxicology: In single-dose toxicity studies in rats and dogs, no deaths occurred at 
a dose of up to 2000 mg/kg and 1000 mg/kg, respectively.  In repeat-dose toxicity studies 
in rats (1 month and 6 months) and dogs (1 month and 9 months), there was a general 
trend for increased toxicity associated with increased duration of treatment.  The main 
target organs were liver, kidney, adrenal gland, immune system (thymus, spleen, and 
lymph nodes), gastrointestinal (GI) system, bone marrow (sternum), and femur.  The 
toxic responses were found to be reversible upon discontinuation of the drug treatment. 
• Reproductive and development toxicology: In the fertility and early embryonic 
development/implantation study, the no observed adverse effect level (NOAEL) for 
fertility in both male rats and female rats was found to be 3 mg/kg and 0.5 mg/kg, 
respectively.  The NOAEL for early embryonic development was 0.15 mg/kg.  In the 
embryo-fetal development study, the NOAEL in rats for both maternal effects and 
embryo-fetal development was found to be 0.1 mg/kg and 0.025 mg/kg, respectively. 
• Genetic toxicology: No genetic toxicity was found in either the bacterial reverse mutation 
test or the micronucleus test in mice.  In the chromosome aberration test, fruquintinib at 
36.0 µg/mL induced a significant increase (compared to the negative control) in the 


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percentages of aberrant cells with structural chromosome aberrations in Chinese hamster 
lung cells treated in vitro for 24 hours without S9 activation.  There was no significant 
increase in the percentages of aberrant cells in other treated groups. 
Refer to the fruquintinib IB for detailed information regarding toxicology studies. 
2.2.5.1.3 
Pharmacokinetics  
Fruquintinib had good intrinsic membrane permeability and was not a substrate of efflux 
transporters (eg, P-glycoprotein [P-gp]).  Following oral administration with [14C]-fruquintinib in 
rat, it was found that fruquintinib was mainly distributed to metabolic and excretory organs. 
Three major metabolites were observed in the incubation with liver microsomes of various 
species (human, mice, rats, dogs and monkeys).  The most abundant metabolite of fruquintinib in 
human plasma was M11 (desmethylation product, HM5025423), and its production was mainly 
mediated by cytochrome P450, family 3, subfamily A4 (CYP3A4)/5. 
Fruquintinib inhibited both P-gp and breast cancer resistance protein (BCRP) in a -dose 
dependent manner, with estimated IC50 values of 4.60 and 1.29 µM, respectively.  No obvious 
inhibitory effects were observed on the following transporters: organic anion transporting 
polypeptide 1b1, 1b3 (OATP1B1, OATP1B3), organic anion transporter 1, 3 (OAT1, OAT3), 
organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and multidrug 
and toxin extrusion 2-K (MATE2-K).  Fruquintinib had no significant inhibitory effects on 
cytochrome P450s (CYPs) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 (IC50 >10 µM) and no 
inductive effects on CYPs 1A2, 2B6, and 3A4 at the test level of 10 µM.  No significant time-
dependent inhibition was observed for CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 at 
10 µM. 
The mass balance study in rats showed that roughly similar proportions (approximately 30%) of 
the drug were excreted in bile, urine and feces, respectively, after a single oral dose of 
[14C]-fruquintinib. 
Refer to the fruquintinib IB for detailed information regarding pharmacokinetics studies. 
2.2.5.2 
Tislelizumab  
2.2.5.2.1 
Pharmacology  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1.  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 PDL-1 and programmed death ligand-2 (PD-L2), 
thus inhibiting PD-1-mediated negative signaling in T cells.  In addition, tislelizumab has no 
effector functions mediated through Fc gamma receptors (Zhang 2018).  Tislelizumab has 
demonstrated in vivo anti-tumor activity in several allogeneic xenograft models. 
Refer to the tislelizumab IB for additional details regarding the pharmacology of tislelizumab. 


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2.2.5.2.2 
Toxicology  
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys and in a 13-week, repeat-dose toxicology study in 
cynomolgus monkeys. 
No apparent toxicity was noted in single-dose or 13-week repeat-dose monkey toxicity studies.  
No tissue cross-reactivity was found in either human or monkey tissues, nor was any effect on 
cytokine release observed in the human whole blood assay and human peripheral blood 
mononuclear cell assay.  The toxicokinetic 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 considered to 
be 30 mg/kg.  The safety profile of tislelizumab is considered adequate to support the current 
study, 2020-013-00US3. 
Refer to the tislelizumab IB for more detailed information on the toxicology of tislelizumab. 
2.2.5.2.3 
Pharmacokinetics  
A pharmacokinetic (PK) study was conducted in cynomolgus monkey at single doses of 3, 10, or 
30 mg/kg or at a repeat dose of 10 mg/kg weekly for 5 doses via intravenous infusion.  The 
systemic exposure appeared to increase dose proportionally without gender difference or 
accumulation.  After single-dose administration of 3, 10, or 30 mg/kg, the half-life (t1/2) ranged 
from 74 to 183 hours, Cmax ranged from 90 to 999 µg/mL, area under the curve (AUC)0-1008h 
ranged from 12,322 to 163,755 h*µg/mL, and volume of distribution (Vd) ranged from 22 to 
52 mL/kg.  The t1/2 of tislelizumab in cynomolgus monkeys supported biweekly (every other 
week) dosing in the repeat-dose toxicology study. 
Refer to the tislelizumab IB for additional details regarding pharmacokinetics of tislelizumab. 
2.2.6 
Supportive Clinical Data  
2.2.6.1 
Fruquintinib  
2.2.6.1.1 
Clinical Pharmacology and Pharmacokinetics  
Single-dose and multiple-dose PK of fruquintinib have been characterized in Chinese and US 
patient populations and single-dose PK has been evaluated in healthy Chinese males.  
In Chinese patients with cancer, plasma fruquintinib exposure increased proportionally over the 
single dose range tested from 1 mg to 6 mg (Study 2009-013-00CH1).  Fruquintinib was rapidly 
absorbed with mean time to maximum concentration (Tmax) ranging from 1.5 to 4.7 hours.  Mean 
t1/2 ranging from 35.2 to 48.5 hours was observed for fruquintinib.  Following continuous dosing 
of fruquintinib 1, 2, 4, 5, or 6 mg QD, plasma fruquintinib concentration reached steady state by 
14 days after dosing with exposure accumulating 3- to 4-fold at steady state compared to Day 1.  
Following dosing of fruquintinib at 5 mg QD and 6 mg QD at the 3 weeks on/1 week off 
schedule, plasma fruquintinib concentrations declined during the off week, as expected.  
Preliminary PK results from the US patient population (Study 2015-013-00US1) that received 
fruquintinib at 3 mg and 5 mg QD 3 weeks on/1 week off suggested that there were no 
meaningful differences in fruquintinib exposure between Chinese and US patients.  Following 


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fruquintinib 5 mg QD 3 weeks on/1 week off, mean fruquintinib Cmax and AUCtau values on 
Day 21 were 326 ng/mL and 5969 h*ng/mL in Chinese patients (Study 2012-013-00CH3), 
respectively, compared with 385 ng/mL and 7530 h*ng/mL in US patients, respectively. 
The effect of a high-fat high-calorie meal on the PK of fruquintinib 4 mg (4×1-mg capsules) was 
studied in healthy Chinese males (Study 2012-013-00CH2).  Food delayed Tmax of fruquintinib 
by 2.6 hours.  A slight decrease in fruquintinib Cmax by 17% was seen, although there was no 
observed effect on AUC0-∞. 
Results from the mass balance study conducted in healthy Chinese patients (Study 2015-013-
00CH2) indicated that 60.31% of total radioactivity was recovered in urine and 29.80% in feces.  
A total of 22 metabolites were identified in the plasma, urine, and feces samples.  The M11 
(N‑desmethylation product) and M9 (carboxylic acid product) were the main metabolites; M11 
accounted for 17.31%, and M9 accounted for 4.46% of the plasma exposure of total 
radioactivity.  Only a small amount of unchanged fruquintinib was detected in urine, which 
accounted for 0.50% of the dose administered.  The amount of fruquintinib in feces accounted 
for 5.34% of the dose administered. 
M11 is a pharmacologically active metabolite found to inhibit VEGFR2 kinase activity and 
VEGF-induced VEGFR2 phosphorylation, with a potency approximately 2 to 10 times lower 
than that of fruquintinib.  After multiple doses of fruquintinib 5 mg QD to patients for 21 days 
(Study 2015-013-00US1, preliminary data), M11 reached Tmax after 1 hour.  The mean (standard 
deviation) Cmax and AUC0-24 values were 144 (56.2) ng/mL and 3080 (1250) h*ng/mL, 
respectively.  M11 accumulated by 31.5-fold after multiple dosing.  The mean (standard 
deviation) metabolite-to-parent ratio of M11 was 0.409 (0.135) at steady state.  Overall, M11 is 
not expected to have a clinically meaningful contribution to the total pharmacological activity of 
fruquintinib at therapeutic exposure. 
In Study 2015-013-00US1, preliminary PK data were comparable between the cancer 
populations in the US and China, suggesting no clinically meaningful effects of ethnicity on 
fruquintinib PK. 
2.2.6.1.2 
Clinical Safety  
As of 03 September 2019, 7 clinical studies have been completed and 5 clinical studies 
(monotherapy and/or combination therapy) were ongoing in cancer patients.  This included 3 
phase 3 studies conducted in China: 1 completed monotherapy study in patients with mCRC, 1 
completed monotherapy study in patients with advanced NSCLC, and 1 ongoing phase 3 study 
of fruquintinib in combination with paclitaxel in GC.  There is 1 ongoing phase 1/1b study of 
fruquintinib being conducted in the US.  In addition, 4 studies of fruquintinib have been 
completed in healthy volunteers. 
A pooled analysis of 4 completed, double-blind, placebo-controlled monotherapy studies was 
conducted to provide a comprehensive safety assessment separate from combination therapy.  
In each study, patients randomized to fruquintinib treatment received 5 mg once daily, 
3 weeks on/1 week off in a 4-week cycle.  A total of 739 patients received at least 1 dose of 
fruquintinib in the pooled analysis of monotherapy studies. 


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Refer to the current version of the fruquintinib IB for more detailed information on fruquintinib 
safety and efficacy data when given as monotherapy or in combination with chemotherapy or 
other agents. 
2.2.6.1.2.1 
Monotherapy Safety  
Data presented in this section is from a pooled analysis of the 4 completed double-blinded, 
placebo-controlled studies, which include 739 patients on fruquintinib and 361 patients on 
placebo.  
• Adverse Events: Of the 739 patients, 729 (98.6%) patients reported treatment-emergent 
AEs (TEAEs) and 711 (96.2%) patients reported treatment-related TEAEs.  TEAEs 
Grade ≥3 were reported by 443 (59.9%) patients.  The most commonly reported TEAEs 
Grade ≥3 (≥5.0% patients) were hypertension (19.9%) and palmar-plantar 
erythrodysesthesia (PPE) syndrome (10.7%).  TEAEs Grade ≥3 reported by 
363 (49.1%) patients were considered to be treatment-related by the investigator. 
• Serious Adverse Events: The most common SAEs (≥1.0%) by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term (PT) included infectious pneumonia in 
24 (3.2%) patients, intestinal obstruction in 17 (2.3%) patients, death in 10 (1.4%) 
patients, pleural effusion in 9 (1.2%) patients, hepatic function abnormal in 8 (1.1%) 
patients, and gastrointestinal hemorrhage in 8 (1.1%) patients.  A total of 112 (15.2%) 
patients reported treatment-related SAEs; 41 (5.5%) patients had a fatal SAE. 
• Adverse Events of Special Interest: The most frequently reported AEs of special interest 
(AESIs) (>10% of patients) in the fruquintinib group were dermatological toxicity 
(59.7%), hypertension (49.7%), thyroid dysfunction (46.3%), proteinuria (40.6%), 
hepatic function abnormal (38.4%), hemorrhages (36.1%), and infections (31.9%).  In the 
fruquintinib group, the AESIs of Grade ≥3 reported by >5% of patients included 
hypertension (22.1%), dermatological toxicity (11.1%), infections (7.3%), and hepatic 
function abnormal (6.5%). 
• Fatal Adverse Events: A total of 44 (6.0%) patients had TEAEs leading to death.   
2.2.6.1.2.2 
Safety Analysis of Study 2015-013-00US1  
This was a Phase 1/1b Dose Escalation/Dose Expansion Study in US Patients with Advanced 
Solid Tumors (Ongoing Study 2015-013-00US1). 
As of the data cut-off date of 03 September 2019, 23 patients had been enrolled and received 
fruquintinib.  Fourteen patients were enrolled in the dose escalation phase (7 patients at 
3 mg QD, 7 patients at 5 mg QD, in 3 weeks on/1 week off [28-day] cycles).  An additional 
6 patients were enrolled in a planned expanded cohort of patients with advanced, refractory solid 
tumors at 5 mg QD 3 weeks on/1 week off regimen. 
The RP2D determined in the dose escalation phase of US patients was 5 mg QD 3 weeks 
on/1 week off regimen, which is consistent with that of the approved drug label in China. 
The AE profile of patients in Study 2015-013-00US1 was consistent with that of other clinical 
studies of fruquintinib.  In the dose escalation phase, there was 1 DLT of Grade 4 hypertension at 
the 3-mg dose level that resolved after 2 days, and no DLTs were observed in the additional 


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3 patients at 3 mg or at the 5 mg 3 weeks on/1 week off regimen.  All (100%) of the 23 patients 
reported TEAEs, among whom 22 (95.7%) patients reported treatment-related TEAEs.  A total 
of 19 (82.6%) patients reported Grade ≥3 TEAEs, of whom 11 (47.8%) patients reported 
treatment-related Grade ≥3 TEAEs.  The most frequently reported treatment-related TEAEs 
(≥20% of patients) by PT were Hypertension (43.5%), Proteinuria (34.8%), Decreased appetite 
(30.4%), Diarrhoea, Nausea, Dysphonia, Fatigue (26.1% each), and Constipation (21.7%).  In the 
dose escalation phase, Grade ≥3 Hypertension was observed in 5 patients (35.7%) and was the 
only Grade ≥3 TEAE that occurred in ≥5% of patients. 
Refer to the most recent version of the fruquintinib IB for additional details on clinical safety. 
2.2.6.1.3 
Clinical Efficacy  
2.2.6.1.3.1 
Monotherapy Efficacy  
As of 03 September 2019, the available efficacy data from the phase 1 study in solid tumors 
(2009-013-00CH1) and phase 1b study in patients with CRC (2012-013-00CH3) showed 
promising clinical activity of fruquintinib, including durable PR and SD, observed in the 
majority of the heavily pretreated patients with advanced cancer, particularly in patients with 
CRC, NSCLC, and GC.  
The phase 3 study in patients with CRC (FRESCO, 2013-013-00CH1) met its primary efficacy 
endpoint of OS and showed that fruquintinib significantly improved the OS, progression-free 
survival (PFS), objective response rate (ORR), and disease control rate (DCR) as compared to 
placebo.  A total of 416 patients were randomized to receive fruquintinib (5 mg QD) or placebo 
in a 2:1 ratio, 3 weeks on/1 week off in a 4-week cycle.  As the primary endpoint, the OS was 
significantly improved in the fruquintinib group compared with the placebo group (9.3 months 
versus 6.6 months; hazard ratio [HR]=0.65; p <0.001).  The secondary endpoints of PFS 
(3.7 months versus 1.8 months; HR=0.26; p <0.001), ORR (4.7% versus 0.0%; p=0.01) and DCR 
(62.2% versus 12.3%; p <0.001), were also significantly increased in the fruquintinib group 
compared with placebo.  Fruquintinib was granted approval for the treatment of patients with 
refractory mCRC by the China National Medical Products Administration (NMPA) based on the 
results of the FRESCO study. 
One phase 3 study of fruquintinib was completed in patients with NSCLC who had failed 
second-line standard chemotherapy (2015-013-00CH1).  There was no significant difference 
between the fruquintinib group and the placebo group in the primary efficacy endpoint (OS) 
(Lu 2020).  However, fruquintinib significantly prolonged the PFS comparing to placebo with an 
HR of 0.34 (95% CI: 0.279, 0.425) with p <0.001 (stratified log-rank test).  Statistically 
significant benefits were also shown with fruquintinib in ORR and DCR. 
In the ongoing study 2015-013-00US1 of fruquintinib in patients with advanced solid tumors, 
15 of 20 patients enrolled into the dose escalation phase and planned expanded cohort of 
6 patients with advanced solid tumors were evaluable as of 03 September 2019.  Two patients 
had a confirmed PR, 11 patients had confirmed SD, and 2 patients had PD.  Of those patients, 
3 patients had mBC (1 each of hormone receptor-positive/HER2-, hormone receptor-
negative/HER2+ and TNBC).  The patient with TNBC had SD. 


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2.2.6.1.3.2 
Combination Therapy Efficacy  
A phase 1b/2 study has been conducted to investigate the treatment of fruquintinib, in 
combination with paclitaxel, as second-line therapy in patients with GC (2014-013-00CH3).  The 
results showed that the ORR and DCR were 27.3% (9/33) and 63.6% (21/33), respectively.  The 
median PFS and median OS at the RP2D (fruquintinib 4 mg plus paclitaxel) were 4.0 months 
and 8.5 months, respectively. 
The efficacy data in 1 ongoing study of fruquintinib in combination with gefitinib in patients 
with NSCLC (2016-013-00CH1) and in 1 ongoing study 2018-013-00CH3 of fruquintinib in 
combination with sintilimab in patients with advanced solid tumor were not available as of the 
data cutoff date (03 September 2019). 
2.2.6.2 
Tislelizumab  
2.2.6.2.1 
Clinical Pharmacology and Pharmacokinetics  
Population PK analysis was conducted using data from 798 patients with solid tumors or 
classical Hodgkin lymphoma who received doses ranging from 0.5 to 10 mg/kg once every 2 or 
3 weeks.  The PK of tislelizumab was best characterized using a 3-compartmental linear 
population PK model with linear CL mechanisms.  No time-varying CL was observed in 
tislelizumab PK.  The typical estimates of CL, central volume (Vc), and peripheral volumes (V2, 
V3) were 0.164 L/day and 2.92, 0.928, and 1.39 L, respectively, with moderate inter-individual 
variability in CL (32.2%), Vc (16.7%), V2 (56.6%), and V3 (94.2%).  Consistent with other 
therapeutic IgG monoclonal antibodies, the volume of distribution at steady state (Vss) was 
5.238 L and the terminal half-life is approximately 25.5 days (Deng 2012, Dirks 2010, 
Keizer 2010, Ryman 2017). 
Population PK analysis demonstrated that baseline age, race, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin, lactate dehydrogenase, estimated glomerular 
filtration rate, Eastern Cooperative Oncology Group (ECOG) performance status score, 
immunogenicity, and sum of products of perpendicular diameters in classical Hodgkin 
lymphoma patients did not show statistically significant impact on the PK of tislelizumab.  
Although tumor size, albumin, and tumor type were significant covariates on CL while body 
weight, sex, and tumor type were significant covariates on Vc, these covariates are not expected 
to have a clinically relevant impact on tislelizumab exposure.  Exposure-response analysis 
indicated that there was a lack of clinically significant exposure-response relationships for ORR 
and safety endpoints across a variety of advanced solid tumors and classical Hodgkin lymphoma 
for tislelizumab.  Population PK analysis supports flat-dosing across different ethnic groups. 
2.2.6.2.2 
Clinical Safety  
As of 20 May 2019, there were 22 ongoing studies with tislelizumab with over 1705 patients 
treated.  Of these, 13 studies have preliminary data available in the IB version 7, 13 September 
2019: 7 monotherapy studies, 2 chemotherapy combination therapy studies, and 4 investigational 
agent combination therapy studies. 
A pooled analysis of 7 monotherapy studies was conducted to provide a comprehensive safety 
assessment separate from combination therapy.  There were 1273 patients in the Pooled 
Monotherapy studies: 1137 patients treated in 5 solid tumor studies and 136 patients treated in 


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2 hematologic malignancies studies.  Of the 1273 enrolled, 544 patients (42.7%) remained on 
study as of 20 May 2019, and 272 patients (21.4%) were still receiving tislelizumab treatment. 
Refer to the current tislelizumab IB for more detailed information on tislelizumab safety data 
when given as monotherapy or in combination with chemotherapy. 
2.2.6.2.2.1 
Monotherapy Safety  
• Adverse Events: Of the 1273 total patients treated in the Pooled Monotherapy studies, 
1210 patients (95.1%) experienced at least 1 TEAE and 846 patients (66.5%) experienced 
at least 1 treatment-related TEAE.  TEAEs Grade ≥3 were reported by 548 patients 
(43.0%).  The most commonly occurring Grade ≥3 TEAEs were anemia (64 patients, 
5.0%), AST increased (35 patients, 2.7%), pneumonia (35 patients, 2.7%), and ascites 
(25 patients, 2.0%).  All other events occurred in under 2.0% of the total Pooled 
Monotherapy population.  A total of 163 (12.8%) patients experienced at least 1 Grade ≥3 
TEAE assessed as related to tislelizumab. 
• Serious Adverse Events: Of the 1273 total patients treated in the Pooled Monotherapy 
studies, 424 patients (33.3%) experienced at least 1 treatment-emergent SAE.  The most 
commonly occurring treatment-emergent SAEs were pneumonia (35 patients, 2.7%), 
pyrexia (22 patients, 1.7%), and ascites (17 patients, 1.3%). 
• Immune-Mediated Adverse Events:  Anti-programmed cell death protein-1 antibody(Anti-
PD-1) therapies are known to cause imAEs in some patients and therefore have been 
defined as AESIs in tislelizumab clinical studies.  Immune-mediated AEs (imAEs) are 
consistent with an immune-mediated mechanism or immune-mediated component for 
which noninflammatory etiologies (eg, infection or tumor progression) have been ruled 
out.  Immune-mediated AEs can include events with an alternate etiology that were 
exacerbated by the induction of autoimmunity.  There is a potential temporal relationship 
between the initiation of treatment with tislelizumab and onset of an imAE that spans a 
window of days to several months.  All imAEs presented here are assessed as related to 
study drug by the investigator and categorized by the HUTCHMED Limited (formerly 
known as Hutchison MediPharma Limited) Safety/Pharmacovigilance team.  Certain 
imAEs have multiple MedDRA terms associated with the same category.  Special 
categories have been created to group patients experiencing these events.  
Immune-mediated AEs of hepatitis, pneumonitis, colitis, endocrinopathies, myocarditis, 
and serious skin adverse reactions have been identified as risks for tislelizumab.  Refer to 
the tislelizumab IB for more detailed information. 
• Infusion-Related Reactions: Infusion-related reactions, including high-grade 
hypersensitivity reactions, following administration of tislelizumab are common.  Of the 
1273 total patients in the Pooled Monotherapy studies, 97 patients (7.6%) experienced at 
least 1 infusion-related reaction of any grade.  The most commonly occurring 
infusion-related reactions of any grade that occurred in the total pooled analysis were 
pyrexia (50 patients, 3.9%), infusion-related reactions (28 patients, 2.2%), and pruritus 
(11 patients, 0.9%).  There were 6 patients who reported a total of 7 Grade ≥3 
infusion-related reactions in the Pooled Monotherapy studies (reported events included 
back pain, hypotension, infusion-related reaction, musculoskeletal chest pain, pyrexia, 
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• A total of 68 patients (5.3%) had TEAEs leading to death.  Refer to tislelizumab (BGB-
A317) IB Edition 7 (Section 5.2.1.9) for a summary of the treatment-emergent fatal AEs 
that occurred in the Pooled Monotherapy studies. 
2.2.6.2.3 
Clinical Efficacy  
Efficacy data are available from 2 of the ongoing monotherapy studies in solid tumors, 
BGB‑A317_Study_001 and BGB-A317-102, as of 20 May 2019. 
2.2.6.2.3.1 
BGB-A317 Study_001  
BGB-A317 Study_001 is a 2-stage study consisting of a phase 1a dose-escalation (0.5 to 
10 mg/kg) and dose-finding component with 3 parts (2 and 5 mg/kg given once either every 2 or 
every 3 weeks and a fixed dose of 200 mg given once every 3 weeks) to establish the maximum 
tolerated dose, if any, and an RP2D followed by a phase 1b component to investigate efficacy in 
select tumor types at the RP2D to further evaluate safety and tolerability of tislelizumab.  
Indication-specific cohorts included esophageal cancer, GC, CRC, and NSCLC. 
Responses were assessed by the investigator per the Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 criteria. 
There were 451 patients treated in the study, and 441 patients were included in the Efficacy 
Evaluable Analysis Set.  The analysis set includes all treated patients who had at least 
1 measurable baseline target lesion and at least 1 evaluable post-baseline tumor assessment.  This 
set included 52 patients in the GC cohort and 21 patients in the CRC cohort. 
Across all disease cohorts, there were 5 patients (1.1%) with a complete response (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 BOR of SD.  A total of 
199 patients (45.1%) had a best response of PD in this study. 
Of the 52 patients in the GC cohort, 7 patients (13.5%) had a confirmed PR.  Additionally, there 
were 9 patients (17.3%) with a BOR of SD.  A total of 31 patients (59.6%) had a best response of 
PD in this cohort, and the assessment for 5 patients (9.6%) was missing.  Of the 21 patients in the 
CRC cohort, 3 (14.3%) had a confirmed PR and 7 patients (33.3%) had a BOR of PD.  Two 
patients (9.5%) had missing assessments. 
2.2.6.2.3.2 
Study BGB-A317-102  
Study BGB-A317-102 is a 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 evaluates the activity and safety of tislelizumab at its RP2D of 200 mg given once every 
3 weeks in indication-specific expansion cohorts in patients who had at least 1 measurable 
baseline target lesion and at least 1 evaluable post-baseline tumor assessment.  This set includes 
12 patients in the GC cohort and 16 patients in the CRC cohort. 
The tumor responses in the Efficacy Evaluable Analysis Set of Study BGB-A317-102 across all 
disease cohorts and study phases was 1 patient (0.4%) with a CR and 44 patients (17.7%) with 
confirmed PR.  The resulting overall clinical response rate was 18.1%.  Additionally, there were 


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91 patients (36.5%) with a BOR of SD.  A total of 113 patients (45.4%) had a best response of 
PD in this study. 
The tumor responses in the Efficacy Evaluable Analysis Set of Study BGB-A317-102 in the GC 
cohort (12 patients) were 3 patients (25.0%) who had a confirmed PR.  Additionally, there were 
2 patients (16.7%) with a BOR of SD.  A total of 7 patients (58.3%) had a best response of PD in 
this cohort.  In the CRC cohort (16 patients), 3 patients (18.8%) had a confirmed PR, 5 patients 
(31.3%) had a BOR of SD, and 8 patients (50.0%) had a best response of PD. 
Refer to the tislelizumab IB for more detailed information on tislelizumab efficacy data when 
given as monotherapy or in combination with chemotherapy. 
2.2.7 
Rationale for Fruquintinib and Tislelizumab in Combination  
2.2.7.1 
Triple Negative Breast Cancer  
Triple negative breast cancer is more aggressive and has a worse prognosis compared to other 
types of breast cancer, with a median OS of 8 to 15 months (Liu 2020).  Chemotherapy is the 
primary treatment for TNBC, but responses are short-lived.  Treatment with immune checkpoint 
inhibitors (ICIs) has improved clinical outcomes in TNBC, and the use of immunotherapy in 
TNBC is supported by higher expression of PD-L1 in TNBC when compared to other breast 
cancer subtypes (Mittendorf 2014), a higher rate of tumor mutation burden (TMB) in high-grade 
tumors (although lower than that observed in other malignancies such as lung cancer and 
melanoma), and relatively higher tumor infiltrated lymphocyte (TIL) density in TNBC 
(Kandoth 2013).  Several studies investigating anti-PD-L1 inhibitors as monotherapy in TNBC 
showed objective response rates of 5.2% to 18.5%, with higher response rates demonstrated in 
earlier lines of therapy.  Based on the results of IMpassion130 study, the combination of 
atezolizumab, a humanized engineered anti-PD-L1 monoclonal antibody, and nab-paclitaxel 
chemotherapy was approved for the treatment of patients with unresectable locally advanced or 
metastatic TNBC whose tumors express PD-L1 (Schmid 2018).  However, treatment options for 
patients who progress on or who are not candidates for the combination remain limited, and 
prognosis remains poor.  Thus, there is a high unmet need to investigate new therapies in patients 
with refractory TNBC and to explore potential mechanisms to overcome acquired or intrinsic 
resistance to anti-PD-L1 therapy.  Although immunotherapy has emerged as an important 
treatment for a variety of cancers, including TNBC, a large proportion of patients do not respond 
to such treatment, and initial responders eventually develop resistance.  One mechanism of 
resistance to immunotherapy is immune suppression through other immune checkpoints that 
regulate lymphocyte activation or through the immunosuppressive cells (Fukuoka 2020).  There 
is increasing evidence that tumor angiogenesis is highly dependent on a suppressive tumor 
microenvironment, and VEGF-A was recently identified as a key factor in tumor-induced 
immunosuppression by facilitating the proliferation of immunosuppressive cells, limiting T-cell 
recruitment into tumors, and promoting T-cell exhaustion (Lapeyre-Prost 2017).  Therefore, one 
strategy for targeting the tumor microenvironment is to inhibit angiogenesis while stimulating an 
effective immune response.  The process of angiogenesis is promoted and influenced by 
inflammatory mediators such as cytokines and immune cells, which can affect the immune 
microenvironment.  Anti-angiogenic agents can stimulate the immune system and act 
synergistically with ICIs to enhance anti-tumor response.  The synergistic effect of anti-
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There is a growing body of evidence supporting the combination of anti-angiogenic agents and 
immunotherapy in TNBC.  Despite the clinical activity observed with ICIs in TBNC, certain 
poorly immunogenic tumors such as breast cancer have intrinsically low-response rates to 
immunotherapy due to a paucity of tumor-infiltrating T lymphocytes and an abundance of 
immunosuppressive myeloid cell populations within the tumor microenvironment.  Even for 
TNBC, which is more immune sensitive, the ORR of PD-1/PD-L1 blockade from early-phase 
monotherapy trials was low (Dirix 2018, Nanda 2016, Emens 2019).  Therefore, there is an 
increased interest in identifying combination treatment strategies to improve the response rate 
and the efficacy of immunotherapy treatment (Emens 2017).  The responsiveness of tumors to 
ICIs is dependent on multiple intrinsic and extrinsic factors.  Notably, tumor vasculature is often 
morphologically abnormal and functionally impaired, resulting in reduced infiltration of immune 
effector cells into the tumor (Huang 2018).  In addition, tumor blood vessels have impaired 
perfusion capacity, which creates increased intratumoral hypoxia that inhibits the activity of 
infiltrated cytotoxic T cells (Lanitis 2015).  This process results in the accumulation of 
suppressive immune cells such as myeloid-derived suppressor cells and regulatory T-cells 
(Corzo 2010).  The hypoxic tumor microenvironment also stimulates the secretion of several 
immunosuppressive cytokines (Facciabene 2011) and promotes the upregulation of PD-L1 on T 
cells (Barsoum 2014).  Normalization of tumor vasculature has been proposed to reduce 
immunosuppression and synergize with cancer immunotherapy (Ali 2018). 
Numerous clinical studies are underway in a variety of indications (eg, renal cell carcinoma, 
NSCLC, CRC, gastrointestinal malignancies, melanoma, urothelial carcinoma, and breast 
cancer) to evaluate the combination of immunotherapies and anti-angiogenics.  Additionally, 
since 2019, a number of similar combinations have been approved for a variety of indications 
demonstrating the therapeutic potential of immunotherapy and anti-angiogenic combinations.  
These include pembrolizumab plus axitinib for patients with advanced renal cell carcinoma 
(KEYNOTE‑426, NCT02853331); pembrolizumab and lenvatinib for patients with advanced 
endometrial cancer (KEYNOTE-146, NCT02501096); and atezolizumab and bevacizumab for 
patients with unresectable or metastatic hepatocellular carcinoma (IMbrave150, NCT03434379). 
There are several completed, ongoing, and planned studies of anti-angiogenic agents in 
combination with PD-L1 inhibitors in TNBC, including a phase 2 study of atezolizumab plus 
bevacizumab plus cobimetinib, a phase 2 study of SHR-1210 (an anti-PD-1 antibody) plus 
apatinib, and a phase 1/2 study of MEDI4738 plus bevacizumab plus olaparib, that support the 
investigation of the combination of fruquintinib and tislelizumab in TNBC, and promising anti-
tumor activity has been seen with the combination.  Preclinical studies with breast cancer models 
demonstrated that combining anti-PD-1 antibody and anti-VEGFR 2 therapy significantly 
improved responses to tumors (Li 2020).  Results from the phase 2 study of SHR-1210 (or 
camrelizumab) in combination with apatinib in patients with advanced TNBC demonstrated a 
PFS of 3.7 months (Liu 2020).  This stands in contrast to PFS of 1.9 months shown in the phase 
1b KEYNOTE-012 with single-agent pembrolizumab (Nanda 2016).  Patients who had a better 
response to the combination were found to have notable vascular remodeling and increase TILs 
when compared to poor responders.  No correlation between PD-L1 expression and tumor 
response was observed (Li 2020).  Taken together, these data suggest a synergistic activity with 
the combination of anti-angiogenic therapy and anti-PD-L1 antibodies and provide rationale for 
the combination in TNBC. 


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Based on the available clinical data from the combination of immunotherapy and 
anti-angiogenics, which demonstrate promising anti-tumor effect compared to the therapeutic 
effect of a single agent alone, the combination of fruquintinib and tislelizumab may provide a 
tolerable, effective treatment option for the patients with TNBC.  This study will be aimed at 
investigating if the combination of fruquintinib with tislelizumab is safe and effective in TNBC 
and could give insight into overcoming potential resistance mechanisms to ICIs in these tumors. 
2.2.7.2 
Endometrial Cancer  
Endometrial cancer, when diagnosed early, has a 5-year overall survival rate of 81%.  The 5-year 
overall survival rate for stages IVa and IVb EC, however, is only 17% and 15%, respectively.  
Deaths associated with EC are increasing globally at a steady rate.  Initial management of EC 
consists of surgery followed by radiation and/or cytotoxic chemotherapy.  Recurrent disease is 
treated with cytotoxic, targeted, or hormonal therapy with or without radiotherapy.  Despite these 
therapies, overall survival remains poor.  EC cells possess the ability to downregulate immune 
response by activating PD-1 signaling.  PD-1 and PD-L1 expression in ECs represent the highest 
expression among gynecologic cancers (Green 2020).   
Multiple clinical studies with PD-1 inhibitors as monotherapy have demonstrated clinical 
efficacy in EC with ORRs between 26.7% and 53%. (Green 2020).  The multi-tyrosine kinase 
inhibitor lenvatinib has been approved as monotherapy for iodine-refractory differentiated 
thyroid cancer and unresectable hepatocellular carcinoma.  It has also been investigated in EC as 
second-line therapy in a phase 2 trial that demonstrated modest tumor activity with an ORR of 
14.3% (Vergote 2020).  There are ongoing studies to examine the efficacy of combinations of 
immunotherapies with differing mechanisms of action to overcome resistance mechanisms 
observed in monotherapy (Green 2020). 
Recently, the combination of the multi-tyrosine kinase inhibitor lenvatinib in combination with 
the PD-1 inhibitor pembrolizumab was granted accelerated FDA approval in advanced EC.  The 
KEYNOTE-146 was a phase 1b/2 study that evaluated this combination in patients with 
advanced tumors, including EC, and provided the basis for the approval.  An analysis of 
108 patients with EC showed the ORR was 38% with an ORR of 63.6% among those with MSI-
H/dMMR tumors and 36.2% among those with microsatellite stable (MSS)/MMR proficient 
(pMMR) tumors.  The overall DCR was 84.3%, including 80.9% among the MSI-H/dMMR 
population and 84.0% among those with MSS/pMMR tumors.  ORR was similar regardless of 
PD-L1 expressions status (median follow-up of 18.7 months) (Vergote 2020).  The confirmatory, 
phase 3 KEYNOTE-775(NCT03517449) randomized 827 patients and met its dual primary 
endpoints.  With a median follow-up of 11.4 months, results demonstrated a median progression-
free survival of 7.2 months vs 3.8 months (hazard ratio [HR]=0.56, p<0.0001) and median 
overall survival of 18.3 months vs 11.4 months (HR=0.63, p<0.0001) (Makker 2020).  The 
KEYNOTE-775 study led to FDA approval of pembrolizumab in combination with lenvatinib in 
patients who had progressed on a platinum-based first-line chemotherapy.  
2.2.7.3 
Colorectal Cancer  
The mainstay of first‐line therapy for mCRC is combination chemotherapy plus an anti‐VEGF or 
anti‐EGFR antibody, depending on tumor characteristics.  However, most patients progress 
within 1 year (Chau and Cunningham 2009).  Patients with mCRC that progress on first-line 
therapy are often treated with second-line chemotherapy.  Beyond the second line, targeted 


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therapy such as regorafenib or TAS-102 have been shown to prolong survival.  However, the 
treatment benefit is short-lived.  Recently, immune checkpoint inhibitors have demonstrated 
activity in patients with CRC and other solid tumors that are MSI‐H/dMMR.  Nivolumab and 
pembrolizumab are currently approved by the FDA for patients with MSI‐H/dMMR  mCRC 
(Morse 2019). However, PD-1 blockade is particularly ineffective in patients with MSS or 
MMR–proficient CRC, which makes up the majority (95%) of mCRC patients (Ali 2018).  This 
can be explained by the lower antigenicity due to the presence of fewer neoantigens, regardless 
of tumor mutation burden, resulting in fewer infiltrating CD8+ T cells in general and fewer 
strongly positive for PD‐1 (Morse 2019).  Recently, several strategies to turn a “cold” CRC 
tumor into an immunoreactive “hot” tumor were being tested in clinical trials.  In a Phase 1b 
trial, 25 patients with advanced CRC received treatment with regorafenib plus nivolumab.  
Objective tumor response was observed in 9 patients (36%).  After exclusion of 1 patient with 
MSI-H mCRC, the ORR was 33.3% in patients with MSS mCRC.  Median PFS was 7.9 months 
(Fukuoka 2020). 
The combination of PD-1/PD-L1 and VEGFR inhibitors warrants further evaluation as a 
treatment paradigm for patients with mCRC. 
2.2.8 
Rationale for Biomarker Strategy  
A number of biomarkers have been identified that correspond with response to immunotherapy 
for patients with TNBC, EC, or MSS mCRC.  PD-L1 expression has been demonstrated to be 
positively correlated with response to anti-PD-1 therapy across tumor types (Cristescu 2018).  
For TNBC, the expression of PD-L1 is positively correlated with response to anti-PD-1 
monotherapy.  For EC, clear correlation between PD-L1 expression and response to anti-PD-1 
has not been reported.  However, there may be a correlation with MSS/MSI status for EC 
(Makker 2020).  For MSS CRC, clear correlation between PD-L1 expression and response to 
anti-PD-L1 has not been reported.  One pilot study has demonstrated the negative correlation 
between PD-L1 expression and response to anti-PD-L1 in combination with VEGFR-TKI 
(Fukuoka 2020).  Due to the limited number of patients, the role of PD-L1 expression in 
predicting response to anti-PD-L1 in combination with VEGFR-TKI warrants further 
exploration.  Hence, post-hoc biomarker studies will be performed in these tumors to evaluate 
signatures that may predict response to this combination.  
TNBC is the most immunogenic breast cancer subtype, with high incidence of PD-L1 expression 
and abundant TILs.  PD-L1 as a predictive biomarker of response to PD-1/PD-L1 blockade in 
TNBC has been recognized in several clinical trials.  One representative is IMpassion130, in 
which a significant OS improvement was observed in PD-L1 positive patients by treatment with 
atezolizumab plus nab-paclitaxel compared to nab-paclitaxel chemotherapy.  However, other 
TNBC studies (eg, KEYNOTE-086 [cohort A, pembrolizumab monotherapy in pretreated 
patients] and KEYNOTE-522 [pembrolizumab plus neoadjuvant chemotherapy]) demonstrated 
little or no difference in response according to PD-L1 status.  Despite inconsistent results likely 
due to the different drugs, disease stages, prior treatments, PDL1 immunohistochemistry (IHC) 
assays, or all of these factors, PD-L1 is still an important and most widely studied biomarker in 
TNBC.   
Accumulating evidence suggests that other biomarkers are predictive of response to ICIs, 
including MSI, MMR deficiency, and TMB.  Microsatellite instability is the genetic hyper-
mutability deriving from impaired deoxyribonucleic acid (DNA) MMR.  High MSI is associated 


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with increased neoantigen production by tumors, greater immunogenicity, and stronger immune 
response.  TMB is a measurement of the number of nonsynonymous mutations carried by tumor 
cells.  Mutations lead to increased expression of neoantigens in the context of MHC class I 
antigens, enhancing the recognition of cancer cells by T cells.  Based on the results from multiple 
KEYNOTE-series clinical trials, the FDA approved pembrolizumab for the treatment of any 
MSI-H or MMR-deficient unresectable or metastatic solid tumor and, recently, for any tumor 
mutation burden-high (TMB-H) solid tumors according to KEYNOTE-158.  However, in breast 
cancer, limited data regarding the incidence of MSI-H, MMR-deficient, and TMB-H as well as 
the associations with the response to ICIs is available.  Additionally, TILs have emerged as a 
predictive biomarker in response to ICI therapy.  In the IMpassion-130 trial, CD8+TILs along 
with PD-L1 expression on immune cells have been associated with increased PFS and OS in 
patients treated with atezolizumab and nab-paclitaxel.  This finding also suggests possible 
interactions among multiple factors in the immune microenvironment.  In fact, evidence has been 
increasingly showing that combined biomarker strategies and incorporated multiple factors 
analysis could be more ideal approaches to enrich responders to PD-L1 blockade, although the 
optimal model has yet to be determined. 
Taken together, these biomarker results mainly come from the clinical studies for anti-PD-L1 
monotherapy or combination with chemotherapies in TNBC.  Biomarker studies in this 
combination trial of fruquintinib and tislelizumab will retrospectively detect immune response 
biomarkers and explore whether there is a dominant population benefit from the combination 
treatment. 
TMB works as the surrogate marker for neo-antigen prediction and has been reported to be 
positively correlated with response to anti-PD(L)-1, and serves as an independent biomarker 
from PD-L1, indicating that its combination with PD-L1 may lead to predictive synergy 
(Fumet 2020; Cristescu 2018).  In CRC, 1 pilot study has shown the trend of patients with high 
TMB benefiting from anti-PD(L)-1 in combination with VEGFR-TKI, compared to those with 
low TMB. Due to the limited number of patients included, this trend needs further verification 
(Fukuoka 2020).  Blood TMB, demonstrated good correlation with TMB if assessed with large 
panels, which has been explored due to its non-invasiveness feature, and has been reported to 
predict clinical benefit with anti-PD-(L)1 therapy in several clinical trials (POPLAR, OAK, 
MYSTIC trials, etc.) (Gandara 2018).  
Gene expression profile (GEP) panels have been designed to investigate immune features (tumor 
immunogenicity, interferon gamma signature, immune cell population abundance, etc.), and 
tumor features (EMT, angiogenesis, hypoxia, cell adhesion, etc.). Interferon gamma signature 
has been shown to be positively correlated with response to anti-PD(L)-1 monotherapy across 
tumor types (Cristescu 2018). Results related to GEP have not been reported in anti-PD(L)-1 
plus VEGFR-TKI studies in patients with MSS mCRC yet, however, publications or 
presentations in hepatocellular carcinoma (GO30140 trial, ASCO 2020), melanoma 
(NCT03086174, ASCO 2020), and RCC have reported the association of GEP panels (selected 
genes) with response to anti-PD(L)-1 in combination with anti-VEGF/VEGFR-TKI 
(McDermott 2018; Wallin 2016), implying GEP panels may play a potential role in predicting 
response to anti-PD-(L)1 plus VEGFR-TKI in patients with MSS mCRC. Apart from its 
potential predictive value, GEP panels can be designed to explore underlying resistance 
mechanism like immunosuppressive cytokines and cells to guide potential combination strategies 
(Fumet 2020; Cristescu 2018).  




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Table 3 
Risk Assessment (List of Risks as per Current IB [Edition 13.0])  
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
infection, urinary tract infection and pneumonia. 
Fatal SAEs have been reported.  
Possible class effect: In some of VEGFR inhibitors 
(such as sorafenib, regorafenib), infections were 
reported as one of the most common adverse 
reactions (≥20%).  Fatal cases have been reported 
with regorafenib. 
Hypertension 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
Possible class effect: Mild to moderate hypertension 
has been observed in most VEGFR inhibitors (eg, 
sorafenib, regorafenib, axitinib, sunitinib). 
AE observations 
Closely monitor blood pressure. 
 Identified Risk 
Refer to the fruquintinib IB 
Dermatological 
toxicity (includes 
palmar-plantar 
erythrodysaesthesia 
[PPE] syndrome, 
rash, dermatitis) 
In patients receiving fruquintinib, there have been no 
fatal events reported. The most frequent events 
included palmar-plantar erythrodysaesthesia 
syndrome, rash and dermatitis.  
Possible class effect: Hand-foot skin reactions and 
rash were common adverse reactions observed in 
Most of the VEGFR inhibitors (eg, sorafenib, 
regorafenib, axitinib, sunitinib). 
AE observations 
Proteinuria 
(includes protein 
urine present, 
albuminuria) 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
Possible class effect: Proteinuria has been observed 
in some VEGFR inhibitors (eg, sorafenib, 
regorafenib, axitinib, sunitinib) and VEGF inhibitors 
(bevacizumab). 
AE observations 
Closely monitor urine routine 
parameters, 24-hour urine protein 
quantification, monitoring of 
blood urea, nitrogen, and 
creatinine. 
Thyroid dysfunction 
(includes 
hypothyroidism, 
thyroid function test 
abnormal) 
In patients receiving fruquintinib, 1 patient 
experienced fatal hyperthyroidism and thyroiditis 
subacute events. 
Possible class effect: Hypothyroidism and TSH 
decreased has been observed in some VEGFR 
inhibitors.  Hyperthyroidism has been reported as an 
uncommon adverse reaction for sorafenib. 
AE observations 
Dysphonia 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Pharyngolaryngeal 
pain/discomfort 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Abdominal 
pain/discomfort 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Diarrhoea (includes 
frequent bowel 
movements) 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Decreased appetite 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 


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Table 3 
Risk Assessment (List of Risks as per Current IB [Edition 13.0])  
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Stomatitis 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Oral pain 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Proctalgia (anal 
pain) 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Weight decreased 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Platelet decreased 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Closely monitor hematology 
parameters. 
WBC 
decreased/neutrophil 
decreased 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Closely monitor blood routine 
parameters. 
Amylase increased 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Asthenia 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Musculoskeletal 
pain 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Back pain 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Arthralgia 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
AE observations 
Important 
Potential Risk 
Refer to the fruquintinib IB, Section 6.5 and Table 57 
Gastrointestinal 
perforation 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
Possible class effect: The risk of severe and fatal 
gastrointestinal perforation has been observed in 
some VEGFR inhibitors (eg, regorafenib, axitinib, 
sunitinib). 
AE observations 
Arterial thrombosis 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
Possible class effect: In some of VEGFR inhibitors 
(such as sorafenib and axitinib), thromboembolic 
events were reported in some of the clinical trials.  
Axitinib includes fatal embolic event. 
AE observations 
RPLS 
In patients receiving fruquintinib, there have been no 
fatal events reported. 
Possible class effect: In some of VEGFR inhibitors 
(such as sorafenib), RPLS was reported as an 
uncommon adverse reaction.  Individual RPLS case 
AE observations 




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Table 3 
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Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
and permanently discontinue for 
severe or life-threatening 
(Grade 3 or 4) pneumonitis. 
Immune-mediated 
colitis 
Immune-mediated colitis and diarrhea, defined as 
requiring use of corticosteroids and with no clear 
alternative etiology, can occur.  
Monitor patients for signs and 
symptoms of colitis or severe 
diarrhea. 
Withhold tislelizumab for 
moderate (Grade 2) or severe 
(Grade 3) diarrhea or colitis. 
Administer prednisolone at a 
dose of 0.5 to 2 mg/kg/day or 
equivalents.  
Permanently discontinue 
tislelizumab for recurrent severe 
(Grade 3) or life-threatening 
(Grade 4) colitis. 
Immune-mediated 
endocrinopathies 
Immune-mediated endocrinopathies, including 
thyroid disorders, diabetes mellitus, adrenal 
disorders, and hypophysitis, which may require 
anti-diabetic treatment or endocrine therapy, can 
occur. 
Hypophysitis: Monitor patients 
for signs and symptoms of 
hypophysitis, including 
hypopituitarism and adrenal 
insufficiency.  
Prednisolone can be administered 
at a dose of 0.5 to 1 mg/kg/day 
prednisolone equivalents and 
hormone replacement as 
clinically indicated. 
Withhold tislelizumab for severe 
(Grade 3) cases when associated 
with headache/visual disturbance 
due to pituitary inflammation 
until resolved/improved to 
Grade 2 or less.  Discontinuation 
is usually not necessary. 
Type I diabetes mellitus: Monitor 
patients for hyperglycemia or 
other signs and symptoms of 
diabetes.  
Withhold tislelizumab for severe 
(Grade 3) hyperglycemia until 
blood glucose has been stabilized 
and the patient is hyperglycemia 
symptom-free.  Withhold or 
discontinue tislelizumab for life-
threatening (Grade 4) 
hyperglycemia. 
Administer insulin as clinically 
indicated for Type I Diabetes. 


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Table 3 
Risk Assessment (List of Risks as per Current IB [Edition 13.0])  
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Thyroid disorders: Monitor 
patients for thyroid disorders and 
changes in thyroid function. 
Administer replacement 
hormones for hypothyroidism 
and thionamides/beta-blockers 
for hyperthyroidism as clinically 
indicated. 
Withhold or discontinue 
tislelizumab for severe (Grade 3) 
or life-threatening (Grade 4) 
hypothyroidism/hyperthyroidism. 
Other: Withhold tislelizumab for 
other severe (Grade 3) or life-
threatening (Grade 4) 
endocrinopathies, and continue 
treatment only when symptoms 
have improved and endocrine 
deficiencies have been corrected. 
Immune-mediated 
myocarditis 
Immune-mediated myocarditis, defined as cardiac 
signs and symptoms with no clear alternative 
etiology, can occur. 
Monitor for cardiac signs and 
symptoms periodically during 
treatment. 
Withhold treatment with 
tislelizumab for asymptomatic 
but significantly increased CK-
MB or increased troponin OR 
signs and symptoms of possible 
myocarditis. 
Corticosteroids can be 
administered at a dose of 1 to 
2 mg/kg/day prednisolone 
equivalents for moderate 
(Grade 2), severe (Grade 3), or 
life-threatening (Grade 4) 
myocarditis. 
Permanently discontinue 
treatment with tislelizumab for 
Grades 2 to 4 myocarditis. 
Immune-mediated 
serious skin 
reactions 
Immune-mediated serious skin reactions can occur. 
Monitor patients for suspected 
severe skin reactions and exclude 
other causes.  
Corticosteroids can be 
administered at a dose of 0.5 to 
2 mg/kg/day prednisolone 
equivalents for severe (Grade 3) 
or life-threatening (Grade 4) 
rash. 


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Table 3 
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Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Withhold tislelizumab for severe 
(Grade 3) rash and permanently 
discontinue for life-threatening 
(Grade 4) rash. 
One case of fatal TEN was reported in a patient 
receiving tislelizumab in combination with 
zanubrutinib. 
For signs or symptoms of SJS or 
TEN, withhold tislelizumab and 
refer the patient for specialized 
assessment and treatment.  If SJS 
or TEN is confirmed, 
permanently discontinue 
tislelizumab. 
Other immune-
mediated adverse 
reactions 
The following imAEs occurred in less than 1% of 
treated patients: encephalitis, rhabdomyolysis, 
myositis, nephritis, pancreatitis, and uveitis. 
Monitor patients for signs and 
symptoms of other imAEs. 
Infusion-related 
reactions 
Symptoms of infusion-related reactions that may be 
observed include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, 
urticaria, rash, vomiting, myalgia, dizziness, or 
hypertension.  Rare life-threatening reactions can 
occur. 
Closely monitor patients for 
signs and symptoms during 
infusion. 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase, CK-
MB=creatine kinase-MB; IB=Investigator’s Brochure; imAE=immune-mediated adverse event; LVEF=left 
ventricular ejection fraction; PPE=palmar-plantar erythrodysesthesia; RPLS=reversible posterior 
leukoencephalopathy syndrome; SJS=Stevens-Johnson Syndrome; TEN=toxic epidermal necrolysis; 
TSH=thyroid stimulating hormone; VEGFR=vascular endothelial growth factor receptor. 
2.3.1.2 
Benefit Assessment  
Fruquintinib 
Robust cumulative efficacy has been demonstrated for fruquintinib from the entire clinical 
program in China, including in patients with mCRC in the randomized, double-blind, placebo-
controlled FRESCO trial, and in the US.  Preliminary efficacy of fruquintinib has been 
demonstrated in mBC, including TNBC, in a phase 1 study conducted in China 
(Study 2009-013-00CH1) and in an ongoing phase 1/1b study conducted in the US 
(Study 2015-013-00US1).  Expansion cohorts in TNBC and hormone-receptor positive, 
HER2-mBC are currently enrolling.  A phase 3 study (FRESCO-2) of fruquintinib in 
combination with the best supportive care in advanced CRC patients has completed enrollment 
globally.  
Tislelizumab 
Preliminary data from ongoing phase 1 and phase 2 trials of single-agent tislelizumab suggest 
that there is anti-tumor activity across a variety of tumor types.  Tislelizumab has also been 
shown to have anti-tumor activity in various solid tumors in ongoing phase 1 and phase 2 trials 
when combined with chemotherapy and poly-ADP ribose polymerase inhibitors.  Across 
monotherapy and combination trials, anti-tumor activity has been seen. 


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2.3.1.3 
Overall Benefit:Risk Conclusion  
There remains an unmet need for patients with advanced TNBC, EC, and CRC.  A growing body 
of evidence suggests that both fruquintinib and tislelizumab may potentially be efficacious in 
TNBC, EC, and CRC populations proposed in this trial. 
Safety data from the completed and ongoing studies show that fruquintinib and tislelizumab were 
both well tolerated, with most of the AEs reported as Grade 1 to 2 (see current IB), and there 
have been no new or unexpected safety findings from the ongoing clinical trials to date. 
The potential drug-drug interaction between fruquintinib, a small-molecule drug product, and 
tislelizumab, a monoclonal antibody, is expected to be very low.  The tolerability of TKI and 
anti-PD-1 therapy combination has been demonstrated in other combination trials (eg, lenvatinib 
plus pembrolizumab in patients with advanced endometrial cancer [Makker 2019] and avelumab 
plus axitinib in patients with advanced hepatocellular carcinoma [Kudo 2019]), and the toxicity 
profile of each therapy has appeared consistent with its monotherapy profile.  Thus, no severe 
overlapping toxicity is expected with fruquintinib in combination with tislelizumab. 
Combining fruquintinib with tislelizumab may have synergistic effects where inhibition of 
angiogenesis along with stimulation of an immune response may enhance the overall anti-tumor 
activity compared to that of each individual agent alone.  Based on the preclinical toxicology 
data, the safety profile from clinical trials, the proposed safety management actions, the limited 
life expectancy of patients with advanced TNBC, EC, or CRC, the lack of effective alternative 
treatments, and efficacy seen in previous and ongoing clinical trials, the overall benefit-risk 
assessment supports the continued administration of fruquintinib and tislelizumab to patients 
with advanced cancer as an investigational treatment. 


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3 
OBJECTIVES AND ENDPOINTS  
The objectives and corresponding endpoints are summarized in Table 4. 
Table 4 
Objectives and Endpoints for Study 2020-013-00US3  
Part 
Tier 
Objectives 
Endpoints 
Part 1: 
Safety 
Lead-in 
Phase 
Primary 
To assess the safety and tolerability of 
fruquintinib in combination with 
tislelizumab in patients with advanced 
solid tumors 
AEs characterized by type, frequency, 
severity per NCI CTCAE v5.0, timing, 
seriousness, relationship to study 
drug(s), and discontinuation of study 
drug(s) due to AEs 
To confirm the RP2D of fruquintinib 
in combination with tislelizumab 
RP2D 
Secondary 
To evaluate the efficacy of fruquintinib 
in combination with tislelizumab per 
investigator assessment 
ORR, PFS, DCR, CBR, DoR, and OS 
To characterize the PK profile of 
fruquintinib and metabolite M11 when 
combined with tislelizumab 
Plasma concentrations of fruquintinib 
and M11 
To evaluate the PK and 
immunogenicity of fruquintinib in 
combination with tislelizumab 
Serum concentrations of tislelizumab 
and incidence of ADA to tislelizumab 
Part 2: 
Dose 
Expansion 
Phase 
Primary 
To evaluate the ORR assessed by the 
investigator in patients with advanced 
or metastatic TNBC, EC, or MSS 
mCRC when treated with fruquintinib 
in combination with tislelizumab  
ORR per RECIST v1.1 
Secondary 
To further evaluate efficacy of 
fruquintinib in combination with 
tislelizumab in patients with advanced 
or metastatic TNBC, EC, or MSS 
mCRC per investigator assessment 
PFS, DCR, CBR, DoR, and OS 
 
 
To characterize the safety of 
fruquintinib in combination with 
tislelizumab 
AEs characterized by type, frequency, 
severity per NCI CTCAE v5.0, timing, 
seriousness, relationship to study 
drug(s), and discontinuation of study 
drug(s) due to AEs. 
To assess the PK profile of 
fruquintinib and metabolite M11 when 
combined with tislelizumab 
Plasma concentrations and derived PK 
parameters of fruquintinib and M11 
To characterize the PK and 
immunogenicity of fruquintinib when 
combined with tislelizumab 
Serum concentrations of tislelizumab 
and incidence of ADA to tislelizumab 
To detect the expression of PD-L1 and 
MSS/MSI status and other biomarkers 
in tumor tissues of patients, and to 
perform relevant efficacy analysis to 
provide reference for the determination 
of dominant population 
Changes from baseline in biomarkers, 
correlation with drug exposure, and 
association with efficacy and safety 
parameters 


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Table 4 
Objectives and Endpoints for Study 2020-013-00US3  
Part 
Tier 
Objectives 
Endpoints 
Exploratory 
To explore potential biomarkers 
associated with anti-tumor effects of 
fruquintinib in combination with 
tislelizumab 
Changes from baseline in tumor 
markers, correlation with drug exposure, 
and association with efficacy and safety 
parameters 
ADA=anti-drug antibody; AE=adverse event; CBR=clinical benefit rate; DCR=disease control rate; 
DoR=duration of response; EC=endometrial cancer; M11=desmethylation product, HM5025423; 
mCRC=metastatic colorectal cancer; MSI=microsatellite instability; MSS=microsatellite stable; 
NCI CTCAE=The National Cancer Institute Common Terminology Criteria for Adverse Events; 
ORR=objective response rate; OS=overall survival; PD-L1=programmed death-ligand 1; PFS=progression 
free survival; PK=pharmacokinetic; RECIST v1.1=response evaluation criteria in solid tumors version 1.1; 
RP2D=recommended Phase 2 dose; TNBC=triple negative breast cancer. 


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4 
STUDY PLAN  
Upon implementation of this protocol amendment, enrollment to expansion cohorts A (TNBC 
immuno-oncology [IO]-treated in the metastatic setting), B (TNBC IO-Naïve in the metastatic 
setting) and C (EC IO Naïve) in this study has been permanently discontinued based upon the 
strategic evaluation of the clinical development of fruquintinib in the United States with 
HUTCHMED as the study Sponsor. This change is not based on any concern for patient safety or 
efficacy relative to fruquintinib and/or tislelizumab treatment. Patients who are currently enrolled 
in these cohorts and are deriving benefit from treatment with fruquintinib and/or tislelizumab 
may continue to participate in the study as per protocol. There is no planned interruption in the 
supply of fruquintinib or tislelizumab to clinical trial sites with active patients. 
4.1 
Study Design  
This is an open-label, multicenter, non-randomized, phase 1b/2 study to assess the safety and 
efficacy of fruquintinib in combination with tislelizumab in patients with advanced or metastatic 
solid tumors.  This study will be conducted in 2 parts: a Safety Lead-in Phase (Part 1) and a Dose 
Expansion Phase (Part 2). 
4.1.1 
Part 1: Safety Lead-in Phase  
Approximately 6 to 12 patients with histologically or cytologically documented advanced or 
metastatic solid tumors of any type who have progressed on standard systemic therapy and for 
which no effective therapy or standard of care exists will be enrolled and assessed for DLTs 
during the 28-day DLT observation period.  Patients may be either immuno-oncology (IO) 
treated or naïve in the metastatic setting.  Patients with TNBC in the Safety Lead-in must meet 
eligibility criteria defined in cohorts A or B, and those with EC in the Safety Lead-in must meet 
eligibility criteria defined in cohort C. 
Part 1 of the study will begin by enrolling the first 6 patients and evaluating for DLTs during the 
DLT observation period.  Study drug administration will begin at the full dose of fruquintinib 
(5 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) in combination with 
tislelizumab (300 mg once every 4 weeks) based on the well-established safety profiles of 
fruquintinib and tislelizumab, the non-overlapping mechanisms of action, and the desire to treat 
patients at doses shown to be effective in previous studies.  A lower dose level of fruquintinib 
(4 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) will be explored as 
necessary depending on observed toxicity.   
Refer to Section 4.1.3 and Section 4.1.4 for assessment of DLT guidance and DLT definitions, 
respectively.  One dose reduction step is allowed for fruquintinib (refer to Figure 1 and 
Section 7.5.2).  Only DLTs during the first cycle of treatment will be assessed. 
• If 0 or 1 of 6 patients experiences a DLT, the study may proceed at the current dose of 
both drugs. 
• If 2 or more patients experience a DLT, then, following consultation with the safety 
review committee (SRC), the study will proceed with enrollment in the next defined 
lower dose (Dose Level -1), an additional 6 patients will be enrolled, and the 28-day DLT 
observation period will be repeated. 
• If 2 or more patients experience a DLT in Dose Level -1, enrollment in the study will 
cease. 


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These criteria constitute the basis for RP2D determination, and the SRC must collectively 
determine the RP2D.  Enrollment to Part 2 (expansion cohorts) will begin once the RP2D has 
been determined in Part 1 of the study. 
The SRC will also review the data during Part 2 on an ongoing basis for safety. 
4.1.2 
Part 2: Dose Expansion Phase  
Approximately 140 patients will be enrolled, including approximately 60 patients with TNBC 
(approximately 30 patients in each cohort [A and B]), and approximately 40 patients with EC in 
Cohort C, and approximately 40 patients with MSS mCRC in Cohort D. Patients will be enrolled 
to one of the following 4 cohorts. Of note, based upon the strategic evaluation of the clinical 
development of fruquintinib, patient enrollment has been permanently discontinued for Cohorts 
A, B, and C in the Dose Expansion Phase, hence, the final actual total number of patients will 
reflect this strategic decision. 
• Cohort A (TNBC, immuno-oncology [IO]-treated in the metastatic setting):  
− Patients must have histologically or cytologically documented, advanced or 
metastatic TNBC as defined by American Society for Clinical Oncology (ASCO)-
College of American Pathologists (CAP) guidelines.  Up to 15 patients in cohort A can 
have ER or PGR low positive disease as defined by ASCO-CAP guidelines, if the 
treating physician considers the patient not eligible for adjuvant endocrine therapy.  
TNBC is defined as ER/PGR positivity of <1%, and ER/PGR low positive disease is 
defined by ER/PGR positivity of 1% to 10% (Allison 2020).  (Note that the guidelines 
use PR as the abbreviation for progesterone receptor.) 
− Patients must have progressed on at least 1 line, but no more than 3 lines, of cytotoxic 
therapy in the locally advanced or metastatic setting.  Patients must have also progressed 
on prior immunotherapy in the metastatic setting (Rakha 2014). 
• Cohort B (TNBC, IO-Naïve in the metastatic setting):  
− Patients must have histologically or cytologically documented, locally advanced or 
metastatic TNBC as defined by ASCO-CAP guidelines.  Up to 15 patients in cohort B 
can have ER or PGR low positive disease as defined by ASCO-CAP guidelines, if the 
treating physician considers the patient not eligible for adjuvant endocrine therapy.  
TNBC is defined as ER/PGR positivity of <1%, and ER/PGR low positive disease is 
defined by ER/PGR positivity of 1% to 10%.  (Note that the guidelines use PR as the 
abbreviation for progesterone receptor.) 
− Patients must have progressed on at least 1 line, but no more than 3 lines, of cytotoxic 
therapy in the locally advanced or metastatic setting.  Patients must not have received 
prior therapy with an ICI or other immunotherapy in the metastatic setting. 
• Cohort C (EC, IO Naïve):  
− Patients must have histologically or cytologically documented, advanced or 
metastatic EC. 
− Patients must have progressed on 1 prior, platinum-based chemotherapy regimen for 
EC.  Participants may have received up to 1 additional line of platinum-based 
chemotherapy if given in the neoadjuvant or adjuvant setting and must not have received 
prior therapy with an ICI or other immunotherapy. 


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• Cohort D (MSS mCRC, IO Naïve): 
− Patients must have histologically or cytologically confirmed, advanced or metastatic, 
unresectable adenocarcinoma of the colon or rectum. All other histological types are 
excluded. 
− Patients must have failed 2 lines of standard chemotherapies, including fluorouracil, 
oxaliplatin, and irinotecan.  Failed chemotherapies are defined as the occurrence of PD or 
intolerable toxicities during the treatment or after the last dose.  
− Notes: a) Each line of treatment for advanced disease until PD includes one or more 
chemotherapy drugs used for ≥ 1 cycle; b) Previous adjuvant/neoadjuvant therapy is 
allowed.  If relapse or metastasis occur during the adjuvant/neoadjuvant treatment period 
or within 6 months after the completion of the above treatment, that adjuvant/neoadjuvant 
therapy is considered as the failure of first line systemic chemotherapy for PD. 
− Patients with RAS wild-type tumor must have received anti-VEGF and/or endothelial 
growth factor receptor (EGFR) antibody treatment.  Patients with RAS mutation or RAS 
status unknown, must have received anti-VEGF antibody treatment. 
− Tumor tissue must have been assessed for MSS status prior to enrollment.  The 
results should be available in the source documents and be those used to make treatment 
decisions for the patient.  A redacted copy of the local results should accompany the 
archival tumor samples submitted as part of the protocol. 
Local tumor assessments will be performed by the investigator using RECIST v1.1 criteria 
(Eisenhauer 2009).  Tumor imaging (computed tomography [CT] with oral/intravenous contrast, 
unless contraindicated, or magnetic resonance imaging) must be performed within 28 days prior 
to enrollment.  On-study tumor assessments will occur every 8 weeks (±7 days) until PD.  If a 
patient discontinues study treatment due to any reasons other than PD, tumor assessments will 
continue to be performed as scheduled until disease progression, loss to follow up, initiation of 
subsequent therapy, withdrawal of consent, death, or study termination, whichever occurs first. 
All patients will be closely monitored for AEs throughout the study and for up to 30 days after 
the last dose of study drug(s).  Immune-mediated AEs (serious or nonserious) will be closely 
monitored until 90 days after the last dose of tislelizumab regardless of whether or not the patient 
starts a new anticancer therapy.  AEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.  Refer to Section 8 for 
additional and specific information regarding AE monitoring and reporting. 
PK analysis will be performed for fruquintinib and tislelizumab (Section 6.1.19).  Biomarker 
analysis will include but is not limited to TMB, cytokine analysis, tumor-infiltrating lymphocytes 
assessment, and gene expression profiling (Section 6.1.17).  Fruquintinib and tislelizumab will 
be administered until PD, intolerable toxicity, death, withdrawal of consent, or study termination.  
Patients may continue to receive fruquintinib and tislelizumab or either of the study drugs 
beyond the initial investigator-assessed PD, as defined by RECIST v1.1, provided that the 
patients have investigator-assessed clinical benefit and are tolerating study drug(s).  Refer to 
Section 6.2.1.1 and Section 6.2.1.2 for additional considerations regarding treatment 
discontinuation and withdrawal.  Patients who, at time of progression, have an ongoing AE that 
leads to treatment discontinuation and who have completed the scheduled Safety Follow-up visit 
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 new anticancer therapy.  If a patient discontinues study 


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drug(s) due to reasons other than PD or death, tumor assessments should continue to be 
performed following the scheduled assessment plan until the start of new anticancer therapy, PD, 
death, lost to follow-up, or withdrawal of consent (Section 6.2). 
Patients who have discontinued study drug(s) should return to the site for an end of treatment 
(EOT) visit within ≤7 days as detailed in Section 6.1.20.  After the EOT visit, patients will have 
scheduled follow-up visits for safety and, if applicable, for efficacy per the Schedule of Events 
(SOE) (Table 1). 
Study conduct and interventions are further detailed in Section 6 and Section 7, respectively, the 
SOE can be found in Table 1, and the study schematic can be found in Section 1.1. 
4.1.3 
Assessment of Dose-Limiting Toxicity  
For patients in the Safety Lead-in Phase (Part 1) described in Section 4.1.1 above, AEs will be 
assessed per the DLT criteria in Section 4.1.4 during the 28-day DLT assessment window, which 
starts with the first day of administration of study drugs.  Patients will be considered evaluable 
for DLTs if they 1) received ≥85% of scheduled fruquintinib and ≥67% (approximately 
two-thirds) of scheduled tislelizumab administration during the DLT assessment window and/or 
2) experienced a DLT. 
Patients will be considered not evaluable for DLTs if during the DLT assessment window they 
1) were withdrawn from the study for a reason other than DLT, 2) did not receive ≥85% of 
scheduled fruquintinib and ≥67% (approximately two-thirds) of scheduled tislelizumab drug 
administration, 3) received prophylactic supportive care that confounds the evaluation of DLTs 
(not including supportive care described as part of the DLT definition), or 4) have taken an  
inducer of enzyme CYP3A (Appendix 4) as the exposure to fruquintinib may be impacted.  
Patients who are not DLT-evaluable must be replaced, if needed. 
Any patient who experiences a DLT may be withdrawn from treatment or may continue at a 
lower dose level following discussion with and approval by the medical monitor. 
4.1.4 
Dose-Limiting Toxicity Definition  
All toxicities or AEs will be graded according to the NCI CTCAE version 5.0.  A DLT is defined 
as 1 of the following toxicities occurring during the DLT assessment window (first 28 study 
days) and considered by the investigator to be related to 1 or more study drugs. 
Hematologic: 
• Grade 4 neutropenia lasting >7 days 
• Grade ≥3 febrile neutropenia 
• Grade 3 thrombocytopenia with clinically significant bleeding 
• Grade 4 thrombocytopenia 
• Grade ≥4 anemia 
Non-hematologic: 
All Grade ≥3 non-hematologic toxicities will be considered DLTs with the following exceptions: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement, does not 
require hospitalization, AND resolves to Grade ≤1 within 7 days 


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• Grade 3 nausea/vomiting or diarrhea for <72 hours with adequate antiemetic and other 
supportive care 
• Grade 3 fatigue for <1 week 
• Grade ≥3 electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions 
• Grade 3 rash that returns to baseline or Grade ≤1 with appropriate supportive treatment 
within 7 days 
• Grade ≥3 amylase or lipase elevation that is not associated with symptoms or clinical 
manifestations of pancreatitis 
• Grade 3 hypertension that returns to baseline or Grade ≤1 with appropriate supportive 
treatment within 7 days 
4.2 
Design Rationale  
Refer to Sections 2.2.2, 2.2.3, and 2.2.4 for the justification of the starting combination doses. 


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5 
POPULATION  
5.1 
Definitions  
Patients officially enter the screening period after providing informed consent, either directly or 
via a legally authorized representative, where it is permitted by local law. 
A consented patient who has been deemed ineligible on the basis of 1 or more eligibility criteria 
or who has withdrawn consent prior to treatment assignment will be considered a screen failure.  
Screen failures may be rescreened once.  
An enrolled patient is one who has been deemed eligible and has been assigned to a treatment 
cohort. 
Inclusion/exclusion waivers will not be granted. 
5.2 
Inclusion Criteria  
Patients may be enrolled in this study only if they satisfy all the following criteria: 
1. Willing and able to provide informed consent signed by the study patient or legally 
acceptable representative, as specified by health authorities and institutional guidelines 
2. Age of ≥18 years 
3. Safety Lead-in: Must have histologically or cytologically documented advanced or 
metastatic solid tumors of any type who have progressed on standard systemic therapy 
and for which no effective therapy or standard of care exists.  Patients with TNBC in the 
Safety Lead-in must meet eligibility criteria defined in cohorts A or B, and those with EC 
in the Safety Lead-in must meet eligibility criteria defined in cohort C. 
Cohorts A and B: Must have histologically or cytologically documented, advanced or 
metastatic TNBC as defined by ASCO-CAP guidelines (Allison 2020).  Up to 15 patients 
in each cohort can have ER or PGR low positive disease as defined by ASCO-CAP 
guidelines, if the treating physician considers the patient not eligible for adjuvant 
endocrine therapy.  TNBC is defined as ER/PGR positivity of <1%, and ER/PGR low 
positive disease is defined by ER/PGR positivity of 1% to 10% (Allison 2020).  (Note 
that the guidelines use PR as the abbreviation for progesterone receptor.) 
Cohort C: Must have histologically or cytologically documented, advanced or metastatic 
endometrial carcinoma. 
Cohort D: Must have histologically or cytologically confirmed advanced or metastatic, 
unresectable adenocarcinoma of the colon or rectum.  All other histological types are 
excluded. 


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4. Cohorts A and B: Must have progressed on at least 1 line, but no more than 3 lines, of 
cytotoxic therapy in the locally advanced or metastatic setting.  For patients who have 
disease recurrence within 12 months of completion of adjuvant therapy, adjuvant 
chemotherapy will be considered first-line chemotherapy in the metastatic setting. 
a. Patients in cohort A must have received prior immunotherapy in the metastatic 
setting. 
b. Patients in cohort B must not have received prior therapy with an ICI or other 
immunotherapy in the metastatic setting. 
Cohort C: Patients must have progressed on 1 prior platinum-based chemotherapy 
regimen for EC.  Participants may have received up to 1 additional line of platinum-based 
chemotherapy if given in the neoadjuvant or adjuvant setting and must not have received 
prior therapy with an ICI or other immunotherapy. 
Cohort D: Patients must have failed 2 lines of standard chemotherapies, including 
fluorouracil, oxaliplatin, and irinotecan.  Failed chemotherapies are defined as the 
occurrence of PD or intolerable toxicities during the treatment or after the last dose.  
Additional requirements:  
a. All patients must have received treatment with an anti-VEGF antibody (eg, 
bevacizumab, aflibercept, or ramucirumab); 
b. Patients with RAS wild-type tumors must have received an anti-EGFR antibody 
treatment (eg, cetuximab or panitumumab); 
c. Each line of treatment for advanced disease until PD includes 1 or more cytotoxic 
chemotherapy drugs used for ≥ 1 cycle;  
d. Previous adjuvant/neoadjuvant therapy is allowed. If relapse or metastasis occurred 
during the adjuvant/neoadjuvant treatment period or within 6 months after the 
completion of adjuvant treatment, that adjuvant/neoadjuvant therapy is considered as 
the failure of first-line systemic chemotherapy for PD. 
5. Must have tumor tissue (fresh or archival tumor tissues as formalin-fixed paraffin-
embedded blocks or approximately 15 unstained slides) collected for retrospective 
analysis of PD-L1 expression level, and/or MSS/MSI status, and other exploratory 
biomarkers related to response and resistance.  Submission of <15 unstained slides is 
permitted, and patients may be enrolled after confirmation with the sponsor. 
6. ECOG performance status of 0 or 1 (Appendix 2). 
7. Expected survival of ≥12 weeks. 
8. Have measurable disease as defined by RECIST v1.1.  Tumors that were treated with 
radiotherapy are not considered measurable per RECIST v1.1 unless there has been 
documented progression of those lesions. 


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9. Adequate organ function indicated by the following laboratory values: 
a. Absolute neutrophil count of ≥1.5×109/L 
b. Platelet count of ≥100×109/L 
c. Hemoglobin ≥9 g/dL 
d. Serum total bilirubin ≤1.5× upper limit of normal (ULN) (total bilirubin must be 
<3× ULN for patients with documented Gilbert’s syndrome) 
e. Patients without liver metastases must have ALT and AST ≤2.5× ULN; patients with 
liver metastases must have ALT and AST ≤5× ULN. 
f. Urine protein ≤1+ by dipstick or 24-hour urine protein <1 g/24 hours.  Patients with 
1+ proteinuria by dipstick must undergo 24-hour urine collection to assess urine 
protein level. 
g. Serum creatinine <1.5× ULN and creatinine clearance (CrCl) ≥60 mL/min per 
Cockcroft Gault- (Appendix 11) 
h. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
≤1.5 ULN unless the patient is receiving anticoagulation therapy and INR and aPTT 
values are within the intended therapeutic range. 
10. For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement to use a highly effective form(s) of contraception that 
results in a low failure rate (<1% per year) when used consistently and correctly, starting 
during the screening period, continuing throughout the entire study period, and for 
120 days after taking the last dose of study drug.  Such methods include oral hormonal 
contraception (combined estrogen/progestogen or progestogen-only) associated with 
inhibition of ovulation together with a barrier method (eg, diaphragm, always containing 
a spermicide), intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
ligation, vasectomized partner, or sexual abstinence.  Oral contraception should always 
be combined with an additional contraceptive method (ie, barrier method) because of a 
potential interaction with the study drug.  The same criteria are applicable to male 
patients involved in this clinical trial if they have a partner of childbirth potential, and 
male patients must always use a condom.  All female patients will be considered to have 
childbearing potential unless the said female patient has had natural menopause, induced 
artificial menopause, or undergone sterilization (hysterectomy and bilateral 
salpingo-oophorectomy). 
11. PD-L1 status, as determined locally, must be documented for each patient in Cohorts A, 
B, and C, and MSS/MSI status must be documented for each patient in Cohorts C and D.  
The results should be available in the source documentation and be those used to make 
treatment decisions for the patient.  A redacted copy of the local results should 
accompany the archival tumor samples submitted as part of the protocol. 


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5.3 
Exclusion Criteria  
Patients are not eligible for enrollment into this study if they have any of the following criteria: 
1. Adverse events due to previous anti-tumor therapy have not recovered to ≤CTCAE 
Grade 1, except alopecia and peripheral neurotoxicity with ≤CTCAE Grade 2. 
2. Other malignancies except for non-melanoma skin cancer, in situ cervical cancer, or 
bladder cancer (Tis and T1) that have been adequately treated during the 5 years prior to 
screening. 
3. Brain metastases and/or spinal cord compression untreated with surgery and/or 
radiotherapy, and without clinical imaging evidence of SD for 14 days or longer; patients 
requiring steroids within 4 weeks prior to start of study treatment are excluded. 
4. Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to 
the first dose of study drug, including chemotherapy, radical radiotherapy, 
hormonotherapy, biotherapy, and immunotherapy.  
5. Systemic small molecule-targeted therapies (eg, tyrosine kinase inhibitors) within 
5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug.  
6. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of 
study drug.  
7. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first 
dose of study drug. 
8. Mean QT interval corrected by the method of Fridericia (QTcF) ≥480 ms. 
9. EXCEPT for Safety Lead-in and Cohort A, patients who have previously received any 
anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, and anti-cytotoxic 
T lymphocyte-associated antigen-4 antibody (or any other antibody acting on T 
cell -co-stimulation or checkpoint pathways) in the metastatic setting are excluded. 
10. Any condition that requires systemic treatment with either corticosteroids (>10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤14 days before the 
first dose of study drug(s), with the following exceptions: 
a. Adrenal replacement (dose of ≤10 mg daily of prednisone or equivalent). 
b. Topical, ocular, intra-articular, intranasal, or inhalational 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 non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen). 
11. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 9), with the following exceptions: 
a. Controlled type 1 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, or alopecia). 


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e. Any other disease that is not expected to recur in the absence of external triggering 
factors. 
12. Live vaccine ≤28 days before the first dose of study drug(s) 
a. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
13. Active infection requiring systemic antibacterial, antifungal, or antiviral therapy (not 
including antiviral therapy for hepatitis) for ≤14 days prior to the first dose of study 
drug(s) or a positive test for severe acute respiratory syndrome coronavirus 2 in the 
absence or presence of symptoms. 
14. Active tuberculosis that is being treated with anti-tuberculosis therapy or that have 
received treatment with anti-tuberculosis therapy within 1 year before the first drug 
administration. 
15. History or presence of interstitial lung disease, noninfectious pneumonitis, or 
uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung 
diseases, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related 
pneumonia, severely impaired lung function, and other patients with conditions that may 
interfere with the detection and treatment of suspected drug-related pulmonary toxicity; 
radiation pneumonitis in the radiation therapy area is allowed. 
16. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA 
>500 IU/mL (or >2500 copies/mL) or active hepatitis C at screening. 
a. Patients with inactive hepatitis B surface antigen (HBsAg carriers who are treated and 
have stable HBV [HBV DNA <500 IU/mL or <2500 copies/mL]) can be enrolled.  
Patients with detectable HBsAg or detectable HBV DNA should be managed per 
treatment guidelines.  Patients receiving antiviral therapy at screening should have 
been treated for >2 weeks before the first dose of study drug(s). 
b. Patients with a negative hepatitis C virus (HCV) antibody test at screening or a 
positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test 
at screening are eligible.  The HCV RNA test should be performed only for patients 
who tested positive for the HCV antibody. 
17. Known history of human immunodeficiency virus (HIV) infection. 
18. Major surgery within 60 days before the first drug administration.  Patients must have 
recovered adequately from the toxicity and/or complications from the intervention prior 
to the first dose of study drug(s). 
19. Patients who had any surgical or invasive therapy (except for puncture biopsy and venous 
catheterization) within 4 weeks before the first drug administration, or have unhealed 
wounds, ulcers, or fractures. 
20. Prior allogeneic stem cell transplantation or organ transplantation. 
21. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living (ADL), ≤28 days before the first dose of study drug(s). 


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b. Pulmonary embolism or venous thromboembolism ≤6 months before the first dose of 
study drug(s). 
c. Acute myocardial infarction ≤6 months before the first dose of study drug(s). 
d. Heart failure meeting New York Heart Association Function Classification III or IV 
(Appendix 12) ≤6 months before the first dose of study drug(s); left ventricular 
ejection fraction (LVEF) of <50%. 
e. Ventricular arrhythmia Grade ≥2 in severity ≤6 months before the first dose of study 
drug(s). 
f. Cerebrovascular accident ≤12 months before the first dose of study drug(s). 
g. Uncontrolled hypertension that cannot be managed by standard antihypertension 
medications, which is specified as systolic pressure ≥140 mmHg and/or diastolic 
pressure ≥90 mmHg.  The patient must have blood pressures below both limits.  
Repeated assessments are permitted. 
h. Syncope or seizure ≤28 days before the first dose of study drug(s). 
22. Inability to swallow capsules, or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the complete small bowel, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
23. Received strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) taken 
within 2 weeks (or 5 times the t1/2 of the drug, whichever is longer) prior to the first 
study treatment. 
24. Active gastrointestinal and duodenal ulcers, ulcerative colitis, and other gastrointestinal 
disease or unresectable tumors with active bleeding; other conditions that the investigator 
determines to possibly cause gastrointestinal bleeding, perforation, and other conditions; 
or prior gastrointestinal perforation or gastrointestinal fistula that has not recovered after 
surgical treatment. 
25. History or presence of hemorrhage from any site (such as melena, hematemesis, 
hemoptysis, fresh in stool) within 2 months before the screening. 
26. Tumor invasion of a large vascular structure (eg, pulmonary artery, the superior or 
inferior vena cava).  
27. History of arterial thrombus or deep vein thrombosis within 6 months prior to the first 
drug administration; patients with implanted intravenous infusion pump or 
catheter -related thrombosis or superficial vein thrombosis, except for patients with stable 
thrombus after routine anticoagulant therapy. 
28. Stroke event and/or transient ischemic attack within 12 months. 
29. Women who are pregnant or lactating. 
30. Patients with known allergy to any of the components of tislelizumab or fruquintinib 
preparations including tartrazine (E102) and sunset yellow (E110) or who have any 
previous history of severe allergy to monoclonal antibodies. 
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32. Except for Cohort D (MSS mCRC), patients must not have received prior treatment with 
a VEGFR antibody. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 3 -0 0 U S 3  
Fr u q ui nti ni b  
A m e n d m e nt  5  
 
 
H U T C H M E D Li mite d  
 
P a ge 7 0  
 
C O N FI D E N TI A L  
 
 
6  
S T U D Y C O N D U C T   
6. 1  
St u d y Pr oce d ures   
E nr oll me nt is esti mate d t o ta ke a p pr o xi matel y  2 0  m o nt hs .  Esti mate d  st u d y d urati o n fr o m o pe n 
e nr oll me nt  u ntil c o m pleti o n of data a n al yses is a p pr o xi matel y 3 0  m o nt hs.  
Patie nts  wi ll be cl osel y m o nit ore d f or safet y a n d t olera bilit y t hr o u g h o ut t he st u d y.  All 
assess me nts m ust be perf or me d a n d d oc u me nt e d i n t he me dical rec or d f or eac h p atie nt . 
W here a p plica ble, d osi n g will occ ur o nl y if t he cli nical assess me nt a n d l ocal la b orat or y tes t 
val ues (t hat m ust be a vail a ble bef ore a n y d osi n g) ha ve bee n re vie we d a n d f o u n d t o be acce pta ble 
per pr ot oc ol g ui deli nes.  
T he f oll o wi n g pr oce d ures will be perf or me d acc or di n g t o t he sc he d ule i n T a ble  1 . 
6. 1. 1  
I nf or me d C o nse nt  
All patie nt s m ust si g n t he i nf or me d c o nse nt f or m (I C F) pri or t o a n y st u d y-relate d e x a mi nati o ns 
or pr ot oc ol pr oce d ures .  T u m or assess me nts c o m plete d as sta n dar d of care pri or t o patie nt -si g ne d 
I C Fs, b ut wit hi n 2 8 da ys of first d ose of st u d y treat me nt, ma y be use d as baseli ne sca ns.  
All patie nt s w h o si g n t he I C F are t o be e ntere d i nt o t he i nteracti ve we b res p o nse s yste m (I W R S).  
T he s yste m will ge nerat e a patie nt  i de ntificati o n n u m ber, w hic h will be assi g ne d t o t he patie nt  
a n d will be use d t hr o u g h o ut t he st u d y.  
6. 1. 2  
Scree ni n g Peri o d   
T he scree ni n g peri o d b e gi ns at t he si g ni n g of I C F.  Scree ni n g e val uati o ns will be perf or me d 
acc or di n g t o t he s c he d ule a n d i nstr ucti o ns set f ort h i n Ta ble  1 .  Scree ni n g e val uati o ns ma y be 
re peat e d as nee de d wit hi n t he scree ni n g peri o d.  T he i n vesti gat or is t o assess patie nt  eli gi bilit y 
acc or di n g t o t he lat est scree ni n g assess me nt r es ults.  
Rescree ni n g ma y b e all o w e d after c o ns ultati o n wit h t he s p o ns or (e g, w he n a patie nt’s  la b orat or y 
res ult narr o wl y misses a l a b orat or y criteri o n a n d it is c orrect a ble a n d n ot d u e t o ra pi dl y 
deteri orati n g c o n diti o n or P D) .  Rescree ni n g is all o we d o nl y o nce.  
6. 1. 3  
E nr oll me nt   
O n da y -2 t o da y 1, after verif yi n g t he patie nt ’s eli gi bilit y, t he site will l o g i nt o t he I W R S a n d t he 
patie nt  will be e nr olle d b y t he s yste m .  T he s yste m will ge nerate a s erial n u m ber matc hi n g a 
b ottle of i n vesti gati o nal pr o d uct i n t he site’s i n ve nt or y .  T he  site will ta ke t he i n vesti gati o nal 
pr o d uct wit h t he serial n u m ber assi g ne d b y I W R S fr o m t he i n ve nt or y a n d dis pe nse it t o t he 
patie nt .  T he first d ose s h o ul d be a d mi nistere d o n cycle 1 d a y 1 wit hi n 2 b usi ness da ys after a 
patie nt’s e nr oll me nt.  
6. 1. 4  
Tre at me nt Peri o d   
Patie nts  i n t he treat me nt p hase will recei ve a c o m bi nati o n d ose base d o n d ose le vel i n P art 1 a n d 
t he R P 2 D i n P art 2.  All patie nt s will u n der g o c o nti n u o us m o nit ori n g f or safet y a n d efficac y as 
descri be d i n Ta bl e  1 .  
 
 
C CI


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6.1.5 
Medical History  
A complete medical history, including the patient’s medical history, disease history, and prior 
therapies for disease prior to signing of the ICF, should be recorded at screening.  Comorbidities 
that began prior to signing the ICF should be recorded and followed as medical history. 
6.1.6 
Tumor Diagnosis and Treatment History  
Tumor diagnosis should include the date of primary diagnosis of disease and its type, disease 
stage, the date of first metastasis, type of previous treatment, start and end date/s, BOR, and date 
of PD. 
The patient’s history of radiation therapy, including the start and end date/s and the site of 
radiation, must be recorded.  Surgical history, including operations and less-invasive diagnostic 
or therapeutic procedures (such as GI endoscopy and biopsy), the start and end date/s, name of 
each procedure, and operation site must also be recorded at screening and in the appropriate 
electronic case report form (eCRF). 
6.1.7 
Demographics  
Demographic information includes sex and race, and in some countries, year of birth should be 
recorded at screening and in the applicable eCRF (as permitted by local regulations). 
6.1.8 
Concomitant Medication and Procedures  
Concomitant medications and procedures should be assessed during the study according to the 
schedule of events in Table 1.  Details of prohibited therapies, medications to be used with 
caution, permitted therapies, drug-drug interactions, and rescue therapies are available in 
Section 7.4. 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient within 28 days 
before the first dose of study drug(s) and 30 days after the last dose of study drug(s) should be 
recorded on the eCRF.  After discontinuation of study treatment, subsequent new anti-tumor 
treatment regimens during the safety and survival follow-up periods should also be recorded. 
6.1.9 
Comprehensive Physical Examination  
Comprehensive physical examinations should be assessed during the study according to the 
schedule of events in Table 1 and include patient height, weight, and general condition, as well 
as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, 
lymph nodes, nervous system, and additional areas/systems as clinically indicated. 
6.1.10 
Limited Physical Examination  
Limited physical examinations should be assessed during the study according to the schedule of 
events in Table 1 and include vital signs and any change from baseline; any new abnormalities; 
and examination of weight, thorax, abdomen, and additional areas/systems as clinically 
indicated.  In order to assess changes from baseline and to evaluate for new abnormalities, the 
limited physical examination should assess for new or changed skin lesions, enlarged lymph 
nodes, palpable masses, and appropriate examination to address any patient-reported symptoms.  


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New or worsened clinically significant abnormalities should be recorded as AEs in the eCRF.  
Refer to Section 8 regarding AE and SAE definitions, reporting, and follow-up requirements. 
6.1.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status  
Patient performance status will be graded according to the ECOG performance status scale at 
study visits as indicated in Table 1.  It is recommended that ECOG performance status scores be 
evaluated by the same investigator throughout the study.  Details on the ECOG performance 
status assessment and grading scale are available in Appendix 2. 
6.1.12 
Vital Signs  
Vital signs should be reviewed during the study according to the schedule of events in Table 1.  
Vital signs include blood pressure, heart rate, respiration rate, and temperature.  For patients with 
a baseline history of hypertension or hypertension that develops on study, blood pressure should 
be monitored per institutional standard practice. 
6.1.13 
Laboratory Evaluations  
6.1.13.1 
Hematology  
Hematology laboratory assessments should be performed during the study according to the 
schedule of events in Table 1 and include red blood cell count, hemoglobin, hematocrit, absolute 
reticulocyte count, white blood cell count and classifications (neutrophils, lymphocytes, 
eosinophils, monocytes, and basophils), and platelet count.  If abnormal or primitive immature 
cells are seen, they must also be recorded.  Any additional routine blood tests during the study 
shall be arranged by the investigator as needed. 
Note: If the neutrophil count is ≤1.0×109/L or the platelet count is ≤25×109/L, hematology 
assessments should be conducted per institutional standard practice. 
6.1.13.2 
Blood Chemistry  
Blood chemistry laboratory assessments should be performed during the study according to the 
schedule of events in Table 1, and the panel includes ALT, AST, alkaline phosphatase (ALP), 
bicarbonate, bilirubin/total bilirubin, lactic dehydrogenase, non-fasting total cholesterol, 
triglycerides, uric acid, total protein, albumin, blood urea nitrogen or urea, creatinine, CrCl rate, 
sodium, potassium, magnesium, chloride, corrected calcium (for patients with hypoproteinemia), 
phosphorus, blood glucose, creatine phosphokinase, and creatine kinase-MB (CK-MB). If CK-
MB fractionation is not available, troponin I and/or troponin T should be tested instead.  Serum 
troponins may be substituted per local guidelines if used consistently throughout the study.  If 
CK-MB fractionation is not available, troponin I and/or troponin T should be tested instead.  
Serum troponins may be substituted per local guidelines if used consistently throughout the 
study.  If tislelizumab has been permanently discontinued, creatine kinase and CK-MB testing 
will be done as clinically indicated.  Note: Blood chemistry tests for patients with ALT or AST 
increase by >3× ULN or increase by >2× baseline value should be performed per institutional 
standard practice. 
Creatinine clearance rate (mL/min) should be calculated using the serum creatinine value 
according to the Cockcroft-Gault formula (see Appendix 11). 


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6.1.13.3 
Blood Amylase and Lipase  
Tests for blood amylase and lipase will be performed during the study according to the schedule 
of events in Table 1. 
6.1.13.4 
Fasting Lipid Panel  
Fasting lipid panel, including total cholesterol, high-density lipoprotein, low-density lipoprotein, 
and triglycerides, will be performed during the study according to the schedule of events in 
Table 1. 
6.1.13.5 
Coagulation Indicators  
Coagulation laboratory assessments should be performed during the study according to the 
schedule of events in Table 1.  Coagulation tests include prothrombin time, activated partial 
thromboplastin time (aPTT), and INR. 
6.1.13.6 
Thyroid Function  
Thyroid function tests should be performed during the study according to the schedule of events 
in Table 1 and include serum free tri-iodothyronine, serum free thyroxine, and thyroid 
stimulating hormone. 
6.1.13.7 
Urinalysis  
Urinalysis should be performed during the study according to the schedule of events in Table 1 
and includes urine pH, protein, glucose, blood, and ketones; microscopic for white blood cell and 
red blood cell count.  On routine urinalysis, if urine protein is ≥1+ by dipstick, a 24-hour urine 
sample for total protein quantitation and a random urine sample for total protein and creatinine 
quantitation are to be obtained to determine the protein-to-creatinine ratio.  For conversions 
between quantitative and qualitative results, see Appendix 8. 
6.1.13.8 
Pregnancy Test  
Pregnancy testing for females of childbearing potential, including women who have had a tubal 
ligation, should be performed according to the schedule of events in Table 1.  Serum pregnancy 
test must be performed ≤7 days before the first dose of study drug(s) and a negative result must 
be recorded. If serum pregnancy test was drawn within 72 hours of Cycle 1 Day 1 (C1D1), then 
urine pregnancy test is not required on C1D1.  Furthermore, a negative urine pregnancy test must 
be completed and recorded before administration of study drug(s) according to the schedule of 
events in Table 1.  A serum pregnancy test must be performed if the urine pregnancy test is 
positive or equivocal.  Unscheduled testing via either method can be performed if there is an 
indication; however, any equivocal urine pregnancy tests should be repeated via serum 
pregnancy testing. 
6.1.13.9 
Virological Screening  
Testing will be performed locally at screening (and as clinically indicated) and will include 
HBV/HCV serology (HBsAg and HCV antibody).  In the case of active HBV or HCV infection 
(ie, HBsAg or HCV antibody is positive), these tests will be followed by viral load assessment 
(HBV DNA and HCV RNA).  Additionally, for patients who have detectable HBV DNA at 


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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 at the EOT visit. 
6.1.14 
Electrocardiograms Monitoring  
Single 12-lead electrocardiograms (ECG) will be collected in all patients using standardized 
equipment according to the schedule of events in Table 1. 
ECG indicators include PR interval, QRS interval, RR interval, QT/QTcF interval, and heart rate.  
ECGs from standard equipment will be evaluated for safety by the principal investigator.  
Patients should reside in a quiet setting without distractions (eg, television, cell phones, and staff 
talking) at each scheduled time point for ECG measurements.  Patients should rest in a supine 
position for at least 10 minutes before and 5 minutes after the scheduled time point and should 
refrain from talking or moving the arms or legs.  Skin preparation should be optimal to obtain 
high-quality ECGs; if deemed appropriate, the chest should be shaved and prepared with light 
abrasion.  
Unscheduled ECG or other cardiac examinations can be performed if clinically indicated.  
All ECGs should be done prior to dosing of study drugs. 
6.1.15 
Echocardiogram/Multigated Acquisition Scan  
To evaluate the ejection fraction of patients, echocardiogram (preferred method) or 
multigated-acquisition scan will be performed during the study according to the schedule in 
Table 2.  Assessment parameters include LVEF and general assessment of cardiac function.  It is 
recommended to use the same assessment method throughout the study for each patient.  
Echocardiograms completed as standard of care prior to signing the informed consent, but within 
28 days of first dose of study treatment, may be used as baseline assessment for LVEF. 
6.1.16 
Anti-Tislelizumab Antibody Test  
Blood sampling will be collected at the time points specified in Table 2. 
Tislelizumab may elicit an immune response.  Patients with signs of any potential immune 
response to tislelizumab should be closely monitored.  Validated screening and confirmatory 
assays will be employed to detect anti-drug antibodies (ADAs) at multiple time points 
throughout the study (see Table 2).  The immunogenicity evaluation will utilize a risk-based 
immunogenicity strategy (Koren 2008, Vergote 2020, Worobec 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.  
Implementation of ADA characterization assays will depend on the safety profile and clinical 
immunogenicity data. 
The following assessments will be performed at a bioanalysis central laboratory:  
• ADA assays: Serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay. 
Shipping, storage, and handling of samples for the assessment of ADA assays will be managed 
through a central laboratory.  Instruction manuals and supply kits will be provided for all central 
laboratory assessments. 


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Refer to the Laboratory Manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples to the central laboratory. 
6.1.17 
Tumor Sample Collection  
Instructions for the processing, storage, and shipping of samples will be provided in the study 
laboratory manual.  Refer to the schedule of events (Table 1) for sample collection time points.  
A fresh tumor biopsy at a tumor lesion is mandatory if there are no available archival tumor 
samples during the screening period.  For fresh biopsies, acceptable samples include core needle 
biopsies for nonsuperficial tumor tissue or excisional, incisional, punch, or forceps biopsies for 
cutaneous, subcutaneous, or mucosal lesions.  Tumor tissue should be of good quality based on 
total and viable tumor content.  Fine-needle aspiration, brushing, cell pellets from pleural 
effusion, and lavage samples are not acceptable. 
6.1.17.1 
Archived Tumor Sample  
For all patients enrolled in the study, archival tumor tissues (formalin-fixed paraffin-embedded 
[FFPE] blocks or approximately 15 freshly cut unstained FFPE slides) need to be sent for post 
hoc confirmation of PD-L1 (for Cohorts A, B, and C) expression and assessment of MSI/MSS 
status (for Cohorts C and D only), and assessment of exploratory markers including but not 
limited to TMB, cytokine analysis, tumor-infiltrating lymphocytes assessment, and gene 
expression profiling in a sponsor‑designated central or test laboratory.  Submission of <15 
unstained slides is not a protocol deviation. 
6.1.18 
Tumor Evaluation/Imaging  
Tumor assessments (local) are to be performed at study visits specified in Table 1. 
All measurable and evaluable lesions should be assessed and documented using image-based 
evaluation.  All patients are to be evaluated utilizing contrast-enhanced CT scan of the chest, 
abdomen, and pelvis, or other acceptable cross-sectional imaging per RECIST v1.1.  Evaluations 
should include other areas of the body, as clinically indicated.  Disease status will be assessed by 
the investigator or designated site staff using RECIST v1.1.  The same imaging procedure used 
to define measurable lesions at baseline must be used throughout the study for each patient, 
unless medically contraindicated.  At the investigator’s discretion, other methods of assessment 
of measurable disease as per RECIST v1.1 may be used. 
Tumor assessments completed as standard of care prior to signing the informed consent, but 
within 28 days of first dose of study treatment, may be used as baseline scans. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms leading to an apparent increase of existing tumor masses or 
appearance of new tumor lesions.  Also, some patients may benefit from additional immune 
therapies or anti-angiogenic therapies despite evidence of PD.  The following criteria must be 
met to treat patients with suspected pseudoprogression or confirmed evidence of PD:  
• Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
• Stable ECOG performance status ≤1 


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• Absence of rapid progression of disease 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. 
• The decision to continue study drug(s) beyond initial investigator-assessed progression 
must be agreed to with the medical monitor and documented in the patient medical 
record.  Tumor assessment should continue as planned in patients receiving study drug(s) 
beyond initial investigator-assessed progression.  Tumor assessment in such patients 
should continue until study treatment discontinuation. 
6.1.19 
Pharmacokinetics Assessments  
Blood samples will be collected for analysis of fruquintinib and metabolite M11 plasma 
concentrations and tislelizumab serum concentration according to the PK schedule of events in 
Table 2.  Serum samples will be collected for the analysis of antibodies to tislelizumab for ADA 
analysis according to Table 2.  The actual dates and times of PK sampling should be recorded on 
the appropriate eCRF.  In addition, the dates and times of fruquintinib dose administration and 
the date, start time, and end time of tislelizumab infusions must be recorded on the eCRF. 
The following assessments will be performed at a central bioanalysis laboratory:  
• PK assays: Serum samples will be assayed for tislelizumab concentration using a 
validated immunoassay, and the plasma concentration of fruquintinib and its metabolite 
M11 will be assayed using the validated liquid chromatography-tandem mass 
spectrometry method by request from the sponsor. 
Shipping, storage, and handling of samples for assessment of PK will be managed through a 
central laboratory.  A study-specific laboratory manual and supply kits will be provided for all 
central laboratory assessments. 
Refer to the laboratory manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples to the central laboratory. 
PK and immunogenicity samples should be collected according to the planned visit if the visit 
occurs prior to 31 December 2023.  Sample collection per planned visit for visits occurring after 
31 December 2023 should not be collected. 
6.1.20 
End of Treatment Visit  
The EOT visit is conducted ≤7 days (±3 days) after the last dose when the investigator 
determines that the patient must permanently discontinue all study drugs.  A tumor assessment is 
not required at the EOT visit if ≤6 weeks have passed since the last assessment. 
See Table 1 for assessments to be performed for the EOT visit.  If any laboratory assessments 
required for the EOT visit were completed ≤7 days before the EOT visit, these assessments do 
not need to be repeated. 
6.1.21 
Safety Follow-up Period  
Patients who permanently discontinue all study drugs will be asked to return to the clinic for the 
Safety Follow-up visit, which is required to be conducted 30 days (±7 days) after the EOT visit.  


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In addition, telephone contact with patients should be conducted to assess imAEs (serious or 
nonserious) reported within 90 days after the last dose of tislelizumab regardless of whether or 
not the patient starts a new anticancer therapy.  If patients report a suspected imAE 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. 
See Table 1 for assessments to be performed at the Safety Follow-up visit. 
6.1.22 
Survival Follow-up Period  
Every 8 weeks (±14 days) after the EOT visit, the investigator or their designee should call the 
patients to collect information related to survival status and their use of other 
anticancer treatments, including drug name, dosage, and treatment start and end dates.  
Information related to radiotherapy received after disease progression is also needed, including 
radiotherapy location, radiation dose, start date, and end date. 
Every effort should be made to obtain information on patients who discontinue study treatment 
but do not withdraw consent to continue participation in the study. 
06 May 2024 will be the final day for survival follow-up.  Any patient who has not had contact 
with the site within 30 days of this date (and not previously reported as deceased or withdrawn 
consent for future follow-up) should have a final survival follow-up conducted via telephone or 
in a manner that follows local site SOPs. 
6.1.23 
End of Study  
The end of the study is defined as the last visit of the last patient in the study. 
6.2 
Discontinuation or Withdrawal  
6.2.1 
Individual Subjects  
6.2.1.1 
Permanent Discontinuation of Treatment  
The investigator has the right to discontinue a patient from the study for any condition that the 
investigator determines is in the best interest of the patient, any reasons of non-compliance (eg, 
missed doses and visits), or pregnancy.  
Any patient who discontinues treatment should be encouraged to return to the study site for an 
EOT visit and Safety Follow-up visit outlined in Table 2, as long as the reason for permanent 
discontinuation is not withdrawal of consent.  The primary reason for discontinuation must be 
recorded on the appropriate eCRF. 
Subjects may be discontinued from treatment for any of the following reasons: 
• Disease progression (according to RECIST v1.1).  If the patient is experiencing a 
treatment benefit, in the opinion of the investigator, the patient may continue study 
treatment beyond radiographic progression until clinical progression.  Determination of 
clinical progression is at the discretion of the investigator and may include both objective 
and subjective data.  The continuation decision must be made by the investigator in 
consultation with the sponsor. 


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• Withdrawal of consent  
• Intolerable toxicity  
• Poor patient compliance  
• Use of other anti-tumor treatment during the study  
• Pregnancy  
• Patient is lost to follow-up 
• The investigator or sponsor determines it is in the best interest of the patient 
• Study is terminated by the sponsor  
• Death 
• End of this study 
Patients must be discontinued if they experience certain high-grade AEs, experience recurrent 
AEs, or experience AEs that warrant withdrawal of study treatment as determined by the 
principal investigator, as outlined in Section 7.5. 
6.2.1.2 
Withdrawal From Study  
All study participants have the right to withdraw from the study at any time.  During the 
treatment period and follow-up period, a patient who withdraws consent to continue participation 
in the study will not be followed for any reason after consent has been withdrawn. If a participant 
withdraws consent for disclosure of future information, the sponsor may retain and continue to 
use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
6.2.1.3 
Replacement of Subjects  
Patients who are not DLT evaluable in the Safety Lead-in cohort will be replaced to guarantee 
the protocol-required number of DLT evaluable patients to evaluate safety and tolerability.  
6.2.1.4 
Subjects Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods).  These 
contact attempts are to be documented in the participant’s medical record. 
Should the participant continue to be unreachable, he/she will be considered to be withdrawn 
from the study, and the withdrawal will be documented in the participant’s medical record. 
6.2.2 
Stopping Rules  
6.2.2.1 
Part 1 (Safety Lead-in)  
Dosing of individual patients will stop immediately in the event of the following: 


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•  A D L T or D L T -e q ui vale nt ( D L T t hat occ urs o utsi de t he D L T ass ess me nt wi n d o w) t hat 
d oes n ot ret ur n t o baseli n e or Gra d e ≤1 wit hi n 2 1 da ys of o nset  
•  A D L T or D L T -e q ui vale nt i n t he setti n g of a d ose re d ucti o n t hat d oes n ot ret ur n t o 
baseli ne or Gra de  ≤1 wit hi n 1 4 da ys of o nset  
•  A n i m m u ne -relate d A E ( n o n -D L T)  attri b ute d t o tisleliz u ma b t hat d oes n ot ret ur n t o 
baseli ne or Gra de  ≤1 wit hi n 1 2 wee ks  of o nset  
T his st u d y sta ge will e n d if t he f oll o wi n g c o n diti o n is met:  
•  E xcessi ve t o xicit y is pres e nt i n d ose le vel -1, defi ne d as ≥2 patie nt s e x perie nce a D L T. 
6. 2. 2. 2  
Part 2 ( D ose E x pa nsi o n)   
S afet y data will be re vie we d o n a n o n g oi n g basis d uri n g st u d y c o n d uct.  At a mi ni m u m of t wice 
a year, st u d y d ata will be re vie we d b y  i n v esti gat ors t o i de ntif y p ote ntial safet y si g nals.  
A d diti o nal safet y re vie w meeti n gs ma y be sc he d ul e d base d u p o n c o ncer ns of t he s p o ns or or 
i nvesti gat ors.  
6. 3  
St u d y Ter mi n ati o n   
T he s p o ns or has t he ri g ht t o ter mi nate t he st u d y pre mat urel y.  Reas o ns ma y i ncl u de efficac y, 
safet y, or f utilit y, a m o n g ot hers.  S h o ul d t he s p o ns or deci de t o ter mi nate t he st u d y, t he 
i n vesti gat or(s) will be n otifie d i n writi n g.  
 
  
Patie nts will be re q uire d t o ha ve  a Safet y F oll o w -u p visit, as descri be d i n Secti o n  6. 1. 2 1 .  T he 
st u d y will be ter mi nate d eit her 9 0 da ys after t he l ast patie nt  has recei ve d tisleliz u ma b, or at t he 
p oi nt at w hic h all i m A Es ha ve res ol v e d or are n o l o n ger bei n g f oll o we d . 
C CI


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7 
STUDY INTERVENTIONS  
7.1 
Description of Products  
Investigational treatments used in this study are described in Table 5. 
Table 5 
Investigational Treatments Used in This Study  
Product* 
Section 
Dose 
Frequency 
Route 
Duration 
Fruquintinib 
7.1.1 
5 mg, 
4 mg, or 
3 mg 
Once daily 
3 weeks on/ 
1 week off 
Oral 
Until radiologically determined 
progressive disease per RECIST 
v 1.1, unacceptable toxicity, death, 
or withdrawal from study 
Tislelizumab 
7.1.2 
300 mg  
Once every 
4 weeks 
IV 
Until radiologically determined 
progressive disease per RECIST 
v 1.1, unacceptable toxicity, death, 
or withdrawal from study 
IV=intravenous; RECIST v 1.1=Response Evaluation Criteria in Solid Tumors version 1.1. 
*If either fruquintinib or tislelizumab is permanently discontinued due to toxicity, the other investigational treatment 
can be continued as a single agent, provided that the patients have investigator-assessed clinical benefit and are 
tolerating study drug. 
7.1.1 
Fruquintinib  
7.1.1.1 
Formulation, Packaging, Storage, and Handling  
Fruquintinib is presented as 2 capsule strengths (1 mg and 5 mg).  The 1-mg capsule is presented 
as a no. 3 hard gelatin capsule containing 52 mg of a blended white to off-white powder that is 
composed of fruquintinib drug substance, microcrystalline cellulose, starch, and talc.  The 5-mg 
capsule is presented as a no. 1 hard gelatin capsule containing 260 mg of the same blended 
powder as the 1-mg capsule.  Additional information is available in the Pharmacy Manual. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
All the investigational drugs should be sealed and stored in a secure, limited access area under 
appropriate conditions.  The storage temperature should be between 10°C to 30°C.  
Investigational drugs should not be used beyond the expiration date provided by the 
manufacturer.  The temperature monitoring log should be recorded and filed in the study binder. 
For further details, refer to the fruquintinib IB. 
7.1.1.2 
Dosing and Administration  
Treatment with study drug(s) on Day 1 of Cycle 1 must begin within 2 business days after a 
patient’s enrollment (Section 6.1.3).  Dose delay, interruption, or modification will be based on 
the specific laboratory and AE criteria, as described in Section 7.5.  Guidelines for study 
treatment modification, delay, or discontinuation as well as management of imAEs or 
infusion-related reactions are provided in Section 8.4, Appendix 9 and Appendix 10. 
Accurate records of all study drug(s) received, dispensed, returned, and disposed of should be 
maintained in the site’s Pharmacy Folder.  Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration.  Dosage, frequency of 
administration, and route of administration for both study drugs are described in Table 5. 


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Fruquintinib will be self-administered orally once daily for 3 weeks, followed by 1 week off in 
28-day cycles with or without food.  The capsules should be swallowed with a glass of water.  
On days when fruquintinib and tislelizumab dosing are both scheduled, the daily dose of 
fruquintinib should precede tislelizumab infusion. 
In Part 1, the Safety Lead-in Phase, the starting dose is 5 mg once daily on a 3 weeks on/1 week 
off schedule.  Depending on safety observations, the fruquintinib dose may be de-escalated to 
4 mg once daily on a 3 weeks on/1 week off schedule.  If dose adjustment is required, four 1-mg 
fruquintinib capsules will be used to comprise the 4 mg dose.  The SRC will confirm the RP2D 
of the combination treatment.  
After completion of Part 1, in Part 2, the Dose Expansion Phase, patients will enroll within 
2 cohorts to receive fruquintinib at the RP2D selected in Part 1 for 4-week cycles. 
There is no predefined duration of treatment for each patient.  It is intended that patients in both 
the Safety Lead-in and expansion phases will be treated until radiologically determined PD per 
RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. 
An adequate supply of fruquintinib will be dispensed to patients on Day 1 of each new cycle 
(once every 4 weeks).  Patients should record the date and time of drug administration and 
amount in the patient diary.  Each time the study drug is dispensed, compliance will be evaluated 
and reinforced.  Treatment compliance will also be monitored by drug accountability and 
recorded in the patient’s medical record and eCRF.  If the number of capsules returned does not 
agree with the expected number, the patient should be counseled and proper dosing should be 
reinforced. 
The following guidelines should be followed for fruquintinib administration:  
• Fruquintinib may be taken either in the fasting state or after meals. 
• Capsules should be taken with 240 mL of water at approximately the same time each day. 
• Patients should swallow the capsules whole and not chew them. 
• If vomiting occurs after dosing, fruquintinib doses should not be replaced. 
• If a dose is missed, the missed dose can be taken within a 12-hour window of the time the 
patient typically takes the dose.  A double dose should not be administered to make up 
for missed individual doses. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs.  Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of fruquintinib therapy.  Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 7.5. 
The administration time should be recorded accurately in the patient diary. 
7.1.2 
Tislelizumab  
7.1.2.1 
Formulation, Packaging, Storage, and Handling  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a sterile glass vial 
containing a total of 100 mg of antibody in 10 mL of isotonic solution.  Tislelizumab has been 
aseptically filled in a single-use glass vial with a rubber stopper and capped by an aluminum 
flip-off seal cap.  Each vial is packaged into a single carton box.  


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The contents of the label will be in accordance with all applicable local regulatory requirements.  
The study drug must be kept under the temperature condition as specified on the label.  
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal.  Refer to the IB for other details regarding tislelizumab. 
7.1.2.2 
Dosing and Administration  
In Part 1 (Safety Lead-in Phase), tislelizumab 300 mg will be administered on Day 1 of each 
28-day cycle (once every 4 weeks). 
There is no predefined duration of treatment for each patient.  It is intended that patients in both 
the Safety Lead-in and expansion phases will be treated until radiologically determined PD per 
RECIST v 1.1, unacceptable toxicity, death, or withdrawal from study. 
Tislelizumab will be administered by intravenous infusion through an intravenous line 
containing a sterile, non-pyrogenic, 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. 
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.  On the days of combination use of fruquintinib and tislelizumab, fruquintinib should 
be administered orally first before administering tislelizumab intravenously. 
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. 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 7.5.3 and 
Appendix 9. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
The administration time should be recorded accurately. 
7.2 
Drug Accountability  
7.2.1 
Assignment/Disposal (Study Site)  
All study drug required for this study will be provided by HUTCHMED Limited.  The recipient 
will acknowledge receipt of the drug by returning the appropriate documentation form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to, and disposed of by 
the study site should be recorded using the Drug Inventory Log. 
Study drug will be disposed of at the study site according to the study site’s institutional standard 
operating procedure or returned to HUTCHMED Limited or a HUTCHMED Limited-identified 


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entity with appropriate documentation, as determined by the study site.  If the study site chooses 
to destroy study drug, the method of destruction must be documented. 
7.2.2 
Assignment/Return (Subject)  
On Day -2 to Day 1, drug assignment will be performed.  Patients will be provided with a pill 
diary and be instructed on how to account for each day’s dose appropriately.  
Patients should return all unused study drug and containers from the previous cycle on Day 1 
(date of scheduled visits) of each subsequent cycle, and new study drug will be dispensed on the 
same day.  Site staff should review the patient’s pill diary and provide a new diary if necessary at 
the day 1 visit of each cycle. 
If a dose adjustment is required (eg, decrease from 5 mg QD to 4 mg QD), the patient must 
return to the investigational site and return all unused study drug.  The site staff must log into 
IWRS, adjust the dose, reassign the drug serial number, and dispense the new study drug dose (in 
1mg capsules) to the patient. 
7.3 
Assessment and Verification of Compliance  
The investigator is responsible for ensuring the patient’s treatment compliance.  The sponsor will 
provide supervision through on-site monitoring visits made by its representatives.  The 
investigators should maintain complete and accurate records of drug dispensation and return.  
The dosing regimen and patient’s actual dosing should be recorded in the original treatment 
records as well as the eCRF.  At each treatment visit, the investigators or site staff should 
comprehensively assess the patient’s treatment compliance according to the drug dispensing and 
return status at each visit and the actual dosing conditions, such as missed doses and overdosing 
reported by the patient.  The patients must return all drug bottles and remaining capsules at the 
end of the study.  The investigational sites must return all remaining supplies and drugs to the 
sponsor or provide evidence of destruction at the conclusion of the study. 
Accurate records of all study drug(s) received, dispensed, returned, and disposed of should be 
maintained in the site’s Pharmacy Folder.  Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration. 
7.4 
Prior and Concomitant Therapies  
7.4.1 
Prohibited Therapies  
The following medications are prohibited during the study or as otherwise noted:  
• Any concurrent anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, and standard or investigational agents (including Chinese [or other 
country] herbal medicine and Chinese [or other country] patent medicines) for the 
treatment of cancer, is not allowed.  Chinese [or other country] herbal and Chinese [or 
other country] patent medicines with anticancer activity are defined as medication with 
approval by the NMPA (or other country) for use as anticancer treatment (regardless of 
the type of cancer). 
• Live vaccines ≤28 days before the first dose of study drug(s) and ≤60 days following the 
last dose of tislelizumab.  Seasonal vaccines for influenza are generally inactivated 
vaccines and are allowed.  Intranasal vaccines are live vaccines and are not allowed. 


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• 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 not abuse alcohol or other drugs. 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions (eg, hypericin) 
≤28 days (or ≤5 half-lives, if applicable, whichever is shorter) before the first dose of 
study drug(s) and during the study.  Patients must notify the investigator of all herbal 
remedies used during the study.  
• Radiation therapy, except for palliative radiation therapy described in Section 7.4.3. 
• Concomitant use of medications that have a known risk of causing QT prolongation 
and/or Torsades de Pointes (Appendix 13). 
7.4.2 
Medications to Be Used With Caution  
The use of potentially hepatotoxic drugs in patients with impaired hepatic function is allowed but 
should be carefully monitored.  
Medications that are strong inducers of CYP3A should not be administered concomitantly with 
fruquintinib (see Appendix 4 for detailed information) unless the investigator considers it 
necessary.  Fruquintinib is metabolized through CYP3A, so a strong inducer of enzyme CYP 
3A4 may significantly influence the metabolism of fruquintinib. 
Fruquintinib showed inhibition of P-gp and breast cancer resistance protein (BCRP) transporter 
in the in vitro studies, so drugs that are sensitive substrates, and substrates with narrow 
therapeutic index for P-gp and BCRP transporters should be avoided if possible (see Appendix 
4). If these are used together, patients should be monitored more frequently for adverse reactions, 
and dose reduction of the P-gp or BCRP substrate medication should be considered. 
7.4.3 
Permitted Therapies  
Unless noted otherwise, most concomitant medications and therapies deemed necessary and in 
keeping with local standards of medical care at the discretion of the investigator for supportive 
care (eg, antiemetics, antidiarrheals, hematopoietic growth factors, and red blood cell/platelet 
transfusions) and in a patient’s interest are allowed. 
Bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are allowed 
for bone metastases if initiated before enrollment and at a stable dose.  Bisphosphonates are 
permitted during the study for a nonmalignant indication. 
Patients who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy may continue their use if indicated. 
Prophylactic use of anticoagulation for the maintenance of patency of permanent indwelling 
central venous access devices or for patients at high risk of venous thromboembolism is 
permitted during study treatment.  If patients are receiving anticoagulation, they should be very 
closely monitored for potential hemorrhage. 
The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic 
drugs during study drug treatment and make a timely decision on whether to continue or stop 
such drugs in patients who report Grade ≥2 hemorrhagic events at any site, based on an 


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individual assessment of the risk-benefit balance (see Appendix 6 for additional information on 
the clinical management of severe or serious hemorrhagic AEs). 
Systemic Corticosteroids: 
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 9 and must be administered at nonimmunosuppressive doses (≤10 mg/day of 
prednisone or equivalent) before the next tislelizumab administration.  The short-term use of 
steroids as prophylactic treatment (eg, patients with contrast allergies to diagnostic imaging 
contrast dyes) is permitted. 
Hepatitis B Treatment: 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA <500 IU/mL or <2500 copies/mL) is at the discretion of the investigator, 
as aligned with local guidance.  Such medications must be documented in the patient’s chart and 
recorded in the eCRF.  Patients receiving antivirals at screening should be treated for >2 weeks 
before enrollment and continue treatment during the study and for 6 months after study drug 
discontinuation.  
Radiation Therapy: 
Palliative (limited-field) radiation therapy is permitted but only for pain control or prophylaxis of 
bone fracture to sites of bone disease present at baseline if the following criteria are met:  
• Repeat imaging demonstrates no new sites of bone metastases. 
• The lesion being considered for palliative radiation is not a target lesion. The case is 
discussed with the medical monitor, and he/she agrees that the conditions required to 
receive palliative radiation are met. 
In addition, palliative radiation or other focally ablative therapy for symptom control to other 
non-target sites of the disease is permitted if clinically indicated per the investigator’s discretion.  
The medical monitor should be informed of the on-study radiotherapy.  These patients should 
have a tumor assessment of the lesion(s) before receiving the radiation therapy to rule out 
progression of disease.  Fruquintinib treatment should be suspended during the radiation period 
and not resumed until at least 7 days after radiation only after meeting the following criteria: 
• Radiation-related toxicities resolves to Grade ≤2 
• No disease progression observed 
7.4.4 
Drug-Drug Interactions  
Drug Interactions with Tislelizumab 
Information about clinical drug interactions with tislelizumab is not available.  The potential for 
drug-drug interaction between tislelizumab and small-molecule drug products, such as 
fruquintinib, is very low, given that tislelizumab is a therapeutic monoclonal antibody.  
Tislelizumab is a therapeutic monoclonal antibody and is not expected to be metabolized by liver 
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.  Even though fruquintinib was mainly 
metabolized via CYP enzymes, the possibility of tislelizumab interfering with this metabolism 
pathway is low. 


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Drug Interactions with Fruquintinib 
Coadministration of fruquintinib with a strong CYP3A inducer reduced systemic exposure of 
fruquintinib by 65%. Therefore, medications that are strong inducers of CYP3A should not be 
administered concomitantly with fruquintinib. 
7.4.5 
Rescue Therapies  
Not applicable. 
7.5 
Dose Delay, Interruption, or Modification  
A dose delay is a deviation from the prescribed dosing schedule (ie, the drug is withheld beyond 
the visit window).  A dose interruption is an interruption of an infusion of tislelizumab or 
of -self-administered dosing of fruquintinib during the three weeks it is scheduled to be received.  
Treatment cycles will be counted continuously regardless of dose delays. 
Every effort should be made to administer the study drug(s) according to the planned dosage and 
schedule.  In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines below.  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. 
Reasons for dose modifications or delays, the supportive measures taken, and the outcome 
should be documented in the patient’s chart and recorded in the eCRF.  The severity of AEs will 
be graded according to the NCI CTCAE v5.0, and the attribution of relatedness to the specific 
study drug should be noted. 
• For any concomitant conditions already apparent at baseline, the dose modifications will 
apply according to the corresponding shift in toxicity grade, if the investigator feels it is 
appropriate.  For example, if a patient has Grade 1 asthenia at baseline that increases to 
Grade 2 during treatment, this will be considered a shift of 1 grade and treated as Grade 1 
toxicity for dose-modification purposes. 
• Patients who develop arterial thromboembolic events should discontinue the study 
drug(s).  If a patient suffers a venous thromboembolic event while still receiving the 
study drug(s), it may still be possible for him or her to remain on study treatment under 
close monitoring and dose modification of study drug(s). 
• For toxicities that are considered by the investigator to be unlikely to develop into serious 
or life-threatening events, treatment can be continued at the same dose. 
• To recover from acute toxicity, unless otherwise indicated, the treatment with 
fruquintinib can be delayed for up to 14 days.  If a treatment delay longer than 14 days is 
required, treatment should be discontinued.  Continuation/resumption of fruquintinib 
treatment after an interruption of more than 14 days must be discussed with the medical 
monitor or his or her designee.  Guidance specific to tislelizumab temporary suspension 
is contained in Section 7.5.1. 
• Where several toxicities with different grades or severity occur at the same time, the dose 
modifications should be according to the highest grade observed. 
• If either fruquintinib or tislelizumab is permanently discontinued due to toxicity, the 
other investigational treatment can be continued as a single agent, provided that the 
patients have investigator-assessed clinical benefit and are tolerating study drug. 


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7.5.1 
Dose Modification for Tislelizumab  
There will be no dose reduction for tislelizumab in this study. 
Tislelizumab treatment may be temporarily suspended if the patient experiences a toxicity that is 
considered related to fruquintinib or tislelizumab and requires a dose to be withheld.  Guidance 
for management of tislelizumab administration in the presence of immune-mediated adverse 
events is located in Section 7.5.4.  Tislelizumab treatment should resume as soon as possible 
after the AEs recover to baseline or Grade 1 (whichever is more severe) and within 12 weeks 
after the last dose of tislelizumab.  If the administration of study drug can resume within ≤10 
days, it should be administered in the current cycle.  If tislelizumab needs to be withheld for >10 
days, it should be omitted from the current cycle and administration should continue at the start 
of the next cycle.  If the patient is unable to resume tislelizumab within 12 weeks after the last 
dose of tislelizumab, then the patient should be discontinued from tislelizumab treatment.  If the 
patient is unable to resume tislelizumab ≤12 weeks after the last dose for unforeseen non-drug-
related reasons, continued treatment may be allowed if approved by the medical monitor.  
7.5.2 
Dose Modification for Fruquintinib  
The dose can be reduced at any time due to the intolerable toxicity following the DLT 
observation window in the Safety Lead-in Phase (Table 6).  Once reduced, the dose cannot be 
re-escalated to the previous level. 
• If the patient’s original dose is 5 mg once daily, up to 2 dose reductions are permitted: 
1 reduction from 5 mg once daily to 4 mg once daily and, if not tolerated, a second 
reduction from 4 mg once daily to 3 mg once daily. 
• If the patient’s original dose is 4 mg once daily, only 1 dose reduction is permitted: a 
reduction from 4 mg once daily to 3 mg once daily. 
Table 6 
Fruquintinib Starting Dose Reductions  
Dose Level 
Dose 
Reduced Dose 
Dose Level 1* 
(original dose) 
5 mg once daily 
4 mg once daily 
Dose Level -1* 
(1st dose reduction)  
4 mg once daily 
3 mg once daily 
Dose Level -2* 
(2nd dose reduction)  
3 mg once daily 
Not available 
*Doses are daily, on days 1 to 21 each 28-day cycle (3 weeks on/1 week off). 
7.5.3 
Fruquintinib Dose Modification Guidance  
7.5.3.1 
Fruquintinib Dose Modification Sequence for General Hematologic and Non-
Hematologic Toxicity  
Dose reduction guidelines for hematologic and non-hematologic toxicities, other than guidance 
for important identified risks (PPE, proteinuria, hypertension, decreased platelet count, 
hemorrhage, and liver function impairment) are provided in Table 7.  Treatment should be held 
until AE/toxicity resolves or improves to Grade ≤1 or baseline level within 14 days.  Patients 
with Grade 3 non-hematologic toxicity not described below that does not resolve to Grade ≤1 or 


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baseline level within 14 days should permanently discontinue the study drug unless approval to 
continue is obtained in writing from the sponsor. 
Table 7 
Fruquintinib Dose Modifications for Hematologic and Non-Hematologic 
Toxicity  
NCI CTCAE v5.0 Toxicity Grading 
Action 
Grade 1 or 2a 
None 
Grade 3b 
Interrupt the dose until the toxicity resolves to Grade ≤1 or baseline 
level within 14 days, then reduce the dose to a lower dose level 
Grade 4 
Discontinue treatment permanently 
a 
Should any arterial thrombosis occur, the treatment should be terminated. 
b 
Including Grade 3 diarrhea and stomatitis that are ineffectively treated by drug therapies, but excluding 
Grade 3 menstrual cycle extension. 
7.5.3.2 
Fruquintinib Dose Modifications for Potential Risks and Important Identified 
Risks  
The dose modification and treatment suggestions for potential risks are provided in Table 8 and 
for specific identified risks are provided in Table 9 (dermatologic toxicities), Table 10 
(proteinuria), Table 11 (hypertension), Table 12 (decreased platelet count), Table 13 
(hemorrhage at any site), and Table 14 (abnormal liver function). 
Table 8 
Fruquintinib Dose Modifications for Potential Risks  
AE 
Dose Adjustment 
Gastrointestinal perforation 
Study drug should be discontinued. 
Arterial Thrombosisa 
Study drug should be discontinued. 
Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS)b 
If suspected as RPLS, the study drug should be 
discontinued. 
Delayed Wound Healing 
The general guidance for dose 
interruptions/reductions/discontinuations in response to 
AEs should be followed. 
RPLS=Reversible Posterior Leukoencephalopathy Syndrome. 
a 
The event term of arterial thrombosis encompasses the preferred terms (PT) of Aortic thrombosis, 
Cerebrovascular insufficiency, Embolism arterial, Peripheral embolism, Retinal artery occlusion, Subclavian 
artery thrombosis, and Transient ischemic attack. 
b 
The signs and symptoms of RPLS include seizure, headache, altered mental status, visual impairment or 
cortical blindness with or without hypertension.  The diagnosis of RPLS must be verified using brain 
magnetic resonance imaging (MRI).  


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Table 9 
Fruquintinib Dose Modifications for Dermatological Toxicities  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1  
None 
Active supportive treatment can be 
adopted to relieve the symptoms, for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment can 
be used.  
Grade 2 
• 
Hold treatment. 
• 
If the AE recovers to 
Grade 1 or baseline level 
within 14 days, resume 
treatment at the same 
dose level. 
Active supportive treatment can be 
adopted to relieve the symptoms, for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment can 
be used. 
Grade 3  
• 
Hold treatment.  
• 
If the AE recovers to 
Grade 1 or baseline level 
within 14 days, resume 
treatment with a dose 
reduction to the next 
lower dose level. 
Active supportive treatment can be 
adopted to relieve the symptoms; 
should the same AE occur for 3 times 
or still occur after 2 times of dose 
reduction, the drug should be 
terminated. 
AE=adverse event; NCI CTCAE v5.0=National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0. 
Table 10 
Fruquintinib Dose Modifications for Proteinuriaa  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1: Proteinuria 1+ by 
urinalysis;  
24-hour urine protein quantitation 
<1.0 g 
None 
Follow up at scheduled study visits.  
Grade 2: Proteinuria 2+ by  
urinalysis; 
24-hour urine protein quantitation 
is between 1.0 to <2.0 g  
None 
Provide supportive treatment and increase 
the frequency of urine monitor to once a 
week; consult nephrologist if necessary. 
Grade 2: Proteinuria 2+ or above 
by urinalysis;  
24-hour urine protein quantitation 
is between 2.0 to <3.5 g 
(excluding 3.5 g) 
• 
Hold treatment. 
• 
If the AE recovers to 
Grade 1 or baseline level 
within 14 days, resume 
treatment with a dose 
reduction to the next lower 
dose level. 
Provide supportive treatment and increase 
the frequency of urine monitor to once a 
week; consult nephrologist if necessary. 
Grade 3 : 24-hour urine protein 
quantitation ≥3.5 
• 
Hold treatment. 
• 
If the AE recovers to 
Grade 1 or baseline level 
within 14 days, resume 
treatment with a dose 
reduction to the next lower 
dose level. 
Provide supportive treatment and increase 
the frequency of urine monitor to once or 
twice a week; consult nephrologist if 
necessary.  Should the same AE occur for 
3 times or still occurs after 2 times of 
dose reduction, the drug should be 
terminated. 


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Table 10 
Fruquintinib Dose Modifications for Proteinuriaa  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
AE=adverse event; NCI CTCAE v5.0=National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0. 
a 
If protein ≥2+ on urinalysis during the study, a 24-hour urine test should be conducted within 1 week, and 
dose modification will be done by the result of 24-hour urine protein quantitation. 
 
Table 11 
Fruquintinib Dose Modifications for Hypertension  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1  
None 
Follow up as planned schedule. 
Grade 2 
None 
Treatment objective: lower the 
blood pressure to <140/90 mmHg 
(or <130/80 mmHg in patients 
with chronic renal disease and/or 
diabetes).  
Refer to  Appendix 7 
Grade 3  
• 
If BP >160/100mmHg lasts for 
>7 days after initiation of anti-
hypertensive treatment or 
modification of current anti-
hypertensive treatment, treatment 
should be held. 
• 
If hypertension resolves to Grade 1 
or baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level. 
Treatment objective: lower the 
blood pressure to <140/90 mmHg 
(or <130/80 mmHg in patients 
with chronic renal disease and/or 
diabetes).  
Refer to  Appendix 7 
Grade 4  
Permanently discontinue study 
treatment. 
Emergent medical treatment. 
AE=adverse event; BP=blood pressure;  NCI CTCAE v5.0=National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0. 


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Table 12 
Fruquintinib Dose Modifications for Decreased Platelet Count  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None 
Perform follow-up visit as scheduled. 
Grade 2 
• 
Hold treatment. 
• 
If the AE recovers to Grade 1 
or baseline level within 
7 days, resume treatment at 
the same dose level. 
Platelet count should be performed every 
2-3 days; active treatment for platelet 
elevation is recommended. 
• 
Hold treatment. 
• 
If the AE recovers to Grade 1 
or baseline level within 
14 days, resume treatment 
with a dose reduction to the 
next lower dose level. 
Platelet count should be performed every 
2-3 days; active treatment for platelet 
elevation is recommended. 
Grade 3 
• 
Hold treatment. 
• 
If the AE recovers to Grade 1 
or baseline level within 
14 days, resume treatment 
with a dose reduction to the 
next lower dose level. 
Platelet count should be performed every 
2-3 days; active treatment (platelet 
transfusion) to elevate the platelet count is 
recommended.  
Platelet count should be performed once 
every week in the follow-up visit. 
Grade 4 
Permanently discontinue study 
treatment. 
Platelet count should be performed once 
daily until the AE recovers to Grade 2 or a 
lower grade; platelet transfusion or other 
active treatment should be provided.  
AE=adverse event; NCI CTCAE v5.0=National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0. 
Table 13 
Fruquintinib Dose Modifications for Hemorrhage at Any Site  
NCI CTCAE v5.0 Toxicity 
Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None 
Perform follow-up visit as 
scheduled. 
Grade 2 
• 
Hold treatment. 
• 
If the AE recovers to Grade 1 
or baseline level within 
14 days, resume treatment with 
a dose reduction to the next 
lower dose level. 
Provide active treatment.b 
Grade 3 or abovea 
Permanently discontinue study 
treatment. 
Emergent medical intervention.b 
AE=adverse event; NCI CTCAE v5.0=National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0. 
a 
Refer to Appendix 6 for clinical management of severe or serious hemorrhage. 
b 
The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic drugs during 
study drug treatment and make a timely decision on whether to continue or stop such drugs in patients who 
report Grade ≥2 hemorrhagic events at any site, based on an individual assessment of the risk-benefit 
balance. 


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Table 14 
Fruquintinib Dose Modifications for Abnormal Liver Function  
NCI CTCAE v5.0 Toxicity 
Gradinga 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None. 
Follow up per planned schedule. 
Grade 2 or 3 (Liver function is 
abnormal but the biochemical 
criteria for Hy’s Lawb are not met) 
• 
Hold treatment. 
• 
If the AE recovers to Grade 1 
or baseline level within 
14 days, resume treatment with 
a dose reduction to the next 
lower dose level. 
Provide supportive care and 
increase the frequency of liver 
function testing to 1-2 times a 
week. 
Grade 2 or 3 (Liver function is 
abnormal and the biochemical 
criteria for Hy’s Lawb are met) 
The study drug should be 
terminated immediately. 
Provide supportive care and 
increase the frequency of liver 
function testing to 2-3 times a 
week.  Urgent medical intervention 
indicated. 
Grade 4 
The study drug should be 
terminated. 
Urgent medical intervention 
indicated. 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE v5.0=National 
Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; ULN=upper limit of normal.  
a 
Including increasing of ALT, AST, and total bilirubin, whether or not the biochemical criteria for Hy’s Law 
have been met. 
b 
Hy’s Law is an increase in serum AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, and no other 
reason can be found to explain the biochemical changes, for example, new or worsening hepatobiliary 
metastases, elevated serum alkaline phosphatase indicating cholestasis, viral hepatitis, another suspect drug, or 
any other specific cause of severe hepatocellular injury.  The elevation in transaminases must precede or be 
coincident with (ie, on the same day as) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur.  See Section 8.2.2 for special 
reporting requirements and Appendix 5 for additional information regarding Hy’s Law. 
7.5.4 
Dose Management for Tislelizumab  
Immune-mediated AEs can escalate quickly.  Study treatment interruption, close monitoring, 
timely diagnostic work-up, and treatment intervention as appropriate is required. 
Immune-mediated AEs should improve promptly after introduction of immunosuppressive 
therapy.  If this does not occur, review the diagnosis, seek further specialist advice, and contact 
the study medical monitor. 
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be considered 
if there is evidence of a clinical response to study treatment, after consultation with the study 
medical monitor. 
Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  Equivalent 
dosages of other corticosteroids can be substituted.  For steroid-refractory imAEs, consider use 
of steroid-sparing agents (eg, mycophenolate mofetil). 
Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term 
immunosuppressive therapy. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
Thyroid 
disorders 
1-2 
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 tislelizumab or 
withhold in cases with 
systemic symptoms. 
3-4 
Refer patient to an endocrinologist. 
If hypothyroid, replace with thyroxine 
0.5-1.6 µg/kg/day (for the elderly or 
those with comorbidities, 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 tislelizumab; resume 
when resolved/improved to 
Grade 0-1.  
 
Hypophysitis 
1-2 
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. 
Continue tislelizumab. 
3-4 
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 endocrinologist’s advice. 
Hold tislelizumab for 
patients with 
headache/visual disturbance 
due to pituitary 
inflammation until 
resolved/improved to 
Grade ≤2.  Discontinuation 
is usually not necessary.  
 
Pneumonitis 
1 
Monitor symptoms every 2-3 days.   
If appearance worsens, treat as 
Grade 2. 
Consider holding 
tislelizumab until 
appearance improves and 
cause is determined. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
2 
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 tislelizumab.  Re-
treatment is acceptable if 
symptoms resolve 
completely or are controlled 
on prednisolone 
≤10 mg/day.  Discontinue 
tislelizumab if symptoms 
persist with corticosteroid 
treatment. 
3-4 
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 tislelizumab. 
Neurological 
toxicity 
1 
— 
Continue tislelizumab. 
2 
Treat with oral prednisolone 
0.5-1 mg/kg/day.  Taper over at least 
4 weeks. 
Obtain neurology consultation. 
Hold tislelizumab; resume 
when resolved/improved to 
Grade 0-1. 
3-4 
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 tislelizumab. 
Colitis/diarrhea 
1 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for >14 days, 
manage as a Grade 2 event. 
Continue tislelizumab. 
2 
Oral prednisolone 0.5 mg/kg/day 
(nonenteric coated). 
Do not wait for any diagnostic tests to 
start treatment.  Taper steroids over 
2-4 weeks. 
Consider endoscopy if symptoms are 
recurring. 
Hold tislelizumab; resume 
when resolved/improved to 
baseline grade. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
3 
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 Class III/IV CHF or 
other immunosuppressive treatment: 
MMF or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/sigmoidoscopy. 
Hold tislelizumab; re-
treatment may be considered 
when resolved/improved to 
baseline grade and after 
discussion with the study 
medical monitor. 
 
4 
Discontinue tislelizumab. 
Skin reactions 
1 
Avoid skin irritants and sun exposure; 
topical emollients recommended. 
Continue tislelizumab. 
2 
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 tislelizumab. 
3 
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 tislelizumab. 
Re-treat when AE is 
resolved or improved to mild 
rash (Grade 1-2) after 
discussion with the study 
medical monitor. 
4 
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 tislelizumab. 
Hepatitis 
1 
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 tislelizumab if 
LFTs are unchanged or 
improving. 
Hold tislelizumab if LFTs 
are worsening until 
improvement is seen. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
2 
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 tislelizumab; resume 
when resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤10 mg. 
3 
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 tislelizumab until 
improved to baseline grade; 
reintroduce only after 
discussion with the study 
medical monitor.  
4 
Initiate intravenous 
methylprednisolone 2 mg/kg/day.  
Convert to oral prednisolone and taper 
over at least 6 weeks.  
Discontinue tislelizumab. 
Worsening LFTs despite steroids: 
If on oral prednisolone, change to pulsed intravenous methylprednisolone. 
If on intravenous methylprednisolone, add mycophenolate mofetil (MMF) 500 to 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 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue tislelizumab. 
2 
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 tislelizumab. 
If not attributed to drug 
toxicity, restart tislelizumab. 
If attributed to study drug 
and resolved/improved to 
baseline grade: restart 
tislelizumab if tapered to 
<10 mg prednisolone. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
3 
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 tislelizumab until the 
cause is investigated.  
If study drug suspected: 
discontinue tislelizumab. 
 
4 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue tislelizumab. 
Diabetes/ 
hyperglycemia 
1 
Monitor closely and treat according to 
local guideline.  Check for C-peptide 
and antibodies against glutamic acid 
decarboxylase and islet cells are 
recommended. 
Continue tislelizumab. 
2 
Obtain a repeat blood glucose level at 
least every week.  Manage according 
to local guideline. 
Continue tislelizumab or 
hold tislelizumab if 
hyperglycemia is worsening.  
Resume tislelizumab when 
blood glucose is stabilized at 
baseline or Grade 0-1. 
3 
Admit patient to hospital and refer to a 
diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold tislelizumab until 
patient is hyperglycemia 
symptom-free, and blood 
glucose has been stabilized 
at baseline or Grade 0-1. 
 
4 
Admit patient to hospital and institute 
local emergency diabetes management. 
Refer the patient to a diabetologist for 
insulin maintenance and monitoring. 
Hold tislelizumab until 
patient is hyperglycemia 
symptom-free and blood 
glucose has been stabilized 
at baseline or Grade 0-1. 
 
Ocular toxicity 
1 
Consider alternative causes and 
prescribe topical treatment as required. 
Continue tislelizumab. 
2 
Refer patient to an ophthalmologist for 
assessment and topical corticosteroid 
treatment. 
Consider a course of oral steroids. 
Continue tislelizumab or 
hold tislelizumab if 
symptoms worsen or if there 
are symptoms of visual 
disturbance. 
3 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper over 
at least 4 weeks. 
Hold tislelizumab until 
improved to Grade 0-1; 
reintroduce only after 
discussion with the study 
medical monitor. 
 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
4 
Initiate intravenous (methyl) 
prednisolone 2 mg/kg/day.  Convert to 
oral prednisolone and taper over at 
least 4 weeks. 
Discontinue tislelizumab. 
Pancreatitis 
2 
Monitor pancreatic enzymes. 
Continue tislelizumab. 
3 
Admit to hospital for urgent 
management.  Initiate intravenous 
(methyl) prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2 
and taper over at least 4 weeks. 
Hold tislelizumab; 
reintroduce only after 
discussion with the study 
medical monitor. 
4 
Admit to hospital for emergency 
management and appropriate referral.   
Discontinue tislelizumab. 
Arthritis 
1 
Management per local guideline.  
Continue tislelizumab. 
2 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist. 
If symptoms worsen on treatment, 
manage as a Grade 3 event. 
Continue tislelizumab or, if 
symptoms continue to 
worsen, hold tislelizumab 
until symptoms improve to 
baseline or Grade 0-1. 
3 
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 tislelizumab unless 
improved to Grade 0-1; 
reintroduce only after 
discussion with the study 
medical monitor. 
Mucositis/ 
stomatitis 
1 
Consider topical treatment or analgesia 
as per local guideline. 
Continue tislelizumab. 
2 
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 tislelizumab. 
3 
Admit to hospital for appropriate 
management. 
Initiate intravenous 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improve to Grade 2 and 
taper over at least 4 weeks. 
Hold tislelizumab until 
improved to Grade 0-1. 
4 
Admit to hospital for emergency care. 
Consider intravenous corticosteroids if 
not contraindicated by infection. 
Discontinue tislelizumab. 
Myositis/ 
rhabdomyolysis 
1 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2. 
Continue tislelizumab. 


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Autoimmune 
Toxicity 
NCI CTCAE v5.0 
Toxicity Grading 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Tislelizumab Management 
2 
If CK is 3× ULN or worse, initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold tislelizumab until 
improved to Grade 0-1. 
3-4 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider bolus 
intravenous (methyl) prednisolone and 
1-2 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. 
For Grade 3: Hold 
tislelizumab until improved 
to Grade 0-1.  Discontinue 
upon any evidence of 
myocardial involvement. 
 
Myocarditis a 
<2 
Initiate cardiac evaluation under close 
monitoring with repeat serum testing 
and including ECG, cardiac 
echo/MUGA, and/or other 
interventions per institutional 
guidelines; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2. 
Hold tislelizumab. 
If a diagnosis of myocarditis 
is confirmed and considered 
immune-mediated, 
permanently discontinue 
tislelizumab in patients with 
moderate or severe 
symptoms. 
Patients with no symptoms 
or mild symptoms may not 
restart tislelizumab unless 
cardiac parameters have 
returned to baseline and after 
discussion with the study 
medical monitor. 
2 
Admit to hospital and initiate oral 
prednisolone or intravenous (methyl) 
prednisolone at 1-2 mg/kg/day.  
Consult with a cardiologist and 
manage symptoms of cardiac failure 
according to local guidelines. 
If no immediate response, change to 
pulsed doses of (methyl) prednisolone 
1 g/day and add MMF, infliximab, or 
antithymocyte globulin. 
3 
4 
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 isoenzyme MB; 
ECG=electrocardiogram; INR=international normalized ratio; LFT=liver function test; MMF=mycophenolate 
mofetil; MUGA=multigated acquisition scan; NCI CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse Events; 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. 
a  
If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial 
cardiac enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly 
be considered until immune-mediated myocarditis has been ruled out. 
 


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8 
SAFETY MONITORING  
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. 
Safety will be monitored through continuous reporting of AEs and SAEs, laboratory 
abnormalities, and incidence of patients experiencing dose modifications (including dose 
reductions and dose delays) and/or dose discontinuation of study drug (and reason for 
discontinuation). 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients.  
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
8.1 
Definitions  
8.1.1 
Adverse Event  
An AE is any untoward medical occurrence in a clinical study patient temporally associated with 
the use of a study intervention, whether or not considered related to the intervention.  An AE can 
therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study intervention, whether or 
not considered related to the study intervention  
• Any new disease or exacerbation of an existing disease (a worsening in the frequency or 
severity of a known condition).  Recurrence of an intermittent medical condition (eg, 
headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (eg, screening invasive procedures such as biopsies) 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent.  Such 
overdoses should be reported regardless of sequelae. 
8.1.2 
Serious Adverse Event  
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 
• Death 
• A life-threatening AE.  An event is considered “life-threatening” if, in the view of the 
investigator, its occurrence places the patient at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
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• An abnormal pregnancy outcome (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, or ectopic pregnancy) in a child born to a female patient 
or female partner of a male patient exposed to study drug 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
The following are NOT considered to be SAEs: 
• Hospitalization for elective treatment of a preexisting 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 
8.2 
Adverse Event Reporting  
8.2.1 
Adverse Event Reporting Period  
After signing the informed consent form, all AEs including SAEs regardless of attribution will 
be collected until 30 days after the last dose of study drug or initiation of a new treatment 
therapy, whichever is earlier.  After this period, investigators should report only SAEs that are 
considered to be related to the study drug.  Immune-mediated AEs (serious or nonserious) should 
be reported until 90 days after the last dose of tislelizumab regardless of whether or not the 
patient starts a new anticancer therapy. 
8.2.2 
Expedited Reporting  
Certain events require immediate reporting to allow the sponsor to take appropriate measures to 
address potential new risks in a clinical trial.  The investigator must report such events (both 
initial and follow-up) to the sponsor or its designee immediately; under no circumstances should 
reporting take place more than 24 hours after the investigator learns of the event.  The following 
is a list of events that the investigator must report to the sponsor within 24 hours after first 
learning of the event, regardless of relationship to study drug: 
• SAEs (from informed consent to 30 days following the last dose of study drug or 
initiation of a new treatment of anti-tumor therapy, whichever is earlier) 
• Abnormal hepatic function is defined as serum AST or ALT ≥3 × ULN together with 
total bilirubin ≥2 × ULN, regardless of seriousness. 
− For management of a hepatic function abnormal event, refer to Table 14.  Hy’s Law 
is an increase in serum AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, 
and no other reason can be found to explain the biochemical changes, for example, new 
or worsening hepatobiliary metastases, elevated serum ALP indicating cholestasis, viral 
hepatitis, another suspect drug, or any other specific cause of severe hepatocellular 
injury.  The elevation in transaminases must precede or be coincident with (ie, on the 


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same day as) the elevation in total bilirubin, but there is no specified timeframe within 
which the elevations in transaminases and total bilirubin must occur.  See Appendix 5 for 
additional information regarding Hy’s Law. 
• CTCAE Grade ≥3 hemorrhagic event 
− When there is a Grade ≥3 hemorrhagic event per NCI CTCAE (version 5.0).  The 
management of severe or serious hemorrhagic events will be conducted according to 
Appendix 6. 
• Pregnancy 
8.3 
Definition of a Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the study drug’s reference safety information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the fruquintinib IB and the tislelizumab IB. 
8.4 
Definition of Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study for tislelizumab.  If the events listed 
below or similar events occur, the investigator should exclude alternative explanations 
(eg, combination drugs, infectious disease, metabolic, toxin, PD, or other neoplastic causes) with 
appropriate diagnostic tests that may include but are not limited to serologic, immunologic, and 
histologic (biopsy) data.  If alternative causes have been ruled out, the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy and is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs 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 imAEs is based on European 
Society for Medical Oncology and American Society of Clinical Oncology guidelines 
(Haanen 2017, Brahmer 2018), and common immune-mediated toxicities are detailed in 
Appendix 9.  For any AEs not included in Appendix 9, refer to the American Society of Clinical 
Oncology Clinical Practice Guideline (Brahmer 2018) for further guidance on diagnostic 
evaluation and management of immune-mediated toxicities. 
Table 15 
Examples of Immune-Mediated Adverse Events  
Body System Affected 
Event 
Skin (mild-common)  
pruritus or maculopapular rash; vitiligo  
Skin (moderate)  
follicular or urticarial dermatitis; 
erythematous/lichenoid rash; Sweet 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  


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Table 15 
Examples of Immune-Mediated Adverse Events  
Body System Affected 
Event 
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  
ALT=alanine aminotransferase; AST=aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 9. 
If a toxicity does not resolve to Grade ≤1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade after restart of study drug should permanently discontinue 
treatment. 
8.5 
Eliciting Adverse Events  
A consistent methodology of non-directive questioning for eliciting AEs at all patient evaluation 
time points should be adopted.  Examples of non-directive questions include the following: 
• “How have you felt since your last clinic visit?” 
• “Have you had any new or changed health problems since you were last here?” 
8.6 
Assessment of Severity  
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs and 
SAEs, whether reported by the patient or noted by authorized study personnel, will be recorded 
in the patient’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable eCRF, the investigator will make an 
assessment of severity through clinical description by referring to the 5-grade determination 
standard in the NCI CTCAE v5.0.  Use the guideline below for the assessment of severity when 
the observed or reported AE is not listed in the NCI CTCAE v5.0: 
• 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 ADL* 


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• 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: 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
8.7 
Causality Assessment  
Investigators should use their knowledge of the patient, the circumstances surrounding the AE, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the study drug.  To ensure consistency of causality assessments, 
investigators should apply the general guidelines provided as below: 
• Related: There is a reasonable possibility that the event may have been caused by the 
product under investigation.  Factors that point toward this assessment include, but are 
not limited to, a positive re-challenge, a reasonable temporal sequence between 
administration of the drug and the event, a known response pattern of the suspected drug, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the drug and the AE, or a lack of an alternative explanation for the 
AE. 
• Not related: There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in cases 
where the disease under study has deteriorated due to lack of effect should be classified as no 
reasonable possibility. 
8.8 
Documenting Adverse Events  
When an AE or SAE is recorded, the preferred medical terminology or concept should be used.  
Abbreviations and colloquialisms (eg, jargon or slang) should be avoided. 
All AEs (including SAEs) should be recorded on the AE eCRF, and the check box for “Serious” 
should be ticked for entries that fit the criteria for SAEs.  The investigator should also complete 
an SAE report and submit this to the sponsor or its designee within 24 hours of knowledge of the 
event. 
Only 1 medical concept should be recorded in the event field on the eCRF. 


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8.8.1 
Diagnosis versus Symptoms and Signs  
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(eg, hepatic failure should be recorded instead of jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be recorded 
as an AE or SAE on the eCRF.  If a diagnosis is subsequently established, it should be reported 
as follow-up information. 
8.8.2 
Adverse Events Occurring Secondary to Other Events  
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause with the exception of severe or serious secondary 
events.  For example, if severe diarrhea is known to have resulted in dehydration, it is sufficient 
to record only diarrhea as an AE or SAE on the eCRF if the dehydration is mild. 
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the eCRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF. 
8.8.3 
Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points.  Such events should only be recorded once in the eCRF unless the severity changes.  
If a persistent AE becomes more or less severe, it should be recorded again in a new eCRF entry. 
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on the eCRF. 
8.8.4 
Abnormal Laboratory Values or Abnormal Vital Signs  
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  A laboratory test 
result/abnormal vital sign must be reported as an AE if it is a change from baseline and meets 
any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (eg, dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Clinically significant in the investigator’s judgment  
Investigators are responsible for reviewing all laboratory findings and abnormal vital signs and 
determining whether or not each abnormality should be reported as an AE. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, ALP 
and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (eg, cholecystitis) needs 
to be recorded on the eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory 


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abnormality can be characterized by a precise clinical term, the clinical term should be recorded 
as the AE or SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be 
recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
8.8.5 
Preexisting Medical Conditions  
A preexisting medical condition is one that is present at screening.  Such conditions should be 
recorded on the eCRF as medical history.  A preexisting medical condition should be recorded as 
an AE or SAE only if the frequency, severity, or character of the condition worsens during the 
study (excluding deterioration of the study disease conditions).  When such events are recorded 
on the eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 
8.8.6 
Pregnancy  
A female patient must be instructed to stop taking the study drug and immediately inform the 
investigator if she becomes pregnant during the study.  The investigator should report all 
pregnancies within 24 hours of awareness to the sponsor (the reporting period for pregnancy 
continues up to 30 days after completion of the study drug).  The investigator should counsel the 
patient and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until outcome of the pregnancy.  Pregnancies 
occurring up to 30 days after the completion of the study drug must also be reported to the 
investigator. 
Male patients must also be instructed to inform the investigator immediately if their partner 
becomes pregnant during the study or within 90 days after the last dose of study drug.  If such an 
event occurs, it should be reported as described above. 
Pregnancy loss of any kind should always be classified as SAE (as the sponsor considers these 
medically significant), recorded on the eCRF, and expeditiously reported to sponsor. 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a 
male patient exposed to the investigational product should be recorded and reported as an SAE. 
8.8.7 
Worsening of Solid Tumor  
Worsening and/or progression of the patient’s solid tumor should not be recorded as an AE or 
SAE.  These data will be captured as efficacy assessment data only.  If there is any uncertainty 
about an AE being related only to the disease under study, it should be reported as an AE or 
SAE. 
8.8.8 
Death  
All deaths that occur during the protocol-specified AE reporting period must have the underlying 
cause reported to the sponsor as an SAE with death listed as the outcome.  Deaths due to the 
progression of disease must also be reported to the sponsor as an SAE.  Death events that occur 
after 30 days following the last dose of study drug must be reported to the sponsor as an SAE 


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only if it is confirmed as related to study drug.  If the primary cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Unknown cause death” on the eCRF, and 
the “unexplained/unknown death” should be reported expeditiously as an SAE.  The SAE should 
be reported before the specific cause of death has been determined. 
8.9 
Duration of Follow-up for Adverse Events  
The investigator will follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the patient is lost to follow-up, patient death, or end of study.  Resolution of AEs and 
SAEs (with dates) should be documented on the appropriate eCRF and in the patient’s medical 
record to facilitate source data verification.  For SAEs, if, after follow-up, return to baseline 
status or stabilization cannot be established, an explanation should be recorded in the additional 
case details section of the eCRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE 
report (eg, hospital discharge summary, consultant report, or autopsy report) may be followed up 
by telephone, fax, email, and/or a monitoring visit. 
All pregnancies that occur during the study should be followed until pregnancy outcome. 
8.10 
Overdose  
For this study, any dose of fruquintinib greater than the 5 mg daily dose or tislelizumab equal or 
greater than 600 mg in a 24-hour period will be considered an overdose.  No specific information 
is available on the treatment of overdose of fruquintinib or tislelizumab.  AEs associated with an 
incorrect administration or overdose of study drug(s) will be recorded on the AE eCRF.  Any 
SAEs associated with an incorrect administration or overdose must be reported within 24 hours 
of awareness via the SAE reporting process as described in Section 8.8.  In the event of an 
overdose, further fruquintinib or tislelizumab administration should be held, and the patient 
should be observed closely for signs of toxicities.  Appropriate supportive treatment should also 
be provided if clinically indicated.  In the event of accidental or intentional overdose, the 
investigator or other site personnel should inform the sponsor’s study representatives 
immediately, or no later than 24 hours.  Sites must contact the medical monitor prior to the 
patient resuming fruquintinib treatment. 
• An overdose with an associated AEs/SAEs should be recorded on the relevant AE/SAE 
eCRF and on the study drug eCRF. 
• An overdose with no associated AEs/SAEs should only be reported on the study drug 
eCRF. 


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9 
STATISTICAL ANALYSIS  
9.1 
Statistics and Analysis Method  
All statistical analysis will be performed under the direction of the sponsor’s personnel.  
Details of the statistical analysis and data reporting will be provided in the Statistical Analysis 
Plan (SAP) document finalized prior to database lock. 
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and the final analysis of the study will be conducted at the time of analysis of the last cohort.  
Data will be summarized using descriptive statistics (continuous data) and/or contingency tables 
(categorical data) for demographic and baseline characteristics, efficacy measurements, safety 
measurements, and PK measurements.  Time to event variables will be summarized descriptively 
using Kaplan-Meier medians and quartiles. If less than 3 patients are enrolled to a particular 
cohort, no summary will be produced for the tumor type represented in that cohort. Patient data 
listings will be provided for all patients. Analyses will be performed using SAS® (version 9.1 or 
higher). 
9.1.1 
Statistical Hypothesis  
No formal hypothesis testing is planned for this study.  For efficacy endpoints, the study will 
provide the estimates and the associated 95% confidence interval (CI) for precision. 
9.1.2 
Sample Size Rationale  
Approximately 146 to 152 patients are estimated to be enrolled in this study (approximately 6 to 
12 patients in the dose escalation phase and approximately 140 patients in the Dose Expansion 
Phase). However, based upon the strategic evaluation of the clinical development of fruquintinib, 
patient enrollment has been permanently discontinued for Cohorts A, B, and C in the Dose 
Expansion Phase, hence, the final actual total number of patients will reflect this strategic 
decision.  
9.1.2.1 
Safety Lead-In Phase  
Approximately 6 to 12 patients will be enrolled into this portion of the study.  The total sample 
size will be determined by the incidence of DLTs in the Safety Lead-in Phase. 
9.1.2.2 
Dose Expansion Phase  
Approximately 30 patients will be enrolled in each of the Cohorts A and B, approximately 
40 patients in Cohort C, and approximately 40 patients in Cohort D in the Dose Expansion Phase 
of the study.  Planned patient enrollment for each cohort can provide adequate precision for the 
estimate of ORR at a specific time point. 
Table 16 shows the range of ORR and the corresponding 95% CIs for a sample size of 30 or 
40 patients. 


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Table 16 
Estimated ORR and 2-Sided 95% Confidence Intervals  
Number of patients 
Number of 
Responders 
Estimated ORR 
95% CI Lower Limit 
95% CI Upper 
Limit 
30 
0 
0.00 
0.00 
0.12 
30 
5 
0.17 
0.06 
0.35 
30 
10 
0.33 
0.17 
0.53 
30 
15 
0.50 
0.31 
0.69 
30 
20 
0.67 
0.47 
0.83 
30 
25 
0.83 
0.65 
0.94 
30 
30 
1.00 
0.88 
1.00 
40 
0 
0.00 
0.00 
0.09 
40 
5 
0.13 
0.04 
0.27 
40 
10 
0.25 
0.13 
0.41 
40 
15 
0.38 
0.23 
0.54 
40 
20 
0.50 
0.34 
0.66 
40 
25 
0.63 
0.46 
0.77 
40 
30 
0.75 
0.59 
0.87 
40 
35 
0.88 
0.73 
0.96 
40 
40 
1.00 
0.91 
1.00 
CI=confidence interval; ORR=objective response rate. 
95% Clopper-Pearson interval for binomial distribution 
However, based upon the strategic evaluation of the clinical development of fruquintinib, patient 
enrollment has been permanently discontinued for Cohorts A, B, and C in the Dose Expansion 
Phase, hence, the final actual total number of patients will reflect this strategic decision.  
9.1.3 
Analysis Sets  
The following analysis sets are defined for the study: 
• Safety analysis set: All enrolled patients who received at least 1 dose of fruquintinib or 
tislelizumab will be included in the safety analysis population.  The safety evaluation will 
be performed based on the first dose of study treatment received by a patient.  This is the 
primary population for safety and efficacy analyses. 
• DLT evaluable analysis set: All patients enrolled in the Safety Lead-in portion of the 
study who are evaluable for DLT assessment.  Patients will be considered DLT evaluable 
if he/she) has (1) received ≥85% of scheduled fruquintinib and ≥67% (approximately two 
thirds) of scheduled tislelizumab administration during the DLT assessment window, 
and/or (2) experienced a DLT. 
• Patients will not be considered DLT evaluable if during the DLT assessment window 
they (1) were withdrawn from the study for a reason other than DLT, (2) did not receive 
≥85% of scheduled fruquintinib and ≥67% (approximately two-thirds) of scheduled 
tislelizumab drug administration, (3) received prophylactic supportive care that 
confounds the evaluation of DLTs (not including supportive care described as part of the 
DLT definition), or ( 4) have taken a strong inducer of enzyme CYP3A (Appendix 4).  


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• Response evaluable analysis set: All patients who receive study treatment and have a 
baseline tumor assessment and at least 1 postbaseline assessment unless any clinical PD 
or death occurred before the first postbaseline assessment will be considered evaluable 
for anti-tumor efficacy endpoints. 
• Anti-drug antibody analysis set: All patients who received at least 1 dose of study 
treatment and have a baseline and at least 1 postbaseline ADA result. 
• Pharmacokinetic analysis set: All patients with at least 1 quantifiable plasma 
concentrations of fruquintinib and its metabolites combined with tislelizumab will be 
included in the pharmacokinetic analysis population. 
9.2 
Statistical Analyses  
All summary tables, listings, and figures (TLFs) will be presented by cohort.  Unless otherwise 
specified, for Cohort A and Cohort B, the TLFs will be presented overall, by cohort, and by 
category of ER/PGR positivity per ASCO-CAP guidelines (Allison 2020).  TNBC will be 
defined as ER/PGR positivity of <1%, and ER/PGR low positive disease will be defined by 
ER/PGR positivity of 1% to 10%.  (Note that the ASCO-CAP guidelines use PR as the 
abbreviation for progesterone receptor.) 
9.2.1 
Subject Disposition  
The number and percentage of patients enrolled in the study, treated, and discontinued from 
study treatment(s) will be presented for the safety analysis set.  The primary reason for treatment 
discontinuation will be summarized according to the categories in the eCRF.  Patient disposition 
will be summarized overall and by cohorts. 
Important protocol deviations will be summarized and listed by category. 
9.2.2 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized for the safety analysis set 
using descriptive statistics. 
A summary of baseline patient and disease characteristics, diagnosis, medical history, and prior 
therapies will be reported using descriptive statistics. 
Other patient characteristics will be summarized as deemed appropriate. 
Demographic and other baseline characteristics will be summarized overall and by cohorts. 
9.2.3 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of first dose of 
study treatment(s).  Concomitant medications will be defined as medications that 1) started 
before the first dose of study treatment(s) and were continuing at the time of the first dose of 
study treatment(s), or 2) started on or after the date of the first dose of study treatment(s) up to 30 
days after the patient’s last dose.  Any steroid use will also be included in the analysis where 
applicable.  Concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes and will be further coded to the appropriate Anatomical Therapeutic 
Chemical code indicating therapeutic classification.  Prior and concomitant medications will be 
summarized and listed by drug and drug class.  Prior and concomitant medication will be 


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summarized overall and by cohorts.  A listing of prior and concomitant medications will be 
provided. 
9.2.4 
Efficacy Analysis  
No formal hypothesis testing is planned for this study. 
9.2.4.1 
Primary Efficacy Analysis  
9.2.4.1.1 
Objective Response Rate  
The ORR is defined as the proportion of patients with a confirmed BOR of CR or PR as 
determined by the investigator using RECIST v1.1.  To be assigned a status of PR or CR, 
changes in tumor measurements must be confirmed by repeat assessments performed no less 
than 4 weeks after the criteria for response are first met.  
The BOR is defined as the best response recorded from the start of study treatment until 
documented RECIST progression or the date of start of new anticancer therapy, whichever 
comes first.  
The ORR and the corresponding 2-sided Clopper-Pearson 95% CI will be presented. 
ORR will be summarized based on patients from the RP2D dose level overall and by cohorts. 
Additional summaries will be based on all dose levels overall and by cohorts if necessary. 
As a sensitivity analysis, ORR will be presented for the response evaluable analysis set. 
9.2.4.2 
Secondary Efficacy Analysis  
9.2.4.2.1 
Progression-Free Survival  
The PFS is defined as the time (months) from start of study treatment until the first radiographic 
documentation of objective progression as assessed by the investigator using RECIST v1.1, or 
death from any cause. Patients who have not objectively progressed or died by the date of the 
analysis cutoff or received any further anti-tumor therapy will be censored at the date of the last 
evaluable objective tumor assessment before the cutoff date or the anti-tumor therapy start date.  
Detailed censoring rules will be specified in the SAP. 
The Kaplan-Meier (KM) method will be used to estimate PFS curves as well as PFS rates at 
various time points for patients in the safety analysis set.  Median PFS (if estimable) will also be 
reported. 
The PFS will be summarized based on patients from the RP2D dose level overall and by cohorts.  
Additional summaries will be based on dose levels overall and by cohorts if necessary. 
9.2.4.2.2 
Disease Control Rate  
Disease control rate (DCR) is defined as the proportion of patients with a BOR of CR, PR, or SD 
as determined by the investigator using RECIST v1.1.  The DCR and the corresponding 2-sided 
Clopper-Pearson 95% CI will be presented. 
DCR will be summarized based on patients from the RP2D dose level overall and by cohorts.  
Additional summaries will be based on all dose levels overall and by cohorts if necessary. 


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9.2.4.2.3 
Clinical Benefit Rate  
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of CR, PR, or 
durable SD as determined by the investigator using RECIST v1.1.  The CBR and the 
corresponding 2-sided Clopper-Pearson 95% CI will be presented.  
CBR will be summarized based on patients from the RP2D dose level overall and by cohorts.  
Additional summaries will be based on all dose levels overall and by cohorts if necessary. 
9.2.4.2.4 
Duration of Response  
Duration of response (DoR) is defined as the time from the first occurrence of PR or CR, 
whichever comes first until disease progression or death.  DoR will be summarized for 
responders using KM methodology. 
DoR will be summarized based on patients from the RP2D dose level overall and by cohorts.  
Additional summaries will be based on all dose levels overall and by cohorts if necessary. 
9.2.4.2.5 
Overall Survival  
Overall survival is defined as the time (months) from start of study treatment until the date of 
death due to any cause.  The KM method will be used to estimate OS curves as well as OS rates 
at various time points.  Median OS (if estimable) will also be reported. 
OS will be summarized based on patients from the RP2D dose level overall and by cohorts.  
Additional summaries will be based on all dose levels overall and by cohorts if necessary. 
9.2.5 
Safety Analysis  
The summary of the exposure to study treatment(s), AEs, AEs leading to drug modification or 
discontinuation including DLTs, changes in laboratory results, and changes in vital signs will be 
presented.  The severity of all AEs will be graded according to NCI CTCAE v5.0, and the AE 
verbatim term will be coded by the MedDRA. 
TEAEs are defined as AEs that started or worsened in severity on or after the first dose of study 
treatment and no later than 30 days after the date of the last study treatment administration.  The 
TEAE classification also applies to imAEs that are recorded up to 90 days after discontinuation 
from tislelizumab, regardless of whether or not 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 number and 
frequency of patients experiencing AEs will be summarized according to system organ class 
(SOC) and preferred terms (PTs).  If a patient reports a TEAE more than once within that 
SOC/PT, the AE with the highest severity will be used in the corresponding severity summaries. 
The following safety summaries will be produced: 
• Overview of AEs 
• Summary of DLTs (Safety Lead-in portion) 
• Summary of DLT-equivalent (DLTs that occur outside the DLT assessment window)  
• Summary of TEAEs including severity and relationship to study drug 
• Summary of imAEs including severity and relationship to study drug 
• Summary of AESIs including severity and relationship to study drug 


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• Summary of serious TEAEs  
• Summary of TEAEs leading to dose interruption, dose reduction, or termination of 
treatment 
The above summaries will be repeated for TEAEs related to study treatment. 
Drug exposure including number of cycles received, total duration of exposure, cumulative dose 
received (mg), dose intensity, and relative dose intensity of fruquintinib and tislelizumab will be 
summarized.  The number and percentage of patients requiring dose interruption, dose delay, 
dose reduction, and treatment discontinuation because of AEs will be summarized for each study 
drug.  Reasons for dose modifications will also be summarized. 
For laboratory tests that are graded by NCI CTCAE v5.0, results will be summarized by grade.  
Treatment-emergent changes will be summarized by maximum postbaseline grade.  A shift table 
summarizing shift from baseline of maximum postbaseline grade will be presented. 
The changes in vital signs and ECOG performance status scores from baseline will be 
summarized.  Changes in 12-lead electrocardiogram (for example, changes in QTcF) will be 
summarized. 
9.3 
Pharmacokinetics Analysis  
Pharmacokinetic samples will be collected in this study.  Evaluation of PK will be performed on 
the PK analysis set.  Concentration data of fruquintinib, metabolite M11, and tislelizumab will be 
tabulated and summarized using descriptive statistics (number of patients, arithmetic mean with 
standard deviation, coefficient of variation, and geometric mean, median, minimum, and 
maximum) as appropriate. 
Additional PK analyses, including population PK analyses and exploratory exposure-response 
(efficacy and safety endpoints) analyses, may be conducted as appropriate, and the results of 
such analysis may be reported separately from the clinical study report (CSR). 
9.4 
Immunogenicity Analysis  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs.  The incidences of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. 
9.5 
Other Exploratory Analyses  
Distribution of PD-L1 expression will be examined in all patients.  Other potential predictive 
markers including, but not limited to, TILs, MSS/MSI, TMB, cytokine expression, and gene 
signature profiling may be detected and analyzed. 
Exploratory biomarker analyses will be performed in an effort to understand the association of 
these markers with study drug response, such as efficacy and resistance. 
Methodology for exploratory analyses will be described in the SAP.  The biomarker data and 
analysis may be reported separately from the CSR. 
9.6 
Interim Analyses  
Not applicable. 


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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be conducted in accordance with the protocol, International Council for 
Harmonisation (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct, consensus, and the ethical principles derived from international guidelines, including 
the Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines, applicable ICH Good Clinical Practice (GCP) Guidelines that 
have their origin in the Declaration of Helsinki, and applicable regulations and guidelines 
governing clinical study conduct. 
10.2 
Ethics Review  
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must review the 
protocol and amendments, IB, ICF, study-relevant materials (such as advertisements for patient 
recruitment), and any other essential documents.  IEC/IRB approval is to be obtained prior to the 
start of the study at the investigator site. 
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented.  All SAEs and other significant safety findings should 
be reported to the sponsor, the IEC/IRB, and applicable regulatory authorities as required.  
During the study, protocol deviations that may increase a patient’s risk should be reported to the 
IEC/IRB in a timely manner. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• 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 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other applicable 
local regulations 
10.3 
Informed Consent  
• Investigators or designees must obtain the signed ICF from patients prior to conducting 
any study-related procedures.  
• The investigator or his/her representative will explain the nature of the study to the 
participant or to their legally authorized representative and answer all questions regarding 
the study. 


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• Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center. 
• Patients must be informed that they may withdraw consent to participate in the study 
without any limitations.  If the patient cannot sign the ICF, a legally acceptable 
representative of the patient must sign the ICF.  
• If the patient and the legally acceptable representative are not able to read and write, an 
impartial witness should be present throughout the whole process of providing informed 
consent.  Once the patient and the legally acceptable representative give their oral 
consent, the ICF should be signed by the impartial witness to confirm that the patient and 
the legally acceptable representative fully understand the study and their right to 
withdraw informed consent without any limitations. 
• Informed consent should be recorded on the eCRF.  
• If the risk/benefit assessment changes after the safety analysis, the ICF needs to be 
reviewed and updated, and all updated information should be provided to patients 
(including patients who have already received the study drug). 
10.4 
Data Privacy  
All information about the study drug (such as patent application, formulation, manufacturing 
process, and basic study information) is considered confidential as long as it is unpublished. 
All information obtained in the study is considered confidential.  The sponsor will open the 
information to investigational personnel and any other regulatory authority, when necessary.  To 
ensure the completeness of the study analysis data, investigational personnel are accountable for 
providing all results and data to the sponsor. 
Investigators must guarantee the privacy of patients by not disclosing patient-related information 
to third parties without authorization.  eCRFs and other documents submitted to the sponsor 
should not contain the patient’s name.  
• Participants will be assigned a unique identifier by the sponsor.  Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred. 
• Patients are identified only by the unique identifier.  Investigators may retain the 
identification forms, which include patient numbers, names, and addresses.  ICFs and 
other documents should be documented properly and should not be given to the sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law.  The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 


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10.5 
Disclosure  
Final study results will be published on a public clinical study website according to applicable 
local guidelines and regulations. 
10.6 
Data Quality Assurance  
• To ensure the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and 
patient medical records in the patient files as original source documents for the study. 
• All participant data relating to the study will be recorded on the eCRF unless transmitted 
to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the eCRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing the strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues, and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations [CROs]). 
10.7 
Biological Specimens and Data  
For participants who provide informed consent agreeing to participate in future biomedical 
research, any unused samples for study-related research, as well as unused PK samples, may be 
stored for no longer than 15 years, or other period as per local requirements, after the final date 
of the database lock.  After this storage period, any residual samples will be destroyed.  The 
sponsor will store the samples in a secure storage space with adequate measures to protect 
confidentiality.  The unused samples may be utilized for future biomedical research as permitted 
by local regulations. 
The results of these future biomedical research analyses will not be shared with patients and will 
not be presented in the CSR. 
If there are specific site or country requirements involving the pharmacogenomics analyses that 
the sponsor is unable to comply with, samples will not be collected at those sites. 
All samples will be single/double-coded as defined by ICH Guideline E15. 


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11 
OVERSIGHT  
11.1 
Independent Monitoring  
No independent data monitoring is planned for this study.  The sponsor will review study safety 
data on an annual basis, or more frequently, if safety concerns arise. 
11.1.1 
Safety Review Committee  
Safety monitoring and evaluation of the dose escalation will be carried out by the SRC, which 
will be comprised of the sponsor’s study team members (including, but not limited to, the 
medical monitor, safety monitor, and PK scientist) and the site principal investigators.  Safety 
and PK data will be evaluated to determine whether it is safe to continue the assigned dosing 
combination for dose escalation, whether the dose should stay at the currently assigned dose 
level, or whether the dose should be de-escalated to the lower dose level.  The SRC will be 
charged with determining the RP2D. 
These criteria constitute the basis for RP2D determination, and the SRC must collectively 
determine the RP2D.  Enrollment to Part 2 (expansion cohorts) will begin once the RP2D has 
been determined in Part 1 of the study. 
The SRC will also review the data during Part 2 on an ongoing basis for safety. 
11.2 
Quality Control and Assurance  
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements, and applicable standard operating procedures, including quality control of 
documents.  
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site.  The sponsor and 
investigator will ensure that any individual or party who performs study-related duties or 
functions on behalf of the sponsor/investigator is qualified to perform the study-related duties or 
functions. 
The overall procedures for quality assurance of clinical study data are described in the sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections. 
11.2.1 
Monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, the sponsor’s 
personnel (or designated CRO) will review the protocol and eCRF with the investigators and 
their staff.  During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to GCP, and the progress of enrollment and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications.  Key study personnel, including 
the investigator, must be available to assist the field monitor during these visits. 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries.  The sponsor’s monitoring standards require full verification 
of the informed consent, adherence to the inclusion/exclusion criteria, and documentation of 


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SAEs.  Additional checks of the consistency of the source data with the eCRFs are performed 
according to the study-specific monitoring plan. 
11.2.2 
Audits  
Authorized representatives of the sponsor, a regulatory/competent authority, and/or an IRB/IEC 
representative may visit the site to perform audits or inspections, including source data 
verification.  Should this occur, the investigator is responsible for the following: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities to 
the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
• Documents patient to audit or inspection include but are not limited to all source 
documents, eCRFs, medical records, correspondence, ICFs, IRB/IEC files, 
documentation of certification and quality control of supporting laboratories, and records 
relevant to the study maintained in any supporting pharmacy facilities.  Conditions of 
study material storage are also subject to inspection.  In addition, representatives of the 
sponsor may observe the conduct of any aspect of the clinical study or its supporting 
activities both within and outside of the investigator’s institution. 
In all instances, the confidentiality of the data must be respected. 
11.2.3 
Records  
11.2.3.1 
Data Capture and Management  
The term eCRF refers to the Case Report Forms within the electronic data capture (EDC) system.  
The EDC system is the database where pertinent study data are collected.  For all patients, 
including screen failures, data will be collected on source documents first.  The principal 
investigator is responsible for assuring that the data entered into eCRFs is complete and accurate 
and that entry and updates are performed in a timely manner.  Data from ECG will be collected 
at the study sites, and the data will be transmitted to a designated CRO for centralized analysis, 
as well as for further processing and data reconciliation.  Imaging data will be collected at the 
study sites, and a designated CRO will perform further processing, data reconciliation, and 
storage. 
At all times, the principal investigator has final responsibility for the accuracy and authenticity of 
all clinical and laboratory data entered in the EDC.  Patient source documents are the 
investigator’s/physician’s patient records maintained at the study site.  In cases where the source 
documents are the hospital or the physician’s chart, the information collected in the EDC must 
match those charts.  
The completed pages of the EDC system are the sole property of the sponsor and should not be 
made available in any form to third parties without written permission from the sponsor, except 
for authorized representatives of the sponsor or appropriate regulatory authorities. 


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11.2.3.2 
Source Documentation  
• The investigator/institution should maintain accurate source documents and study records 
for all patients that support the information entered in the eCRF. 
• Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete.  Changes to source data should be traceable and not obscure the original entry. 
• All information recorded on eCRFs must be traceable to source documents in the 
patient’s file.  Any changes should be explained if necessary (eg, via an audit trail). 
11.2.3.3 
Records Retention  
Records and documents, including signed ICFs, source documents, study drug documents, 
monitoring visit records, regulatory documents, and all other correspondence and documents 
pertaining to the conduct of this study must be retained by the investigator for at least 5 years 
after study completion, unless local regulations or institutional policies require a longer retention 
period.  
If the documents cannot be stored properly at the investigational site, the documents can be 
transferred by the investigator and sponsor to an approved storage facility.  The documents must 
be sealed for storage and easily found for review in the case of a regulatory authority audit.  No 
records may be transferred to another location or party without written notification to the 
sponsor. 
No records may be destroyed during the retention period following study completion or 
discontinuation without the written approval of the sponsor.  Records must be destroyed in a 
manner that ensures confidentiality. 
11.3 
Study Termination or Study Site Closure  
The sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close out a site in writing, providing at 
least 30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close out a study site in writing.  
Reasons may include the following, among others: 
• The investigator has received all items and information necessary to perform the study 
but has not enrolled any patient within a reasonable period of time.  
• The investigator has violated any fundamental obligation in the study agreement, 
including, but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines. 
• The total number of patients required for the study is enrolled earlier than expected.  
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 


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reason for termination or suspension, as specified by the applicable regulatory requirements.  
The investigator shall promptly inform the patient and should assure appropriate patient therapy 
and/or follow-up. 


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12 
PUBLICATION POLICY  
The study results may be published in scientific journals.  The names of investigators who make 
an important contribution to the study implementation and management and personnel who make 
an important contribution to the study design, analysis, and interpretation (such as the sponsor’s 
staff or consultants) will be listed in the publication.  The sponsor will provide the article to 
investigators for review prior to publishing any study results.  Investigators must obtain approval 
from the sponsor before contributing to any related articles or abstracts. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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13 
FINANCING AND INSURANCE  
Financing and insurance information will be addressed in a separate agreement. 


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14 
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Si g nat ure Pa ge f or 
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A d de d A p p e n di x 7 t o defi ne c o n versi o n 
ta bles f or uri nal ysis res ults  
2 9J ul 2 0 2 4 
2. 0  
U p date d ue t o H M P c o m me nts a n d 
pr ot oc ol a me n d me nt 4 date d 0 2 
Fe br u ar y 2 0 2 3 a n d a me n d me nt 5 date d 
0 6 Dece m b er 2 0 2 3.  
U p date pri or t o t h e D ata b ase L oc k. 
 
U p date d t he D L T- E val ua ble 
A nal ysis Set a n d P K A nal ysis 
Set defi niti o ns. 
Re m o ve d A p pe n di x 5. 
C o nsi d erati o ns f or assi g ni n g 
res p o nse cate g or y a n d patie nts 
wit h o ut a n y p ost- baseli ne t u m or 
assess me nt ( patie nts w h o die d or 
pr o gresse d cli nicall y pri or t o t h e 
first sc he d ule d t u m or 
assess me nt) were a d d e d i n 
Secti o ns 4. 2. 1 a n d 4. 2. 2. 
Details o n ce ns ori n g f or P F S 
were a d de d i n Ta bl e 3. 
Te xt i n Secti o n 6. 2 was ali g ne d 
wit h t h e i nteri m a nal yses 
perf or me d d uri n g t he st u d y 
c o n d uct. 
A d diti o nal d etails pr o vi de d o n 
prese ntati o n of P K data i n 
Secti o n 4. 5. 1 a n d A D A d ata i n 
Secti o n 4. 5. 2 . 
 
 
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T A B L E O F C O N T E N T S 
T A B L E O F C O N T E N T S ................................................................................................................. 5  
LI S T O F T A B L E S ........................................................................................................................... 8  
LI S T O F A B B R E VI A TI O N S .......................................................................................................... 9  
1.  
I N T R O D U C TI O N ...................................................................................................... 1 1 
2.  
S T U D Y D E T AI L S ..................................................................................................... 1 2  
2. 1.  
St u d y O bjecti ves ......................................................................................................... 1 2  
2. 2.  
St u d y Desi g n ............................................................................................................... 1 4  
2. 3.  
Deter mi n ati o n of S a m pl e Siz e .................................................................................... 1 7  
3.  
A N A L Y SI S S E T S ...................................................................................................... 1 9  
3. 1.  
Defi niti o n of A nal ysis Sets ......................................................................................... 1 9  
3. 1. 1.  
E nr olle d Set ................................................................................................................ 1 9  
3. 1. 2.  
Safet y A nal ysis Set ..................................................................................................... 1 9  
3. 1. 3.  
D L T- E v al ua bl e A nal ysis Set ...................................................................................... 1 9  
3. 1. 4.  
Res p o nse E val ua ble A n al ysis Set ............................................................................... 1 9  
3. 1. 5.  
P har mac o ki n etics ( P K) A nal ysis Set .......................................................................... 1 9  
3. 1. 6.  
A nti dr u g A nti b o d y ( A D A) A nal ysis Set .................................................................... 1 9  
3. 2.  
Pr ot oc ol De viati o n ...................................................................................................... 1 9  
4.  
E N D P OI N T S .............................................................................................................. 2 0  
4. 1.  
Ge neral Pri nci ples f or D eri v e d a n d Tra nsf or me d Data .............................................. 2 0  
4. 1. 1.  
Refere n ce Start D ate a n d E n d Date a n d St u d y Da y ................................................... 2 0  
4. 1. 2.  
Baseli ne a n d C h a n g e fr o m Baseli ne ........................................................................... 2 0  
4. 1. 3.  
Treat m e nt Peri o d ........................................................................................................ 2 0  
4. 2.  
Efficac y E n d p oi nts ...................................................................................................... 2 1  
4. 2. 1.  
Pri mar y E n d p oi nt ........................................................................................................ 2 1  
4. 2. 2.  
Sec o n dar y E n d p oi nts .................................................................................................. 2 2  
4. 2. 2. 1.  
Pr o gressi o n-free S ur vi v al ( P F S) ................................................................................. 2 2  
4. 2. 2. 2.  
Disease C o ntr ol Rate .................................................................................................. 2 3  
4. 2. 2. 3.  
Cli nical Be nefit Rate ................................................................................................... 2 4  


 
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4. 2. 2. 4.  
D urati o n of Res p o nse ................................................................................................. 2 4  
4. 2. 2. 5.  
O verall S ur vi val .......................................................................................................... 2 4  
4. 3.  
E x p os ure E n d p oi nts .................................................................................................... 2 5  
4. 4.  
Safet y E n d p oi nts ......................................................................................................... 2 7  
4. 4. 1.  
D ose Li miti n g T o xicities ( D L Ts) or D L T-e q ui v ale nt ................................................ 2 7  
4. 4. 2.  
A d vers e E v e nts ( A Es) ................................................................................................. 2 7  
4. 4. 3.  
La b orat or y ................................................................................................................... 2 9  
4. 4. 4.  
E C G ............................................................................................................................ 3 1  
4. 4. 5.  
Vital Si g ns .................................................................................................................. 3 2  
4. 4. 6.  
Perf or ma nc e Stat us ..................................................................................................... 3 2  
4. 4. 7.  
Ec h ocar di o gra m .......................................................................................................... 3 3  
4. 4. 8.  
P h ysi cal E xa mi n ati o n ................................................................................................. 3 3  
4. 5.  
Ot her E n d p oi nts .......................................................................................................... 3 3  
4. 5. 1.  
P har mac o ki n etic E n d p oi nt .......................................................................................... 3 3  
4. 5. 2.  
I m m u n o ge nicit y .......................................................................................................... 3 3 
4. 5. 3.  
E x pl orat or y E n d p oi nts ................................................................................................ 3 3  
5.  
A N A L Y SI S M E T H O D S ............................................................................................ 3 4  
5. 1.  
Ge neral Pri nci ples ....................................................................................................... 3 4  
5. 1. 1.  
Ge neral Met h o d ol o g y ................................................................................................. 3 4  
5. 1. 2.  
Ha n dli n g Missi n g Data ............................................................................................... 3 5  
5. 1. 2. 1.  
A d vers e E v e nts St art/ E n d D ate .................................................................................. 3 5  
5. 1. 2. 2.  
C o nc o mita nt Me dicati o n/ Pr oce d ure/ S ur ger y Start/ E n d Date ..................................... 3 6  
5. 1. 2. 3.  
S u bse q ue nt A nti- Ca ncer T hera p y D ate ...................................................................... 3 7  
5. 1. 2. 4.  
Pri mar y Dia g n osis Date a n d Metastati c Disease Dia g n osis D ate .............................. 3 7  
5. 1. 3.  
Visit Wi n d o wi n g ......................................................................................................... 3 7  
5. 1. 4.  
A dj ust me nt of C o vari ates ........................................................................................... 4 1  
5. 2.  
A nal ysis Met h o ds ....................................................................................................... 4 1  
5. 2. 1.  
Patie nt Dis p ositi o n ...................................................................................................... 4 1  
5. 2. 2.  
Pr ot oc ol De viati o n ...................................................................................................... 4 1  


 
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5. 2. 3.  
De m o gra p hic a n d Ot her Baseli n e C h aracteristics ...................................................... 4 1  
5. 2. 4.  
Disease C haracteristi cs ............................................................................................... 4 2  
5. 2. 5.  
Me dical Hist or y .......................................................................................................... 4 2  
5. 2. 6.  
Pri or a n d S u bse q ue nt A nti- Ca ncer T h era p y ............................................................... 4 2  
5. 2. 6. 1.  
Pri or a n d S u bse q ue nt A nti- Ca ncer Me di cati o n .......................................................... 4 3  
5. 2. 6. 2.  
Pri or a n d S u bse q ue nt A nti- Ca ncer Ra di ot hera p y ....................................................... 4 3  
5. 2. 6. 3.  
Pri or a n d S u bse q ue nt A nti- Ca ncer Pr oce d ure or S ur ger y .......................................... 4 3  
5. 2. 7.  
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 4 4  
5. 2. 8.  
C o nc o mita nt Pr oce d ure .............................................................................................. 4 4  
5. 2. 9.  
Efficac y A nal yses ....................................................................................................... 4 4  
5. 2. 9. 1.  
Pri mar y Efficac y A nal ys es ......................................................................................... 4 5  
5. 2. 9. 2.  
Sec o n dar y Efficac y A nal yses ..................................................................................... 4 5  
5. 2. 9. 3.  
Se nsiti vit y A nal ysis f or Efficac y E n d p oi nt ................................................................ 4 5  
5. 2. 1 0.  
E x p os ure of St u d y Treat me nt ..................................................................................... 4 5  
5. 2. 1 1.  
Safet y A nal yses .......................................................................................................... 4 6  
5. 2. 1 1. 1.  
D ose- Li miti n g T o xicit y ( D L T) ................................................................................... 4 6  
5. 2. 1 1. 2.  
A d vers e E v e nts ........................................................................................................... 4 6  
5. 2. 1 1. 3.  
Deat h ........................................................................................................................... 4 8  
5. 2. 1 1. 4.  
La b orat or y E v al uati o ns ............................................................................................... 4 8  
5. 2. 1 1. 5.  
E C G ............................................................................................................................ 4 9  
5. 2. 1 1. 6.  
Vital Si g ns .................................................................................................................. 4 9  
5. 2. 1 1. 7.  
Perf or ma nc e Stat us ..................................................................................................... 4 9  
5. 2. 1 1. 8.  
Ec h ocar di o gra m .......................................................................................................... 4 9  
5. 2. 1 1. 9.  
P h ysi cal E xa mi n ati o n ................................................................................................. 4 9  
5. 3.  
S u b gr o u p A nal yses ..................................................................................................... 4 9  
5. 4.  
Ot her A nal yses ............................................................................................................ 4 9  
5. 4. 1.  
P har mac o ki n etic A nal ysis .......................................................................................... 4 9  
5. 4. 1. 1.  
Ha n dli n g of Missi n g Data ........................................................................................... 5 0  
5. 4. 1. 2.  
Ha n dli n g of D ose Re d u cti o n or I nterr u pti o n. ............................................................. 5 0  


 
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5. 4. 1. 3.  
Ha n dli n g of bel o w t he l o wer li mit of q ua ntificati o n ( B L Q) Data .............................. 5 0  
5. 4. 1. 4.  
S u m mar y of P K c o nce ntr ati o n D ata ........................................................................... 5 0  
5. 4. 1. 5.  
Ha n dli n g of t he Differe nce bet w ee n t he Sc he d ule d ( n o mi nal ti m e) a n d t h e 
Act u al Sa m pli n g Ti mes (act ual ti me) ......................................................................... 5 1  
5. 4. 2.  
I m m u n o ge nicit y A n al ysis ........................................................................................... 5 1 
5. 4. 3.  
E x pl orat or y A nal yses .................................................................................................. 5 2  
6.  
P L A N N E D A N A L Y SI S ............................................................................................. 5 3  
6. 1.  
I n d e pe n d e nt Safet y D ata M o nit ori n g.......................................................................... 5 3 
6. 2.  
I nteri m A nal ysis .......................................................................................................... 5 3 
6. 3.  
Fi nal A nal ysis ............................................................................................................. 5 3  
7.  
C H A N G E F R O M T H E P R O T O C O L ........................................................................ 5 4  
R E F E R E N C E ................................................................................................................................. 5 5  
A P P E N DI X .................................................................................................................................... 5 6  
 
List of Ta bles 
Ta ble 1  
Esti m ate d O R R a n d 2- Si de d 9 5 % C o nfi de nce I nter vals ............................................ 1 8  
Ta ble 2  
Best O verall Res p o nse W he n C o nfir mati o n of C R a n d P R are Re q uire d .................. 2 1  
Ta ble 3  
Ce ns ori n g R ules f or P F S ............................................................................................ 2 3  
Ta ble 4  
Al g orit h ms f or Calc ulati n g Para meters Rele va nt t o t he D ose E x p os ure a n d 
I nte nsit y ...................................................................................................................... 2 6 
Ta ble 5  
Me d D R A Ter ms Use d f or A d vers e E ve nts of S pecial I nterest .................................. 2 8  
Ta ble 6  
La b orat or y Ass ess m e nt ............................................................................................... 2 9  
Ta ble 7  
P ote ntiall y Cli nicall y Si g nifica nt Criteria f or E C G .................................................... 3 1  
Ta ble 8  
P ote ntiall y Cli nicall y Si g nifica nt Criteria f or Vital Si g ns .......................................... 3 2  
Ta ble 1 0  Treat m e nt/ C o h ort Dis pl a y i n T L Fs ............................................................................ 3 4  
Ta ble 1 1  Visit Wi n d o wi n g ......................................................................................................... 3 9  
 
 
 
 


 
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LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n 
Ter m 
A D A 
A nti dr u g A nti b o d y 
A E 
A d verse E ve nt 
A E SI 
A d verse E ve nt of S pecial I nterest 
A S C O 
A merica n S ociet y f or Cli nical O nc ol o g y 
A T C 
A nat o mic T hera pe utic Classificati o n 
B L Q 
Bel o w t he L o wer Li mit of Q ua ntificati o n 
B MI 
B o d y Mass I n de x 
C A P 
C oll e ge of A merica n Pat h ol o gists 
C B R 
Cli nical Be nefit Rate 
C F B 
C ha n ge fr o m Baseli n e  
CI 
C o nfi de nce I nter val 
C R 
C o m plete Res p o nse 
C S R 
Cli nical St u d y Re p ort 
C T C A E 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
C Y P 3 A 
C yt oc hr o me P 4 5 0, fa mil y 3, s u bfa mil y A 
D B L 
Data bas e L oc k 
D B P 
Diast olic Bl o o d Press ure 
D C R  
D is eas e C o ntr ol R ate 
D L T 
D ose-li miti n g T o xicit y 
D o R  
D urati o n of R es p o nse 
D M C  
Data M o nit ori n g C o m mittee  
E C 
E n d o m etrial Ca ncer 
E C G  
E lectr ocar di o gra m 
E C H O  
E c h ocar di o gra m  
E C O G 
Easter n C o o perati ve O nc ol o g y Gr o u p 
E O C  
E n d of C ycle  
E OI  
E n d of Inf usi o n  
E O T 
E n d of Treat me nt 
E R/ P R or E R/ P G R  
E str o ge n R ece pt or/ P r o gester o ne R ece pt or 
I C H 
I nt er nati o nal C o u ncil o n Har m o nizati o n 
I CI  
I m m u ne C hec k p oi nt I n hi bit or  
i m A E 
Im m u ne -me diate d A E  
I O 
Im m u n o -o nc ol o g y  


 
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A b bre vi ati o n 
Ter m 
L L O Q 
L o wer Li mit of Q ua ntificati o n 
m C R C 
Metastatic C ol orect al Ca ncer 
Me d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M SI 
Micr osatellite I nsta bilit y 
M S S 
Micr osatellit e Sta ble 
N CI C T C A E 
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Crit eria f or A d verse 
E ve nt 
O R R 
O bjecti ve Res p o nse Rate 
O S 
O verall S ur vi val 
P F S 
Pr o gressi o n-free S ur vi val 
P D- L 1 
Pr o gra m me d Deat h Li ga n d 1 
P T 
Preferre d Ter m 
R E CI S T 1. 1 
Res p o nse E val u ati o n Crit eria i n S oli d T u m ors, V ersi o n 1. 1 
R P 2 D 
Rec o m m e n de d P hase 2 D os e 
S A E 
Seri o us A d verse E ve nt 
S A P 
Statistical A nal ysis Pla n 
St d De v 
Sta n dar d De viati o n 
S M Qs 
St a n dar dize d Me d D R A Q ueries 
S O C  
S yst e m O r ga n C lass 
S R C  
Safet y Re vie w C o m mittee  
T E A E 
Treat me nt-e mer ge nt A d verse E ve nt 
T L F  
T a ble, L isti n g, F i g ure 
T N B C  
T ri pl e N e gati v e B reast C a ncer  
T P R 
Ti me p oi nt Res p o nse 
W H O -D D  
W orl d Healt h Or ga ni zati o n Dr u g Dicti o nar y  


 
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1.  I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) descri b es t h e pla n ne d statistical a nal yses a n d data 
prese ntati o ns f or st u d y 2 0 2 0- 0 1 3- 0 0 U S 3. T he S A P is base d o n t he Pr ot oc ol A me n d me nt 5, date d 
0 6 Dece m b er 2 0 2 3. St u d y meas ure me nts a n d assess m e nts, pla n ne d statisti cal met h o ds, a n d 
deri ve d varia bles are s u m m arize d i n t his pla n. Pla n ne d ta bles, fi g ures, a n d listi n gs are s pecifie d. 
All decisi o ns re gar di n g fi nal a nal yses, as d efi ne d i n t his S A P d oc u me nt, ha ve bee n ma d e pri or t o 
l oc ki n g t he data base. A n y de viati o ns fr o m t hese g ui deli nes will be d oc u me nte d i n t he cli nic al 
st u d y re p ort ( C S R). 
T his is a n a me n d me nt t o t he a p pr o ve d S A P ( dat e d 2 1 J ul y 2 0 2 2) base d o n t he m ost rece nt 
Pr ot oc ol A me n d me nt 5 date d 0 6 Dece m ber 2 0 2 3. U p o n i m ple me ntati o n of  Pr ot oc ol 
A me n d me nt # 4, e nr oll m e nt t o e x p a nsi o n c o h orts A ( T N B C i m m u n o- o nc ol o g y [I O]-treate d i n t h e 
metastatic setti n g), B ( T N B C I O- Naï ve i n t he metastatic setti n g) a n d C ( E C I O N aï ve) i n t his 
st u d y has bee n per ma ne ntl y disc o nti n ue d base d u p o n t he strate gic e val uati o n of t he cli nical 
de vel o p me nt of fr u q ui nti ni b i n t he U nit e d St ates wit h H U T C H M E D as t h e st u d y S p o ns or. F or 
C o h ort D ( M S S m C R C, I O N aï ve), at t he ti me of t his decisi o n ma ki n g, t he e nr oll me nt was 
c o m plete d. T his c ha n g e is n ot base d o n a n y c o n cer n f or patie nt safet y or efficac y relati ve t o 
fr u q ui nti ni b a n d/ or tisleliz u ma b treat m e nt. Patie nts w h o are c urre ntl y e nr olle d i n t hese c o h orts 
a n d are d eri vi n g be nefit fr o m treat m e nt wit h fr u q ui nti ni b a n d/ or tisleliz u ma b ma y c o nti n ue t o 
partici pate i n t he st u d y as per pr ot oc ol. T here is n o pla n ne d i nterr u pti o n i n t he s u p pl y of 
fr u q ui nti ni b or tisleli z u ma b t o cli nical trial sites wit h acti ve patie nts.  
S y ne os Healt h is t o list a n d ta b ulate c o nce ntrati o n data f or fr u q ui nti ni b, its meta b olite M 1 1, 
tisleliz u ma b.  I m m u n o ge nicit y data will als o be ta b ulate d. S y ne os Healt h are res p o nsi ble f or t he 
pr o d ucti o n a n d q ualit y c o ntr ol of all St u d y Data Ta b ulati o n M o del ( S D T M) datasets, A nal ysis 
Data M o del ( A Da M) d atasets, a n d t he ta bles, listi n gs, a n d fi g ures ( T L Fs) ass o ciate d wit h t hese 
datasets. T he S A P f or p o p ulati o n P K will be pre p are d i n a s e par ate a n al ysis pla n b y a n ot h er 
c o ntract r esearc h or g a niz ati o n ( C R O). 


 
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2.  S T U D Y D E T AI L S 
2. 1.  St u d y O bjecti ves 
P art  
Tier  
O bjecti ves  
E n d p oi nts  
P art 1:  
S afet y  
Le a d-i n  
P h ase  
Pri m ar y  
T o assess t h e safet y a n d t olera bilit y of  
fr u q ui nti ni b i n c o m bi nati o n wit h 
tisleliz u ma b i n p atie nts wit h a d va nce d 
s oli d t u m ors 
A d verse e v e nts ( A Es) c haracterize d b y 
t y p e, fre q ue nc y, se v erit y p er T h e 
Nati o nal Ca ncer  I nstit ute C o m m o n 
T er mi n ol o g y Criteria f or A d verse 
E ve nts ( N CI C T C A E) versi o n 5. 0, 
ti mi n g, seri o us n ess, relati o ns hi p t o 
st u d y dr u g(s), a n d disc o nti n uati o n of 
st u d y dr u g(s) d ue t o  
A Es 
T o c o nfir m t h e rec o m m e n de d p has e 
2 d ose ( R P 2 D) of fr u q ui nti ni b i n 
c o m bi nati o n wit h tisleliz u ma b 
R P 2 D 
Sec o n d ar y 
T o e val uate t he efficac y of fr u q ui nti ni b  
i n c o m bi n ati o n wit h tisleliz u m a b p er 
i n v esti gat or assess me nt 
o bjecti ve res p o nse rate ( O R R) 
pr o gressi o n free s ur vi val ( P F S),  
disease c o ntr ol rate ( D C R),  
cli nical be n efit rate ( C B R),  
d urati o n of res p o nse ( D o R)  
o verall s ur vi val ( O S) 
T o c haracterize t he P K pr ofile of  
fr u q ui nti ni b a n d meta b olite M 1 1 w he n 
c o m bi ne d wit h tisleliz u ma b 
Plas ma c o n ce ntrati o ns of fr u q ui nti ni b  
a n d M 1 1 
T o e val u ate t h e P K a n d  
i m m u n o ge nicit y of fr u q ui nti ni b i n 
c o m bi nati o n wit h tisleliz u ma b 
Ser u m c o nce ntrati o ns of tisleliz u m a b  
a n d i nci d e nce of a nti- dr u g a nti b o d y 
( A D A) t o tisleliz u ma b 
P art 2:  
D ose  
E x p a nsi o n  
P h ase  
Pri m ar y  
T o e val uate t h e O R R assesse d b y t h e  
i n v esti gat or i n patie nts wit h a d va nce d 
or m et astatic T N B C, E C, or M S S 
m C R C w he n treate d wit h fr u q ui nti ni b  
i n c o m bi nati o n wit h tisleliz u ma b 
O R R per res p o nse e v al u ati o n criteria i n 
s oli d t u m ors versi o n 1. 1 ( R E CI S T v 1. 1) 
Sec o n d ar y 
T o f urt her e val u ate efficac y of  
fr u q ui nti ni b i n c o m bi nati o n wit h 
tisleliz u ma b i n p atie nts wit h a d va nce d 
or m et astatic T N B C, E C, or M S S 
m C R C per i n vesti gat or assess me nt 
P F S, D C R, C B R, D o R, a n d O S 
T o c haracterize t he safet y of  
fr u q ui nti ni b i n c o m bi nati o n wit h 
tisleliz u ma b 
A Es c h aracterize d b y t y p e, fre q ue nc y,  
se verit y p er N CI C T C A E v 5. 0, ti mi n g, 
seri o us ness, relati o ns hi p t o st u d y 
dr u g(s), a n d disc o nti n uati o n of st u d y  
dr u g(s) d u e t o A Es. 


 
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P art  
Tier  
O bjecti ves  
E n d p oi nts  
T o assess t h e p h ar mac o ki n eti c ( P K) 
pr ofile of  fr u q ui nti ni b a n d meta b olite 
( M 1 1) w h e n c o m bi ne d wit h 
tisleliz u ma b 
Plas ma c o nce ntrati o ns a n d deri v e d P K 
p ara m eters of fr u q ui nti ni b a n d M 1 1. 
T o c haracterize t he P K a n d  
i m m u n o ge nicit y of fr u q ui nti ni b w he n 
c o m bi ne d wit h tisleliz u ma b 
Ser u m c o nce ntrati o ns of tisleliz u m a b  
a n d i nci d e nce of A D A t o tisleliz u m a b 
T o d etect t h e e x pressi o n of 
pr o gra m me d d eat h-li ga n d ( P D- L 1), 
M S S/ M SI stat us, a n d  ot h er 
bi o mar kers i n t u m or tiss ues of  
p atie nts, a n d t o p erf or m rele v a nt  
efficac y a nal ysis t o pr o vi d e refere nce  
f or t h e d eter mi n ati o n of d o mi na nt  
p o p ulati o n 
C h a n ges fr o m baseli n e i n bi o mar kers  
mar kers, c orrelati o n wit h dr u g e x p os ure,  
a n d ass ociati o n wit h efficac y a n d safet y  
p ara m eters 
E x pl orat or y  T o e x pl ore p ote ntial bi o mar kers 
ass ociate d wit h a nti-t u m or effects of 
fr u q ui nti ni b i n c o m bi nati o n wit h 
tisleliz u ma b 
C h a n ges fr o m b aseli n e i n t u m or mar kers, 
c orrelati o n wit h dr u g e x p os ure, a n d 
ass ociati o n wit h efficac y a n d safet y 
p ara m eters 
 
 
 


 
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2. 2.  St u d y Desi g n 
T his is a n o pe n-la bel, m ultice nter, n o n-ra n d o mize d, p has e 1 b/ 2 st u d y t o assess t he safet y 
a n d efficac y of fr u q ui nti ni b i n c o m bi n ati o n wit h tisleli z u ma b i n patie nts wit h a d va nce d or 
metastatic s oli d t u m ors. T his st u d y will be c o n d ucte d i n 2 parts: a Safet y Lea d-i n p hase 
( Part 1) a n d a d ose e x pa nsi o n p hase ( Part 2). T he o verall st u d y sc he matic is prese nte d i n 
Fi g ure 1.  
Fi g ure 1 St u d y Desi g n Sc he m a 
  
2 L =sec o n d li ne; 3 L =t hir d li ne; E C =e n d o metrial ca ncer; E C O G = Easter n C o o perati ve 
O nc ol o g y Gr o u p; I O =i m m u ne- o n c ol o g y; m C R C = metastatic c ol orectal ca n cer; 
M S S = micr osatellite sta ble; n =t otal n u m b er of p ati e nts; P S = perf or ma nce stat us; Q D = o nce 
dail y; Q 4 W =e v er y 4 wee ks; R P 2 D =rec o m m e n de d P hase 2 d ose; T N B C =tri ple ne gati ve 
breast ca ncer. 
P art 1: S afet y Le a d-i n P h ase  
A p pr o xi matel y 6 t o 1 2 patie nts wit h hist ol o gicall y or c yt ol o gicall y d oc u me nte d a d v a nce d or 
metastatic s oli d t u m ors of a n y t y pe w h o h a ve pr o gresse d o n sta n dar d s yste mi c t hera p y a n d f or 
w hic h n o effecti ve t hera p y or sta n dar d of care e xists will be e nr olle d a n d assesse d f or D L Ts 
d uri n g t he 2 8- da y peri o d D L T o bser vati o n peri o d. Patie nts ma y be eit h er i m m u n o- o nc ol o g y (I O) 
treate d or n aï ve i n t he metastatic setti n g. Patie nts wit h T N B C i n t he Safet y Lea d-i n m ust meet 
eli gi bilit y crit eria defi n e d i n c o h orts A or B, a n d t h ose wit h E C i n t he Safet y Lea d-i n m ust meet 
eli gi bilit y crit eria defi n e d i n c o h ort C.  
Part 1 of t he st u d y will be gi n b y e nr olli n g t h e first 6 patie nts a n d e val uati n g f or D L Ts d uri n g 
t he D L T o bser vati o n peri o d. St u d y dr u g a d mi nistrati o n will be gi n at t he f ull d ose of 


 
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fr u q ui nti ni b ( 5 m g dail y, 3 wee ks o n f oll o w e d b y 1 w ee k off e ver y 4- wee k c ycle) i n 
c o m bi nati o n wit h tisleliz u ma b ( 3 0 0 m g o nce e ver y 4 wee ks). A l o wer d ose le vel of 
fr u q ui nti ni b ( 4 m g dail y, 3 wee ks o n f oll o we d b y 1 wee k off e ver y 4- wee k c ycle) will be 
e x pl ore d as necessar y de pe n di n g o n o bser ve d t o xicit y.  
O nl y d ose li miti n g t o xicities ( D L Ts) d uri n g t he first c ycle of treat m e nt will be assesse d. 
If 0 or 1 of 6 patie nts e x perie nces a D L T, t he st u d y ma y pr ocee d at t h e c urre nt d ose 
of b ot h dr u gs. 
If 2 or m ore p atie nts e x perie nce a D L T, t he n, f oll o wi n g c o ns ultati o n wit h t he s afet y 
re vie w c o m mittee ( S R C), t he st u d y will pr ocee d wit h e nr oll m e nt i n t he ne xt defi ne d 
l o wer d ose ( D ose Le vel - 1), a n a d diti o nal 6 patie nts will be e nr olle d, a n d t he 2 8- da y 
D L T o bser vati o n peri o d will be re peate d. 
If 2 or m ore p atie nts e x perie nce a D L T i n D ose Le vel - 1, e nr oll me nt i n t h e st u d y 
will cease. 
P art 2: D ose E x p a nsi o n P h ase  
A p pr o xi matel y 1 4 0 patie nts will be e nr olle d, i ncl u di n g a p pr o xi matel y 6 0 patie nts wit h T N B C 
(a p pr o xi m atel y 3 0 patie nts i n eac h c o h ort [ A a n d B]) a n d a p pr o xi mat el y 4 0 patie nts wit h E C 
i n C o h ort C, a n d a p pr o xi matel y 4 0 patie nts wit h M S S m C R C i n C o h ort D. Patie nts will be 
e nr oll e d t o o ne of t he f oll o wi n g 4 c o h orts. Of n ote, base d u p o n t he strate gi c e val uati o n of t he 
cli nical de vel o p me nt of fr u q ui nti ni b, patie nt e nr oll me nt has bee n per ma ne ntl y disc o nti n ue d f or 
all c o h orts i n t he d ose e x pa nsi o n p hase. At t h e ti me of deci di n g o n disc o nti n uati o n of 
e nr oll me nt, t he C o h ort D ha d c o m pl ete d t he e nr oll me nt. He nce, t h e fi nal a ct ual t otal n u m b er 
of patie nts will refle ct t his strate gic decisi o n. 
C o h ort A ( T N B C, i m m u n o- o nc ol o g y [I O]-treate d i n t he metastatic setti n g):  
Patie nts m ust ha ve hist ol o gicall y or c yt ol o gicall y d oc u m e nte d, a d v a nce d or metastatic 
T N B C as defi ne d b y A m erica n S ociet y f or Cli nical O nc ol o g y ( A S C O)- C olle ge of 
A merica n Pat h ol o gists ( C A P) g ui deli nes. U p t o 1 5 patie nts i n c o h ort A ca n ha ve E R or 
P R l o w p ositi ve disease as defi ne d b y A S C O- C A P g ui deli n es, if t he treati n g p h ysicia n 
c o nsi ders t h e patie nt n ot eli gi ble f or a dj u va nt e n d ocri ne t hera p y. T N B C is defi ne d as 
E R/ P R p ositi vit y of < 1 %, a n d E R/ P R l o w p ositi v e disease is defi ne d b y E R/ P R p ositi vit y 
of 1 % t o 1 0 % ( Allis o n 2 0 2 0 ). 
Patie nts m ust ha ve pr o gresse d o n at l east 1 li ne, b ut n o m ore t ha n 3 li nes, of c yt ot o xic 
t hera p y i n t he l o call y a d v a nce d or m etastatic setti n g. Patie nts m ust h a ve als o pr o gresse d 
o n pri or i m m u n ot h era p y i n t he metastatic setti n g ( Ra k ha 2 0 1 4) Ra k ha 2 0 1 4. 
C o h ort B ( T N B C, I O- N aï ve i n t h e metastatic setti n g):  
Patie nts m ust ha ve hist ol o gicall y or c yt ol o gicall y d oc u me nte d, l ocall y a d v a nce d or 
metastatic T N B C as defi ne d b y A S C O- C A P g ui deli nes. U p t o 1 5 patie nts i n c o h ort B 
ca n ha v e E R or P R l o w p ositi ve disease as defi n e d b y A S C O- C A P g ui deli nes, if t he 
treati n g p h ysicia n c o nsi d ers t h e p ati e nt n ot eli gi ble f or a dj u v a nt e n d ocri n e t hera p y. 


 
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T N B C is defi n e d as E R/ P R p ositi vit y of < 1 %, a n d E R/ P R l o w p ositi ve disease is 
defi ne d b y E R/ P R p ositi vit y of 1 % t o 1 0 %. 
Patie nts m ust ha ve pr o gresse d o n at least 1 li ne, b ut n o m ore t ha n 3 li n es, of c yt ot o xic 
t hera p y i n t he l o call y a d v a nce d or m etastatic setti n g. Patie nts m ust n ot ha ve recei v e d 
pri or t hera p y wit h a n I CI or ot her i m m u n ot hera p y i n t he m etastatic setti n g. 
C o h ort C  ( E C, I O Naï ve):  
Patie nts m ust ha ve hist ol o gicall y or c yt ol o gicall y d oc u m e nte d, a d v a nce d or metastatic 
E C. 
Patie nts m ust ha ve pr o gresse d o n 1 pri or, plati n u m- base d c he m ot hera p y re gi me n f or E C. 
Partici pa nts ma y ha ve recei ve d u p t o 1 a d diti o nal li ne of plati n u m- base d c h e m ot hera p y if 
gi ve n i n t he ne oa dj u va nt or a dj u va nt setti n g a n d m ust n ot ha v e recei ve d pri or t hera p y 
wit h a n I CI or ot her i m m u n ot hera p y. 
C o h ort D ( M S S m C R C, I O N aï ve): 
Patie nts m ust ha ve hist ol o gicall y or c yt ol o gicall y c o nfir me d, a d v a nce d or metast atic, 
u nresect a ble a de n ocarci n o ma of t he c ol o n or rect u m. All ot her hist ol o gical t y pes are 
e xcl u de d. 
Patie nts m ust ha ve faile d 2 li nes of sta n dar d c h e m ot hera pies, i ncl u di n g fl u or o uracil, 
o xali plati n, a n d iri n oteca n.  Fail e d c he m ot hera pi es are defi ne d as t he o cc urre nce of P D or 
i nt olera ble t o xicities d uri n g t he treat m e nt or after t he last d ose.  
N otes: a) Eac h li ne of treat m e nt f or a d va nce d dis ease u ntil P D i ncl u des o ne or m ore 
c he m ot h era p y dr u gs use d f or 
all o we d.  If rela ps e or metastasis occ ur d uri n g t he a dj u va nt/ ne oa dj u va nt treat m e nt p eri o d 
or wit hi n 6 m o nt hs after t he c o m pl eti o n of t he a b o ve treat m e nt, t hat a dj u v a nt/ ne oa dj u va nt 
t hera p y is c o nsi d ere d as t he fail ure of first li ne s yste mic c he m ot h era p y f or P D. 
Patie nts wit h R A S wil d-t y pe t u m or m ust ha ve recei v e d a nti- V E G F a n d/ or e n d ot helial 
gr o wt h fact or rece pt or ( E G F R) a nti b o d y treat m e nt.  Patie nts wit h R A S m utati o n or R A S 
stat us u n k n o w n m ust ha ve recei v e d a nti- V E G F a nti b o d y treat m e nt. 
T u m or tiss u e m ust ha ve bee n assess e d f or M S S stat us pri or t o e nr oll me nt.  T he res ults 
s h o ul d be a vaila ble i n t he s o urce d oc u m e nts a n d b e t h ose use d t o ma ke treat me nt 
decisi o ns f or t h e patie nt.  A re dacte d c o p y of t he l ocal res ults s h o ul d acc o m p a n y t h e 
arc hi v al t u m or sa m ples s u b mitt e d as part of t he pr ot oc ol. 
O ver all st u d y c o n d uct 
I n all parts of t he st u d y, t here is n o pre defi ne d d urati o n of treat me nt f or eac h patie nt. T hat is, 
patie nts will c o nti n ue recei vi n g st u d y dr u g a d mi nistrati o n u ntil ra di ol o gicall y deter mi ne d P D per 
R E CI S T v 1. 1, u nacce pta ble t o xicit y, deat h, or wit h dra w al fr o m st u d y.  
Treat m e nt c ycles will oc c ur c o nsec uti vel y wit h o ut i nterr u pti o n, e xce pt w h e n necessar y t o 
ma na ge t o xicities or f or a d mi nistrati ve reas o ns. 


 
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T he d ose f or fr u q ui nti ni b ca n be re d uce d at a n y ti me d ue t o t he i nt olera ble t o xicit y f oll o wi n g t he 
D L T o bser vati o n wi n d o w i n t he safet y le a d-i n p h ase. O nc e re d u ce d, t h e d ose ca n n ot be 
re-es calate d t o t he pre vi o us le vel. T here is n o d ose re d ucti o n f or tisleli z u ma b i n t his st u d y. 
T he i n vesti gat or has t he ri g ht t o disc o nti n ue a patie nt fr o m t he st u d y f or a n y c o n diti o n t hat t he 
i n vesti gat or deter mi nes is i n t he best i nterest of t he patie nt, a n y r eas o ns of n o n-c o m plia nce (e g, 
misse d d oses a n d visits), or pre g na n c y.  
A n y pati e nt w h o disc o nti n ues treat m e nt is pr ot oc ol-re q uire d t o ret ur n t o t h e st u d y sit e f or a n 
E O T (e n d of treat me nt) visit a n d safet y f oll o w- u p visit. 
T he E O T (e n d of treat m e nt) visit is c o n d ucte d 
t he l ast d ose w he n t he 
i n vesti gat or deter mi nes t h at t h e patie nt m ust per m a ne ntl y dis c o nti n ue all st u d y dr u gs.  
Patie nts w h o per ma ne ntl y disc o nti n ue all st u d y dr u gs will be as ke d t o ret ur n t o t he cli nic f or t he 
safet y f oll o w- u p visit, w hic h is re q uire d t o be c o n d ucte d 3 0 da ys ( ± 7 da ys) after t he E O T visit.   
E ver y 8 wee ks ( ± 1 4 da ys) after t h e E O T visit, t he i n vesti gat or or t heir desi g nee s h o ul d call t he 
patie nts t o c ollect i nf or mati o n relate d t o s ur vi val stat us a n d t h eir use of ot h er 
a ntica ncer treat me nts, i ncl u di n g dr u g na me, d osa ge, a n d treat m e nt start a n d e n d dates. 
T he e n d of t he st u d y is d efi ne d as t he l ast visit of t h e last patie nt i n t he st u d y. 
T he S R C will re vie w t h e data d uri n g Part 2 o n a n o n g oi n g basis f or safet y.  
T he st u d y sc he d ule d assess m e nts are prese nte d i n A p pe n di x 1. 
2. 3.  D eter mi n ati o n of S a m pl e Si ze 
A p pr o xi matel y 1 4 6 t o 1 5 2 pati e nts are esti mate d t o be e nr oll e d i n t his st u d y (a p pr o xi matel y 
6 t o 1 2 patie nts i n t h e d ose escalati o n p hase a n d a p pr o xi matel y 1 4 0 patie nts i n t he d ose 
e x pa nsi o n p hase). 
Safet y Lea d-I n P h ase 
A p pr o xi matel y 6 t o 1 2 patie nts will be e nr oll e d i nt o t his p hase of t he st u d y. T he t otal sa m ple 
size will be deter mi ne d b y t he i nci de nce of D L Ts i n t he safet y lea d-i n p hase. 
D ose E x pa nsi o n P hase 
A p pr o xi matel y 3 0 patie nts will be e nr olle d i n eac h of t he C o h orts A a n d B, a p pr o xi m atel y 4 0 
patie nts i n C o h ort C, a n d a p pr o xi matel y 4 0 pati e nts i n C o h ort D i n t he d ose e x pa nsi o n p hase 
of t he st u d y. Pla n ne d patie nt e nr oll me nt f or eac h c o h ort ca n pr o vi de a de q uat e precisi o n f or t he 
esti mate of O R R at a s pecific ti me p oi nt. 
Ta ble 1 S h o ws t h e ra n ge of O R R a n d t he c orres p o n di n g 9 5 % CIs f or a sa m ple size of 3 0 or 
4 0 patie nts. 


 
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T a bl e 1  
Esti m ate d O R R a n d 2- Si de d 9 5 % C o nfi d e nce I nter v als
 
N u m ber of p atie nts 
N u m ber of 
Res p o n ders 
Esti m ate d O R R 
9 5 % CI L o wer 
Li mit 
9 5 % CI 
U p per Li mit 
3 0 
0 
0. 0 0 
0. 0 0 
0. 1 2 
3 0 
5 
0. 1 7 
0. 0 6 
0. 3 5 
3 0 
1 0 
0. 3 3 
0. 1 7 
0. 5 3 
3 0 
1 5 
0. 5 0 
0. 3 1 
0. 6 9 
3 0 
2 0 
0. 6 7 
0. 4 7 
0. 8 3 
3 0 
2 5 
0. 8 3 
0. 6 5 
0. 9 4 
3 0 
3 0 
1. 0 0 
0. 8 8 
1. 0 0 
4 0 
0 
0. 0 0 
0. 0 0 
0. 0 9 
4 0 
5 
0. 1 3 
0. 0 4 
0. 2 7 
4 0 
1 0 
0. 2 5 
0. 1 3 
0. 4 1 
4 0 
1 5 
0. 3 8 
0. 2 3 
0. 5 4 
4 0 
2 0 
0. 5 0 
0. 3 4 
0. 6 6 
4 0 
2 5 
0. 6 3 
0. 4 6 
0. 7 7 
4 0 
3 0 
0. 7 5 
0. 5 9 
0. 8 7 
4 0 
3 5 
0. 8 8 
0. 7 3 
0. 9 6 
4 0 
4 0 
1. 0 0 
0. 9 1 
1. 0 0 
CI =c o nfi de nce i nter val; O R R = o bjecti v e res p o nse rate     
9 5 % Cl o p p er- Pears o n i nter val f or bi n o mial distri b uti o n 


 
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3.  A N A L Y SI S S E T S 
3. 1.  D efi niti o n of A n al ysis Sets  
3. 1. 1.  
E nr olle d Set 
T he e nr oll e d set i ncl u des all patie nts w h o ha ve si g ne d I C F (i nf or m c o nse nt f or m). 
3. 1. 2.  
S afet y A n al ysis Set 
T he safet y a nal ysis set i ncl u des all e nr olle d p ati e nts w h o recei v e d at least o ne d ose of 
fr u q ui nti ni b or tisleli z u ma b. T he safet y e val u ati o n will be perf or me d b ase d o n t he first d ose of 
st u d y treat m e nt recei ve d b y a pati e nt. T his is t he pri mar y p o p ulati o n f or s afet y a n d efficac y 
a nal yses. 
3. 1. 3.  
D L T- E v al u a ble A n al ysis Set  
T he D L T-e val ua ble a nal ysis set i ncl u de d all patie nts e nr olle d i n t he S afet y Lea d-i n p orti o n of 
t he st u d y w h o recei ve d at least 1 d ose of fr u q ui nti ni b or tisleliz u ma b a n d w ere c o nsi d ere d D L T 
e val ua ble b ase d o n t h e S R C re vie w, acc or di n g t o t he pre-s pecifie d criteria fr o m t he pr ot o c ol.  
3. 1. 4.  
Res p o nse E v al u a ble A n al ysis Set 
T he res p o nse e val ua bl e a nal ysis set will i n cl u de all patie nts w h o are i n t h e safet y a nal ysis set a n d 
ha ve a baseli n e t u m or assess me nt, a n d eit her (i) ha ve ha d at least o ne p ost- baseli ne t u m or 
assess me nt, or (ii) d o n ot ha ve p ost- d ose t u m or assess m e nt b ut ha ve cli nical pr o gressi o n as n ote d 
b y t he i n vesti gat or or ha ve die d d ue t o diseas e pr o gressi o n bef ore t heir first p ost- baseli ne t u m or 
sca n. Se nsiti vit y a nal ysis f or efficac y e n d p oi nts O R R, D C R, a n d C B R will be c o n d ucte d usi n g 
t his a nal ysis s et. 
3. 1. 5.  
P h ar m ac o ki n etics ( P K) A n al ysis Set 
T he p har ma c o ki n etic a n al ysis s et i ncl u des all patie nts i n t h e safet y a nal ysis set t hat ha ve at 
least o ne q ua ntifia ble plas ma c o nce ntrati o n of fr u q ui nti ni b a n d/ or tisleliz u ma b. 
3. 1. 6.  
A nti dr u g A nti b o d y ( A D A) A n al ysis Set  
T he a nti dr u g a nti b o d y a n al ysis set i ncl u des all patie nts w h o recei ve d at least o ne d ose 
of tisleliz u ma b a n d ha ve a baseli ne a n d at least o ne p ost- baseli n e A D A res ult. 
3. 2.  P r ot oc ol De vi ati o n  
Pr ot oc ol de viati o ns i ncl u di n g de viati o ns t h at are relate d t o C O VI D- 1 9 are rec or de d i n t he 
Cli nical Trial Ma na ge me nt S yste m as o utli ne d i n t he latest versi o n of t he Pr ot oc ol De viati o n a n d 
N o n-c o m plia nce M a na ge me nt Pla n. Pr ot oc ol de viati o ns are cate g orize d as m aj or/ mi n or b ef ore 
data base l oc k. C ertai n pr ot oc ol de viati o ns are m aj or i n t h at t h e y ma y affect t he a bilit y t o assess 
t he safet y a n d efficac y of st u d y dr u g.  


 
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4.  E N D P OI N T S 
4. 1.  Ge ner al P ri nci ples f o r Deri ve d a n d Tr a nsf o r me d D at a 
4. 1. 1.  
Refe re nce St a rt D ate a n d E n d D ate a n d St u d y D a y 
Refere n ce start d ate is defi ne d as t h e first dat e w he n a n o n-zer o d os e of a n y st u d y dr u g (i.e. 
fr u q ui nti ni b or tisleli z u ma b w hic he ver o cc urs first) was a d mi nistrate d (first a d mi nistrati o n/ d ose 
date). Da y 1 is t he d a y of t he first d os e of st u d y treat me nt i n C y cle 1.  
St u d y Da y will be calc ul ate d fr o m t he r efere nce st art date, a n d it will be us e d t o s h o w start/st o p 
da y of assess me nts a n d e ve nts relati ve t o t he first a d mi nistrati o n of st u d y treat m e nt. 
If t h e d ate of t he e v e nt is o n or after t h e refere nce start date, St u d y D a y = ( d ate of e ve nt  
refere nce start dat e) + 1. 
If t h e d ate of t he e v e nt is pri or t o t he refere nce start date, St u d y Da y = ( dat e of e ve nt  
refere nce start dat e). 
I n t he sit u ati o n w h ere t he e ve nt date is partial or missi n g, t he date will a p pear partial or missi n g 
i n t h e listi n gs. 
Refere n ce e n d date is defi ne d as t h e last date w he n a n o n-zer o d ose of a n y st u d y dr u g was 
a d mi nistere d. 
4. 1. 2.  
B aseli n e a n d C h a n ge fr o m B aseli ne 
Baseli ne is defi ne d as t he last n o n- missi n g assess me nt pri or t o t he first a d mi nistrati o n of a n y 
st u d y dr u g ( w hic he v er o cc urs first), i ncl u di n g sc he d ule d a n d u nsc he d ule d visits, u nless 
ot her wise s pecifie d. F or q ua ntitati ve meas ure me nts:  
c ha n ge fr o m baseli n e ( C F B) will be cal c ul ate d as: C F B = Assess me nt val u e at visit X  
Baseli ne val ue;  
perce nt a ge C F B ( % C F B) will be calc ulat e d as % C F B = ( Assess me nt val u e at eac h visit X 
 
Baseli ne val ue)/ Baseli ne val ue × 1 0 0. 
4. 1. 3.  
Tre at me nt Peri o d 
U nless ot her wise s pecifie d, t he treat m e nt peri o d is defi ne d as t he peri o d fr o m first a d mi nistrati o n 
date t o [ 3 0 da ys + 7 d a ys pr ot oc ol defi n e d wi n d o w] after last a d mi nistrati o n date o n treat m e nt. 
F or safet y data, o nl y t he assess m e nts/e ve nts c oll ecte d d uri n g t he treat m e nt peri o d will be 
e val uate d (e xce pt f or relate d S A E a n d i m m u ne- me diate d A E [i m A Es]). 
T he w orst p ost baseli ne is defi n e d as t he w orst ass ess me nts/e ve nts d uri n g t he treat me nt peri o d 
i ncl u di n g b ot h sc he d ule d a n d n o n-sc he d ul e d visits. T he last assess m e nt o n treat me nt 
meas ure me nt is defi ne d as t he latest n o n- missi n g meas ure me nt ta k e n d uri n g t he treat m e nt 
peri o d. 




 
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P R 
S D 
S D [ d] 
U nc o nfir me d P R 
P R 
P D 
S D [ b] or P D 
U nc o nfir me d P R 
P R 
N E or N A  
S D [c] or N E or N A  
U nc o nfir me d P R 
N E 
N E 
N E 
N E 
N E 
C R 
S D 
U n c o nfir me d C R 
N E 
P R 
S D 
U nc o nfir me d P R 
N E 
S D 
S D 
S D 
N E or N A  
P D 
P D 
P D 
S D 
P D 
S D [ b] or P D 
S D [ b] or P D 
S D 
C R 
S D 
S D 
S D 
P R 
S D 
S D 
S D 
S D 
S D 
S D 
S D 
N E or N A  
S D [c] or N E or N A  
S D [c] or N E 
P D 
N o f urt her 
e val u ati o n  
P D 
P D 
C R = C o m plete Res p o nse; N E = N ot E v al u a ble; N A = N ot A vaila ble; O R R = O bjecti v e Res p o nse Rate; P D = Pr o gressi v e 
Disease; P R = Partial Res p o ns e; S D = Sta ble Disease.  
[a] T h e mi ni m u m i nter val f or c o nfir mati o n of C R a n d P R is 4 w ee ks.  
[ b] Best res p o nse will b e S D if t he first ti me p oi nt o v erall res p o nse is after 4 9 d a ys ( 8 wee ks fr o m start of treat m e nt a n d all o wi n g 
a 7 d a y visit wi n d o w) o n st u d y. Ot h er wis e, t h e b est res p o nse will be P D. 
[c] Best res p o nse will be S D if t he first ti me p oi nt o verall res p o nse if after 4 9 da ys o n st u d y. Ot h er wise, t h e best r es p o ns e will be 
N E. 
[ d] Best res p o nse will b e S D pr o vi d e d t h e criteria f or P D h a ve n ot bee n met fr o m t he first t o s ec o n d assess m e nt. 
* A b est o v erall res p o ns e of S D ca n o nl y b e ma d e after t he p atie nt is o n st u d y f or a mi ni m u m of 4 9 da ys (c o u nte d fr o m C y cle 1 
Da y 1). If t he p atie nt is o n st u d y f or less t h a n 4 9 da ys, a n y t u m or assess me nt i n dicati n g sta ble disease b ef ore t his ti me peri o d will 
h a ve a b est r es p o ns e of N E u nless P D is i d e ntifie d.  
^ S u bse q u e nt d o c u me ntati o n of a C R ma y pr o vi d e c o nfir mati o n of a pre vi o usl y i d e ntifie d C R e v e n wit h a n i nter ve ni n g N E (e. g., 
C R N E C R). S u bse q ue nt d o c u me ntati o n of a P R ma y pr o vi d e c o nfir mati o n of a pre vi o usl y i de ntifie d P R e ve n wit h a n 
i nter v e ni n g N E or S D (e. g., P R N E P R or P R S D P R). H o we ver, o nl y o n e ( 1) i nter v e ni n g N E or S D will b e all o we d b et wee n P Rs 
f or c o nfir mati o n. N ote: i n t h e f oll o wi n g sce n ari o, P R S D N E P R, t h e sec o n d P R is n ot a c o nfir m ati o n of t h e first P R. 
4. 2. 2.  
Sec o n d ar y E n d p oi nts 
4. 2. 2. 1.  
Pr o gressi o n-free S u r vi v al ( P F S) 
Pr o gressi o n-free s ur vi val ( P F S) is defi ne d as t he ti me ( m o nt hs) fr o m start of st u d y treat m e nt 
(fr u q ui nti ni b or tisleliz u ma b) u ntil t he first ra di o gra p hic d oc u me ntati o n of o bjecti v e 
pr o gressi o n as assesse d b y t he i n vesti gat or usi n g R E CI S T v 1. 1, or deat h fr o m a n y ca use.  
M ore s pecifi call y, P F S will be deter mi ne d usi n g all t he assess m e nt data u p u ntil t he last 
e val ua ble visit pri or t o or o n t h e date of:  
(i) disease pr o gressi o n as defi ne d b y R E CI S T V ersi o n 1. 1 or deat h; or 
(ii) wit h dra wal of c o nse nt or l ost t o f oll o w- u p; or 
(iii) recei pt of s u bs e q ue nt a nti-ca ncer t h era p y (i.e. me dicati o n, n ot i ncl u di n g t he 
ra di ot hera p y a n d pr oce d ure), w hic h e ver is earlier. 


 
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Patie nts wit h o ut re p ort of P D or deat h fr o m a n y ca use at t h e ti me of a n al ysis are ce ns ore d as 
descri b e d i n Ta bl e 3 bel o w. 
T he P F S ti me will al wa ys be deri v e d base d o n sca n dates n ot t u m or ass ess me nt dates. R E CI S T 
assess me nts/sca ns c o ntri b uti n g t o war ds a partic ul ar visit ma y be perf or m e d o n differe nt d ates. 
T he f oll o wi n g r ules are a p plie d: 
Date of pr o gressi o n is deter mi ne d base d o n t h e earliest of t he d ates of t he c o m p o ne nt t hat 
tri g gere d t he pr o gressi o n. 
W he n ce ns ori n g a patie nt f or P F S, t he p atie nt is ce ns ore d at t he latest of t h e dates 
c o ntri b uti n g t o a partic ular o verall visit assess m e nt. 
T a bl e 3  
Ce ns ori n g R ules f or P F S 
R ule  Sit u ati o n 
D ate of Pr o gressi o n or C e ns o ri n g 
O utc o me 
1  
P D d o c u me nte d fr o m ra di ol o gical 
assess m e nt visits 
Date of d o c u me nte d disease pr o gressi o n 
E ve nt 
2  
Deat h wit h o ut P D or d eat h bef ore first 
d oc u me nte d P D or d eat h after o ne 
missi n g ra di ol o gical assess m e nt visit 
Date of d eat h 
E v e nt 
3 
N o b aseli n e or p ost- b aseli n e 
ra di ol o gical assess me nts a v aila ble 
Date of start of st u d y treat m e nt  
Ce ns ore d 
4 
N o d eat h or P D b y t he ti me of data 
c ut- off f or fi n al a n al ysis 
Date of last a d e q u ate ra di ol o gical assess m e nt  
Ce ns ore d 
5 
E arl y disc o nti n uati o n (l ost t o f oll o w-
u p or wit h dra wal of c o nse nt) of st u d y 
wit h o ut d eat h or P D  
Date of last a d e q u ate ra di ol o gical assess m e nt  
Ce ns ore d 
6  
Ne w a nti-t u m or me dicati o n starte d 
pri or t o P D or d eat h 
Date of last a d e q u ate ra di ol o gical assess m e nt pri or 
t o or o n date of i nitiati o n of ne w m e dicati o n visit. 
I n case of n o p ost- b aseli n e t u m or assess m e nts, it 
will b e t he d at e of first st u d y treat me nt 
a d mi nistrati o n  
Ce ns ore d 
7  
Deat h or P D o cc urre d after t w o or 
m ore c o nsec uti ve misse d ra di ol o gical 
assess m e nt visits 
Date of last a d e q u ate ra di ol o gical assess m e nt pri or 
t o misse d visits. I n case of n o p ost- baseli n e t u m or 
assess m e nts, it will b e t he d ate of first st u d y 
treat m e nt a d mi nistrati o n 
Ce ns ore d 
N ote: A n a de q u ate ra di ol o gic ass ess me nt is d efi n e d as a n assess me nt w here t h e I n v esti g at or d eter mi n e d ra di ol o gic al res p o nse is 
C R, P R, S D, or P D. If P D a n d n e w a nti-ca n cer t h era p y o cc ur o n t he sa me d a y, will ass u me t h at t h e pr o gressi o n was 
d o c u me nte d first, e. g. o utc o me is pr o gressi o n a n d t h e date is t h e d ate of t h e assess me nt of pr o gressi o n 
N ote: T w o c o nsec uti ve s c he d ule d t u m or assess me nts is e q u al t o 1 2 6 d a ys ( = 2 * ( 8 w ee ks * 7 + 7 d a ys)) si nce pre vi o us e v al u a ble 
R E CI S T 1. 1 or b aseli n e assess me nt if t here is n o p ost baseli n e t u m or assess me nt.  
4. 2. 2. 2.  
Dise ase C o ntr ol R ate 
Disease c o ntr ol rate ( D C R) is defi ne d as t he pr o p orti o n of patie nts wit h a B O R of C R, P R, or 
S D lasti n g f or at least 7 wee ks as deter mi ne d b y t he i n vesti gat or usi n g R E CI S T v 1. 1. A patie nt 
w h o is i n t h e safet y a nal ysis set b ut n ot i n res p o nse e val ua bl e a nal ysis set, or i n res p o nse 


 
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e val ua ble a nal ysis set, b ut d oes n ot ha ve a n y p ost- baseli n e t u m or assess me nt ( patie nts w h o 
die d or pr o gress e d cli nicall y pri or t o t he first sc he d ule d t u m or assess m e nt), t he res p o nse 
 
4. 2. 2. 3.  
Cli ni c al Be nefit R ate 
Cli nical be nefit rate ( C B R) is defi ne d as t he pr o p orti o n of patie nts wit h a B O R of C R, P R, or 
d ura ble S D (i.e. lasti n g f or at least 6 m o nt hs) as deter mi ne d b y t he i n vesti gat or usi n g R E CI S T 
v 1. 1. A pati e nt w h o is i n t he safet y a nal ysis set b ut n ot i n res p o nse e val ua bl e a nal ysis set, or i n 
res p o nse e val ua ble a n al ysis set, b ut d oes n ot h a ve a n y p ost- baseli ne t u m or assess me nt 
( patie nts w h o die d or pr o gresse d cli nic all y pri or t o t he first sc he d ule d t u m or assess m e nt), t he 
 
4. 2. 2. 4.  
D ur ati o n of Res p o nse 
D urati o n of res p o nse ( D o R) is defi n e d as t h e ti me fr o m t he first occ urre nce of P R or C R b y 
R E CI S T Versi o n 1. 1, u ntil disease pr o gressi o n or deat h, w hic he ver c o m es first.  
O nl y t h ose patie nts wit h c o nfir me d  o bjecti ve res p o nses of C R or P R will be i ncl u de d i n t his 
a nal ysis.  
Ce ns ori n g will f oll o w t h e r ules o utli ne d f or P F S i n Ta ble 3  of Secti o n 4. 2. 2. 1.   
F or t h ose patie nts wit h c o nfir me d o bjecti v e res p o nses of C R or P R, D o R is calc ulate d as ( date of 
deat h or P D or last ass ess m e nt  date of first occ urre nce of C R or P R + 1)/ 3 0. 4 3 7 5. 
4. 2. 2. 5.  
O ver all S ur vi v al 
O verall s ur vi val is defi n e d as t h e ti me ( m o nt hs) fr o m t he start of st u d y treat me nt (fr u q ui nti ni b 
or tisleliz u ma b) u ntil t h e date of deat h d ue t o a n y ca use. 
T hat is, O S will be calc ulate d as ( d ate of deat h or l ast k n o w n ali v e 
 date of start of st u d y 
treat me nt + 1)/ 3 0. 4 3 7 5. 
I n rare cas e, if year a n d m o nt h of deat h date are k n o w n b ut t h e da y is u n k n o w n, da y will be 
i m p ute d as 1 5. F or e x a m ple, if a patie nt is re p orte d t o die o n Dec 2 0 1 7, t he deat h date will be 
i m p ute d as 1 5 Dec 2 0 1 7. I n t he cas e of t he i m p ute d deat h date bei n g aft er t he e n d of st u d y date 
a n d t he d eat h d ate a n d e n d of st u d y date bei n g t he sa me m o nt h, t h e deat h date will be assi g ne d t o 
be t he d ate of e n d of st u d y. 
Patie nts wit h n o e ve nt d uri n g t h e st u d y will be ce ns ore d at t h e dat e last k n o w n t o be ali ve. O S 
will n ot be ce ns ore d if a patie nt recei ves s u bse q ue nt a ntica n cer treat me nts aft er disc o nti n uati o n 
of t he st u d y dr u gs. 
M ore o v er, t h e last k n o w n ali ve date will be deri ve d f or patie nts n ot k n o w n t o ha ve die d at t he 
a nal ysis c ut- off d ate usi n g t he latest date (i ncl u di n g c o m pl ete date a n d partial date wit h M o nt h 
a n d Year i nf or mati o n) a m o n g t h e f oll o wi n g data: 
All assess me nt dates (e. g. la b orat or y, vital si g ns assess me nts, E C G, E C O G, perf or ma n ce 
stat us assess me nt, t u m or assess me nt dates etc.). 


 
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Me dicati o n dates i ncl u di n g st u d y me dicati o n, c o n c o mita nt me dicati o ns, a ntica ncer t h era pies 
a d mi nistere d after st u d y treat m e nt disc o nti n uati o n. 
A d vers e e ve nts start a n d e n d date. 
Date latest k n o w n ali v e c oll ecte d d uri n g t he s ur vi val f oll o w- u p. 
After s orti n g pr o p erl y f or all t h ose a vail a ble dates, if t he last k n o w n ali ve d ate is a partial dat e 
wit h M o nt h a n d Year i nf or mati o n, da y will be i m p ute d as 1 5, u nless t his is after t he c ut off d ate 
i n w hic h case t he c ut off d ate will be use d as last ali ve date. 
4. 3.  E x p os ure E n d p oi nts 
Dr u g e x p os ure, i ncl u di n g n u m ber of c ycles recei v e d, t otal d urati o n of e x p os ure, c u m ulati ve d ose 
recei v e d ( m g), d ose i nte nsit y, a n d r elati ve d ose i nte nsit y of fr u q ui nti ni b a n d tisleliz u ma b will be 
calc ulate d as per al g orit h ms i ncl u de d i n  T a bl e 4. 
T he t otal d urati o n of e x p os ure ( da ys) f or fr u q ui nti ni b will be calc ulate d fr o m t he first d ose date 
of fr u q ui nti ni b i n C ycle 1 t o t he last d os e date of fr u q ui nti ni b + 8 da ys or deat h date, w hic he ver 
c o mes earlier if treat me nt is disc o nti n ue d, or t o t he c ut- off d ate if treat me nt is still o n g oi n g. T he 
t otal d urati o n of e x p os ure ( da ys) f or tisleliz u ma b will be calc ulate d fr o m t he first d ose d ate of 
tisleliz u ma b i n C ycle 1 t o t he last d ose d ate of tisl eliz u ma b + 2 8 da ys or deat h date, w hi c he ver 
c o mes earlier if treat me nt is disc o nti n ue d, or t o t he c ut- off d ate if treat m e nt is still o n g oi n g. T he 
t otal d urati o n of e x p os ure ( da ys) will be calc ulate d fr o m t he first d os e date of eit her st u d y dr u g 
(fr u q ui nti ni b or tisleliz u ma b) i n C y cle 1 t o t he earlier d ate b et wee n t h e l ast d ose date of 
fr u q ui nti ni b + 8 da ys a n d last d ose date of tisleliz u ma b + 2 8 da ys, or d eat h date, w hic he v er 
c o mes earlier if treat me nt is disc o nti n ue d, or t o t he c ut- off d ate if treat me nt is still o n g oi n g.  
N u m ber of C ycles Recei ve d 
Patie nts are c o nsi d ere d t o ha v e starte d a c y cle if t he y ha ve recei ve d at least o ne d ose of a n y st u d y 
dr u g (fr u q ui nti ni b or tisleliz u ma b). I n a d diti o n t o t he n u meric s u m mar y f or t h e n u m b er of c y cles, 
t he n u m ber of c y cles will be cate g orize d as 1, 2, 3, 4, 5
 
T ot al D ose A d mi nistere d ( m g) i n a C ycle f o r fr u q ui nti ni b  
I n t he st u d y, fr u q ui nti ni b (at a d ose of 5 m g) is pr o vi d e d f or oral a d mi nistrati o n, a n d i n t he e ve nt 
of d ose a dj ust me nt, 1 m g fr u q ui nti ni b ca ps ules ca n be use d.   
Base d o n dr u g acc o u nta bilit y data, t he n u m ber of ca ps ules ta ke n f or eac h d ose le vel will be 
calc ulate d as t otal dis pe nse d  t otal ret ur ne d i n a c ycle, t he n, t he t otal d ose a d mi nistere d ( m g) i n 
a c ycle will be t he s u m mati o n as ( n u m ber of 5 m g ca ps ules ta ke n × 5 + n u m ber of 1 m g ca ps ules 
ta ke n).  




 
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D ose re d u cti o n : n u m b er of patie nts wit h a n y d ose re d ucti o n a n d reas o ns f or d ose re d u cti o n, 
a n d cate g orize d fre q u e nc y of d ose re d u cti o n ( 0, 1, 2, > 2). T his will be deri ve d o nl y f or 
fr u q ui nti ni b.  
4. 4.  S afet y E n d p oi nts  
T he safet y a nal ysis set is use d t o e val uate t he s afet y varia bles i ncl u di n g a d v erse e ve nts, cli nical 
la b orat or y dat a, vital si g ns, si n gle 1 2-lea d E C G para m eters, E C H O/ M U G A para met ers, p h ysi cal 
e xa mi n ati o ns, E C O G perf or ma n ce stat us, a n d deat h. T he safet y d ata d uri n g t he treat m e nt p eri o d 
will b e e val u ate d, a n d t he treat m e nt peri o d is defi ne d as t he d urati o n fr o m t he date of t he first 
st u d y dr u g a d mi nistrati o n u ntil [ 3 0 da ys + 7 da ys pr ot oc ol defi ne d wi n d o w] after t h e last st u d y 
dr u g (fr u q ui nti ni b or tisleliz u ma b) a d mi nistrati o n or t h e date of d eat h, w hic he ver c o m es first.  
4. 4. 1.  
D ose Li miti n g T o xicities ( D L Ts) or D L T-e q ui v ale nt 
A Es will be assess e d per t he D L T criteria, f or patie nts fr o m part 1, d uri n g t he 2 8- da y D L T 
assess me nt wi n d o w i n C ycle 1, w hic h starts wit h t he first da y of a d mi nistrati o n of st u d y dr u gs. 
M ore o v er, f or patie nts fr o m Part 1, after t he 2 8- da y D L T e val uati o n wi n d o w of C y cle 1, a n A E 
will als o be e val uate d f or D L T-e q ui vale nt acc or di n g t o t he D L T criteria. H e nce, a n A E will be 
deter mi n e d w het h er it is a D L T/ D L T-e q ui vale nt or n ot.  
4. 4. 2.  
A d verse E ve nts ( A Es) 
All A Es will b e c o de d fr o m ver b ati m t e xt t o preferre d ter m ( P Ts) a n d gr o u p e d b y s yste m or ga n 
class ( S O C) usi n g t he Me d D R A ( Me dical Dicti o nar y f or Re g ul at or y Acti vities) Versi o n 2 5. 0 or 
hi g her. A Es will be c ollecte d fr o m t he ti me of si g nat ure of i nf or me d c o nse nt t hr o u g h o ut t he 
treat me nt peri o d. A Es will be gra de d b y i n vesti gat or acc or di n g t o C T C A E, Versi o n 5. 0, missi n g 
se verit y gra d e is i m p ute d as Gra d e 3. 
A n A E is c o nsi dere d a T E A E base d o n t he f oll o wi n g defi niti o n: 
1. D uri n g t he treat m e nt p eri o d fr o m t he d ate of t he first st u d y dr u g a d mi nistrati o n u ntil 3 7 da ys 
after t he l ast st u d y dr u g (fr u q ui nti ni b or tisleliz u ma b) a d mi nistrati o n:  
1. 1 if t he o nset date is o n or after t h e start of st u d y treat m e nt (fr u q ui nti ni b or 
tisleliz u ma b); or 
1. 2 if t he A E has a n o nset date bef ore t he st art of st u d y treat m e nt b ut w orse ne d i n 
se verit y; 
2. After t h e tr eat m e nt peri o d re gar dless of w het her or n ot t he patie nt starts a ne w a ntica n cer 
t hera p y, t h at is, at 3 7 da ys after t he last d ose of st u d y dr u g (fr u q ui nti ni b or tisleliz u ma b) 
a d mi nistrati o n: 
2. 1 treat me nt-relate d S A Es; or  
2. 2 i m m u ne- me diate d A Es (i m A Es) rec or de d u p t o 9 0 da ys after t h e last d ose of 
tisleliz u ma b. 
Ot her A E varia bles i ncl u de dr u g-relate d A Es, A Es lea di n g t o st u d y dr u g m o dificati o ns (i.e. d ose 
i nterr u pti o n, d ose re d u cti o n, or st u d y dr u g wit h dra w al), A Es lea di n g t o deat h, a n d S A Es.  












 
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4. 4. 7.  
Ec h oc ar di o gr a m 
E C H Os will be d o ne at Scree ni n g a n d e ver y 1 2 wee ks fr o m C 1 D 1 t hereafter t hr o u g h t h e e n d of 
treat me nt visit. Assess m e nt para meters i ncl u de left ve ntric ul ar ejecti o n fracti o n ( L V E F) a n d 
o verall i nter pretati o n of car diac f u ncti o n. M ulti ple- gate d ac q uisiti o n sca ns ( M U G As) are 
per mitte d if E C H Os ca n n ot be perf or m e d. 
4. 4. 8.  
P h ysic al E x a mi n ati o n 
A c o m pre h e nsi v e p h ysic al e xa mi nati o n ( P E) at Scr ee ni n g, it i ncl u des ge n eral a p p eara nce, e y es, 
ears, n ose a n d t hr oat, hea d a n d nec k, res pirat or y, car di o vasc ular, a b d o me n ( gastr oi ntesti nal), 
s ki n, ge nit o uri nar y s yste m, l y m p h n o des, m usc ul os k eletal, ne ur ol o gi cal assess me nts. 
Li mit e d p h ysical e xa mi nati o n at sc he d ule d visits is a s u bset t he c o m pre he nsi v e p h ysic al 
e xa mi n ati o n as dee m e d a p pr o priate b y t he i n vesti g at or. 
A b n or mal cli nicall y si g nifica nt fi n di n gs i n P E w ere t o be re p orte d as A Es ( p ost- baseli ne) or 
M Hs (scree ni n g). 
T hese data will o nl y be a vail a ble i n listi n gs.  
4. 5.  Ot her E n d p oi nts  
4. 5. 1.  
P h ar m ac o ki n etic E n d p oi nt 
Bl o o d sa m ples will be c ollecte d f or a nal ysis of fr u q ui nti ni b a n d meta b olite M 1 1 plas ma 
c o nce ntrati o ns a n d tisleliz u ma b ser u m c o nce ntrati o ns acc or di n g t o t he P K sc he d ule of e ve nts 
i n Ta ble 2 of t h e pr ot oc ol. 
4. 5. 2.  
I m m u n o ge nicit y  
Ser u m sa m ples will be c oll ecte d f or a nti dr u g a nti b o d y ( A D A) a nal ysis t o tisleliz u ma b acc or di n g 
t o t h e P K sc he d ule of e ve nts i n Ta ble 2 of t h e pr ot oc ol.  
4. 5. 3.  
E x pl or at or y E n d p oi nts 
Distri b uti o n of P D- L 1 e x pressi o n or M S S/ M SI stat us will be e xa mi n e d i n all patie nts. Ot h er 
p ote nti al pre dicti ve 
mar kers i n cl u di n g, b ut n ot li mite d t o, TI Ls, T M B, c yt o ki n e e x pressi o n, 
a n d ge ne si g nat ure pr ofili n g ma y be d etecte d a n d a nal yze d. 




 
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Part of t he 
st u d y 
Gr o u p  
Gr o u p Descri pti o n i n Data 
Dis pla y 
S u b gr o u p 
 
4  
C o h ort D M S S m C R C (I O 
Naï v e) 
N A 
e pe n di n g o n o bser ve d t o xicit y fr o m t h e d ose c o h ort 5 m g P O Q D 
 E R/ P G R : rece pt or/ pr o g ester o n e rece pt or 
[a] Patie nts wit h T N B C or E C e nr olle d i n P art 1 m ust meet all i n cl usi o n a n d n o e xcl usi o n criteria f or t he res p ecti ve 
c o h orts n ot e d i n Part 2 a n d will b e i ncl u de d i n rele va nt c o h ort f or a n al ysis.  
F or c o nti n u o us data, u nl ess ot h er wise s pecifi e d, t h e mea n, me dia n, Q 1, a n d Q 3 will be prese nt e d 
wit h o ne m ore si g nifica nt di git t ha n t he ori gi nal val ues, a n d sta n dar d de viati o n will be re p orte d 
wit h 2 m ore si g nifica nt di gits t ha n t he ori gi nal val ues. T he mi ni m u m a n d ma xi m u m s h o ul d 
re p ort t h e sa me si g nifica nt di gits as t he ori gi n al val ues. T he deri ve d varia bl es will be prese nte d 
wit h o ne deci mal place. Perce nta ges will be re p orte d wit h o ne deci m al p oi nt; if t he c o u nt is 0, n o 
will b e d o ne aft er all calc ulati o ns are ma de.   
5. 1. 2.  
H a n dli n g Missi n g D at a 
I n g e neral, t he o bser ve d cas e ( O C) data f or a visit will c o nsist of t he act ual o bser vati o ns rec or de d 
f or t h e visit. If missi n g, t he O C data will re mai n missi n g 
 n o missi n g i m p utati o n will be 
perf or me d. Safet y a n al yses will be c o n d ucte d o n t he O C data o nl y.  
H o we ver, i m p utati o n of missi n g A E a n d c o n c o mita nt me dicati o n o nset a n d st o p dates will be 
use d t o deter mi ne t he stat us of eac h A E a n d t he pri or/c o nc o mita nt stat us of eac h me dicati o n. T he 
s pecific i m p utati o n r ules are pr o vi d e d bel o w, refer t o S ecti o n 5. 1. 2. 1  f or t h e met h o d of 
i m p utati o n of missi n g A E o nset a n d st o p date a n d Secti o n 5. 1. 2. 2 f or t h e m et h o d of i m p utati o n 
of missi n g c o nc o mita nt o nset a n d st o p dates. H o w e ver, t he i m p ute d dates s h o ul d n ot be s h o w n i n 
listi n gs. 
F or de m o gra p hic a n d b as eli ne c haracteristics, eac h varia ble will be a n al yze d a n d/ or s u m marize d 
usi n g t h e a vaila ble d ata. U nless ot her wise s pecifie d, patie nts wit h missi n g data will be e xcl u d e d 
o nl y fr o m a nal yses f or w hic h d ata are n ot a vail a ble. 
5. 1. 2. 1.  
A d verse E ve nts St art/ E n d D ate 
A Es wit h o nset/e n d dates t hat are partiall y/c o m pletel y missi n g will be i m p ute d as f oll o ws.  
(i) A E start date: 
If t h e A E o nset d ate is c o m pletel y missi n g, t he A E start d ate will be i m p ute d as t he refere nce 
start date (i.e., d ate of first treat me nt). 
If t h e A E o nset d ate is partial missi n g, t h e n  


 
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If b ot h t he year a n d t h e m o nt h are a vaila ble a n d t he year a n d t h e m o nt h are t he 
c orres p o n di n g y ear a n d m o nt h of t h e refere n ce st art date, t h e n t h e A E start date will be 
i m p ute d as t h e refere n ce start date;  
If b ot h t he year a n d t h e m o nt h are a vaila ble a n d t he year a n d t h e m o nt h are n ot e q ual t o 
t he c orres p o n di n g year a n d m o nt h of t he refere n ce start date, t he n t h e A E st art d ate will 
be i m p ute d as t he 1 st da y of t h e m o nt h; 
If o nl y t he year is a vaila ble a n d t he a vaila ble year is t h e c orres p o n di n g year of t h e 
refere nce start dat e, t h e n t he A E start date will b e i m p ut e d as t he refere nce start date; 
If o nl y t he year is a vaila ble, a n d t he a vaila ble year is n ot e q ual t o t h e c orres p o n di n g year 
of t he refere nce start date, t h e n t h e A E start date will be i m p ut e d as t he J a n uar y 1 st of t he 
year 
(ii) A E e n d date will be i m p ute d as bel o w f or t h e partial date o nl y, t he i m p utati o n r ules o nl y 
a p pl y w he n t h e A E is n ot o n g oi n g: 
If b ot h t he year a n d t h e m o nt h are a vaila ble, A E e n d d ate will be i m p ute d as t h e last da y of 
t he m o nt h; 
If o nl y t he year is a vaila ble, A E e n d date will be i m p ute d as t h e Dece m b er 3 1st of t h e year. 
If t h e i m p ute d A E e n d d ate is after t h e d eat h date f or patie nts k n o w n t o be d ea d at e n d of st u d y 
or c ut off d ate, t he date of t h e deat h will be use d f or A E e n d dat e. If t he i m p ute d A E e n d date is 
after t he l ast k n o w n ali v e date f or p atie nts ali ve at t h e e n d of st u d y or c ut off date, t he date of last 
k n o w n ali ve date will be use d f or A E e n d date.  
F or A E c o nti n ui n g at t h e c ut- off dat e, t he e n d d ate will n ot be i m p ute d a n d i nstea d will be 
 
5. 1. 2. 2.  
C o nc o mit a nt Me dic ati o n/ Pr oce d ure/ S u r ger y St art/ E n d D ate 
C o nc o mita nt Me dicati o n/ Pr oce d ure/ S ur ger y wit h o nset/e n d dates t hat are p artiall y/c o m pletel y 
missi n g will be i m p ute d as f oll o ws. 
(i) start date: 
1 st da y of t h e m o nt h will be use d t o i m p ute t he start date if o nl y t he da y is missi n g 
Ja n uar y 1 st will b e use d t o i m p ute t he start date if b ot h t he da y a n d m o nt h are missi n g 
If t h e d ate is c o m plet el y missi n g, t h e n t h e da y bef ore t he refere nce start date will be i m p ute d 
as t he start date. 
(ii) e n d d ate: 
Last da y of t h e m o nt h will be use d t o i m p ute t he e n d date if o nl y t he da y is missi n g 


 
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Dece m b er 3 1 st of t he year will be use d t o i m p ute t he e n d date if b ot h t he d a y a n d m o nt h are 
missi n g 
If t h e d ate is c o m plet el y missi n g, assi g n 
 
If t h e i m p ute d e n d dat e is after t h e d eat h date or last k n o w n ali v e date, t he d ate of t h e deat h or 
last k n o w n ali ve date will be i m p ute d as t he c o nc o mit a nt me di cati o n/ pr oce d ure/s ur g er y e n d date. 
5. 1. 2. 3.  
S u bse q ue nt A nti- C a ncer T h er a p y D ate 
W he n a p artial ne w a nti-t u m or t h era p y start d ate is re p orte d, e ver y eff ort will be ma de t o i de ntif y 
t he prece de nce relati o ns hi p of starti n g date of ne w a nti-t u m or t hera p y relati v e t o t he refere nce 
e n d date. Bel o w r ul es will be use d: 
If t h e d ate is c o m plet el y missi n g, ne w a nti-t u m or t h era p y date will be i m p ute d as refere nce 
e n d date + 1; 
If o nl y t he da y is missi n g, 1 5t h da y will be i m p ute d as t he ne w a nti-t u m or t hera p y dat e; 
If b ot h t he da y a n d t h e m o nt h are missi n g, t he n J ul y 1 st will b e i m p ute d as t he ne w a nti-t u m or 
t hera p y; 
If t h e i m p ute d date is earli er t h a n refere nce e n d date, t he n it will be re place d wit h refere nce e n d 
date + 1, if t he i m p ute d d ate is later t h a n t he d ate of d eat h or last k n o w n ali v e date, it will be 
re place d wit h t he date of deat h or last k n o w n ali v e date. 
5. 1. 2. 4.  
Pri m ar y Di a g n osis D ate a n d Met ast atic Dise as e Di a g n osis D ate 
W he n a p artial date of pri m ar y dia g n osis or a partial date of first met astatic disease dia g n osis is 
re p orte d, t he b el o w i m p utati o n r ules will be use d: 
If t h e d ate is c o m plet el y missi n g, n o i m p utati o n will be c o n d ucte d; 
If o nl y t he da y is missi n g, 1 5t h da y will be assi g ne d; 
If b ot h t he da y a n d t h e m o nt h are missi n g, t he n J ul y 1st will be assi g ne d. 
C hec k t hat t h e i m p ute d date is n ot s u peri or or e q u al t o t he i nf or me d c o nse nt date. 
5. 1. 3.  
Visit Wi n d o wi n g 
It is e x p ecte d t hat t h ere will be a variati o n bet w ee n patie nts i n t h e act u al n u m b er of st u d y da ys 
fr o m t he start of a d mi nistrati o n of st u d y dr u g wit hi n eac h c ycle d efi ne d as Da y 1, t o t he d ates 
t hat t he sc he d ule d visits o cc ur. T o h a n dle t his, f or ta bles a n d fi g ures w here data are gr o u pe d b y 
visit, assess me nts will be cate g oriz e d usi n g visit wi n d o ws base d o n st u d y da ys (relati ve t o t he 
Da y 1 of eac h c ycle). T h e visit- wi n d o w ma p pi n g is descri b e d i n Ta ble 1 0.  Visit- base d 
s u m maries will be base d o n t he wi n d o we d visits. All data, w het her or n ot wit hi n t he visit 
Descri be t he visit wi n d o wi n g practice f or t he 
a nal ysis of safet y a n d efficac y varia ble, it is rec o m me n de d t o kee p i n mi n d t he pri nci ple t hat 
t here are n o ga ps b et wee n t w o a djace nt visit wi n d o ws. 


 
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F or wi n d o w e d visits d uri n g t h e treat m e nt c ycles, if m ore t ha n o ne visit occ urs d uri n g a visit 
wi n d o w, t he visit cl osest t o t h e sc he d ule d da y will be assi g ne d t o t he wi n d o w e d visit. If t w o 
visits are e q ui dista nt fr o m t he s c he d ule d da y, t he later visit will be assi g ne d t o t he wi n d o we d 
visit. If t h ere are m ulti ple ass ess me nts o n t h e sa me da y, t he w orst case will b e use d.  
F or a p atie nt w h o pre m at urel y disc o nti n ues t he st u d y, t he pre mat ure visit will b e sl otte d 
acc or di n gl y. T h e wi n d o w f or e n d of treat m e nt visit will be "last d ose date of last c ycle + 4 da ys 
t o last d ose date of last c ycle + 1 0 da ys" a n d t he wi n d o w f or safet y f oll o w-
d ose date of last c y cle + 1 1 t o last d os e date of last c ycle + [ 3 0 da ys + 7 d a ys pr ot o c ol- defi n e d 
 






 
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5. 1. 4.  
A dj ust me nt of C o v ari ates 
N ot a p plica ble  
5. 2.  A n al ysis Met h o ds  
5. 2. 1.  
P atie nt Dis p ositi o n 
S u m mar y of st u d y dis p ositi o n will be pr o vi de d b y c o h ort as defi n e d i n Ta ble 9 f or t h e f oll o wi n g: 
N u m ber of patie nts w h o si g ne d t he i nf or me d c o ns e nt  
N u m ber of scree n fail ures 
Reas o n f or scree n fail ure 
N u m ber of patie nts w h o di d n ot recei v e st u d y treat m e nt 
N u m ber of patie nts w h o recei v e d st u d y treat me nt 
Patie nts still o n st u d y treat me nt, if a p plica ble  
Reas o n f or st u d y treat me nt disc o nti n uati o n 
N u m ber of patie nts g oi n g i nt o s ur vi val f oll o w- u p 
N u m ber a n d p erce nta ge of patie nts w h o disc o nti n ue t he st u d y 
Reas o n f or disc o nti n uati o n of t he st u d y  
A se parat e t a ble will be prese nte d t o s h o w t he patie nts i ncl u de d i n eac h a nal ysis set a n d s u m mar y 
reas o ns f or e xcl usi o n fr o m a n a nal ysis set.  
Patie nt dis p ositi o n a n d a nal ysis sets will be als o liste d. 
5. 2. 2.  
Pr ot oc ol D e vi ati o n 
Pr ot oc ol de viati o ns (i ncl u di n g C O VI D- 1 9 relat e d pr ot oc ol de viati o ns) will be s u m marize d 
descri pti vel y f or patie nts wit h at least o ne maj or pr ot oc ol de viati o n b y c o h ort. A patie nt ca n ha ve 
m ulti ple maj or a n d/ or mi n or de viati o ns a n d will be c o u nte d o nce per maj or a n d/ or mi n or de viati o n. 
T he pr ot o c ol de viati o n s u m mar y is base d o n t he s afet y a n al ysis set.  
I n a d diti o n, all pr ot oc ol de viati o ns i n cl u di n g de viati o ns t hat are relate d t o C O VI D- 1 9 will be 
pr o vi de d i n a b y- patie nt listi n g. 
5. 2. 3.  
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics 
T he f oll o wi n g de m o gra p hic a n d ot h er bas eli ne c haracteristics will b e s u m m arize d b y c o h ort as 
defi ne d i n  Ta ble 9  o n t h e safet y a nal ysis set:  
A ge ( years) at scree ni n g, a ge gr o u ps ( 1 8- 6 5, 
 6 5 years),  
Ge n d er, c hil d beari n g p ot e ntial (fe male o nl y) 
Race  
Et h nicit y  
Baseli ne hei g ht (c m)  
 
 


 
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Baseli ne wei g ht ( k g)  
Baseli ne B MI ( k g/ m 2) calc ulate d as baseli ne wei g ht ( k g)/ [ baseli ne hei g ht ( m)] 2, B MI 
2) 
Baseli ne E C O G stat us. 
5. 2. 4.  
Dise ase C h ar acteristi cs  
O nc ol o g y hist or y will be s u m marize d descri pti vel y b y c o h ort as defi n e d i n  Ta ble 9  f or t he safet y 
a nal ysis set f or t he f oll o wi n g: 
T y pe of ca ncer at first di a g n osis 
Ca ncer St a ge at First Dia g n osis ( Sta ge 1, Sta ge 2, Sta ge 3, Sta ge 4) 
Pri mar y T u m or L ocati o n at First Dia g n osis  
E C Hist ol o gical Cl assificati o n 
T N B C Hist ol o gical Classificati o n (I n vasi ve D uctal Carci n o ma, Ot her) 
N o n- T N B C/ N o n- E C Hist ol o gical Classificati o n 
Ti me si nce first dia g n osis ca ncer ( m o nt hs): it is calc ulate d as ( date of first st u d y treat me nt 
a d mi nistrati o n  date of first dia g n osis of disease + 1)/ 3 0. 4 3 7 5. 
Ti me si nce dia g n osis of metastatic disease ( m o nt hs): it is calc ulate d as ( dat e of first st u d y 
treat me nt a d mi nistrati o n  date of dia g n osis of metastasis disease + 1)/ 3 0. 4 3 7 5. 
Pri or o nc ol o g y treat m e nts ( pri or a nti-ca ncer me dicati o n, pri or a nti-ca ncer ra di ot hera p y, 
pri or a nti-ca n cer pr oce d ures)  
5. 2. 5.  
Me dic al Hist or y  
T he c o n diti o ns/ diseases fr o m me dical hist or y are t h ose c o n diti o ns/ dis eases t hat st o p pe d pri or t o 
t he st u d y e ntr y. Me di cal hist or y will be c o de d t o S O C a n d P T usi n g Me d D R A v ersi o n 2 5. 0 or 
hi g her. 
T he n u m ber a n d p erce nta ge of patie nts wit h a n y p ast me di cal/s ur gical hist or y wit hi n eac h S O C 
a n d P T will be pr o vi de d b y c o h ort o n t he safet y a nal ysis set.  
A pati e nt will o nl y be c o u nte d o nce wit hi n a partic ular S O C ( P T) e v e n if h e/s he has m ulti ple 
c o n diti o ns/ diseases i n t he sa me S O C ( P T).   
Eac h s u m m ar y will be or dere d b y des ce n di n g or der of i nci d e nce of S O C acc or di n g t o t otal 
c ol u m n a n d P T wit hi n eac h S O C. If t he fre q ue ncies tie, a n al p ha betic or der will be a p plie d.  
5. 2. 6.  
Pri or a n d S u bse q ue nt A nti- C a ncer T h er a p y 
Pri or a n d s u bse q u e nt a nti-ca ncer t h era p y, i n cl u di n g me di cati o n, ra di ot hera p y, a n d pr oce d ure or 
s ur ger y, will be s u m marize d descri pti vel y b y c o h ort a n d o verall f or t he safet y a nal ysis set. 


 
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5. 2. 6. 1.  
Pri or a n d S u bse q ue nt A nti- C a ncer Me dic ati o n 
Pri or a nti-ca n cer me di cati o ns are defi n e d as t h ose ta ke n b y t he patie nt pri or t o t he a d mi nistrati o n 
of st u d y dr u g. S u bse q ue nt a nti-ca ncer me dicati o ns are defi ne d as t h os e t a ke n b y t h e pati e nt after 
t he disc o nti n uati o n of t he st u d y dr u g.  
Pri or a n d s u bse q u e nt a nti-ca ncer m e di cati o ns will be c o de d t o A nat o mical T hera pe utic 
Classificati o n ( A T C) t hera pe uti c gr o u p (i.e., A T C Le vel 2) a n d P T usi n g t he W orl d Healt h 
Or ga nizati o n Dr u g Dicti o nar y ( W H O- D D) v ersi o n Mar 2 0 2 2 or later. 
T he pri or a nti-ca nc er me dicati o ns will be s u m m arize d b y pres e nti n g t he n u m ber a n d perce nt a ge 
of patie nts b y P T a n d A T C. Patie nts ta ki n g t he sa me m e dicati o n m ulti ple ti m es will o nl y be 
c o u nte d o nce f or t hat P T or A T C. E ac h s u m mar y will b e or dere d b y d esce n di n g or der of 
i nci de nce of A T C acc or di n g t o t ot al c ol u m n a n d P T wit hi n eac h A T C. If t h e fre q ue ncies tie, a n 
al p ha betic or d er will be a p plie d.   
Si milarl y, t he s u bse q u e nt a nti-ca ncer me dicati o ns will be s u m marize d. 
All pri or a n d s u bse q ue nt a nti-ca ncer me dicati o ns will be prese nte d i n pati e nt listi n g. 
5. 2. 6. 2.  
Pri or a n d S u bse q ue nt A nti- C a ncer R a di ot her a p y 
Pri or a nti-ca n cer ra di ot h era p y is defi n e d as t h ose ta ke n b y t he patie nt pri or t o t h e a d mi nistrati o n 
of st u d y dr u g.  
S u bse q ue nt a nti-ca n cer ra di ot hera p y is d efi n e d as t h ose ta ke n b y t he patie nt after t h e 
disc o nti n uati o n of t he st u d y dr u g.  
T he n u m ber a n d p erce nta ge of patie nts wit h at least o ne pri or a nti-ca ncer ra di ot hera p y will be 
s u m marize d.  
All pri or a n d s u bse q ue nt a nti-ca ncer ra di ot hera p y will be prese nte d i n p atie nt listi n g.  
5. 2. 6. 3.  
Pri or a n d S u bse q ue nt A nti- C a ncer P r oce d ure or S ur ger y 
Pri or a nti-ca n cer pr o ce d ure or s ur g er y are defi ne d as t h os e ta ke n b y t he p atie nt pri or t o t he 
a d mi nistrati o n of st u d y dr u g.  
S u bse q ue nt a nti-ca n cer pr oce d ures or s ur g er y are defi n e d as t h os e ta k e n b y t he pati e nt after t h e 
disc o nti n uati o n of t he st u d y dr u g.  
Pri or a n d s u bse q u e nt a nti-ca ncer pr o ce d ures or s ur ger y will be c o de d t o S O C a n d P T usi n g 
Me d D R A versi o n 2 5. 0 or hi g her. 
T he pri or a nti-ca ncer pr oce d ure or s ur g er y will be s u m m arize d b y prese nti n g t he n u m ber a n d 
perce nt a ge of p atie nts b y P T a n d S O C. Patie nts ta ki n g t he sa me me dicati o n m ulti ple ti mes will 
o nl y be c o u nte d o nce f or t hat P T or S O C.  
Eac h s u m m ar y will be or dere d b y des ce n di n g or der of i nci d e nce of S O C t o t otal c ol u m n a n d P T 
wit hi n eac h S O C. If t he fre q u e nci es ti e, a n al p h a betic or der will be a p plie d.  
Si milarl y, t he s u bse q u e nt a nti-ca ncer pr o ce d ure or s ur g er y will be s u m marize d.  


 
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All pri or a n d s u bse q ue nt a nti-ca ncer pr o ce d ures or s ur ger y will be prese nte d i n a patie nt listi n g. 
5. 2. 7.  
Pri or a n d C o nc o mit a nt Me dic ati o ns 
Pri or a n d c o nc o mita nt m e dicati o ns ( C Ms) will be c o de d t o A nat o mical T h era pe utic 
Classificati o n ( A T C) t hera pe uti c gr o u p (i.e. A T C Le vel 2) a n d P T usi n g t h e W H O- D D versi o n 
Mar 2 0 2 2 or hi g her. 
Me dicati o ns ta ke n pri or t o t he first d os e of st u d y treat me nt a n d c o nti n ui n g be y o n d t h e first d ose 
of st u d y treat me nt or t h ose me dicati o ns starte d o n or after t h e first d ose of st u d y treat m e nt b ut n o 
 
Me dicati o n wit h start dat e/ti m e bei n g partiall y or c o m pletel y missi n g will be ass u me d t o be 
c o nc o mita nt if it ca n n ot be d efi nitel y s h o w n t hat t he me dicati o n was n ot recei ve d d uri n g t he 
treat me nt peri o d. 
T he pri or me dicati o ns will be s u m marize d b y prese nti n g t he n u m ber a n d perce nta ge of patie nts 
b y P T a n d A T C. Patie nts ta ki n g t he sa me m e dicati o n m ulti ple ti m es will o nl y be c o u nte d o nce 
f or t h at P T or A T C. Eac h s u m mar y will be or dere d b y desce n di n g or der of i n ci de nce of A T C 
acc or di n g t o t otal c ol u m n a n d P T wit hi n eac h A T C. If t he fre q u e ncies tie, a n al p ha betic or der 
will b e a p plie d.  
Si milarl y, t he c o nc o mita nt me dicati o ns will be s u m marize d. 
All pri or a n d c o nc o mita nt me dicati o ns will be prese nte d i n patie nt listi n g.  
5. 2. 8.  
C o nc o mit a nt Pr oce d u re 
Me dical or s ur gical pr oce d ures t hat starte d after t he first d ose date b ut n o lat er t h a n 3 7 da ys after 
t he last d ose date 
 
C o nc o mita nt me dical or s ur gical pr oce d ures will be classifie d usi n g t h e M e d D R A versi o n 2 5. 0 or 
hi g her.  
T he c o nc o mita nt me dical or s ur gical pr oce d ures will be s u m marize d b y prese nti n g t h e n u m ber a n d 
perce nt a ge of pati e nts b y P T a n d S O C. Pati e nts ha vi n g t he sa me m e dical or s ur gical pr oce d ure 
m ulti ple ti mes will o nl y be c o u nte d o nce f or t hat P T or S O C. Eac h s u m mar y will be or dere d b y 
desce n di n g or der of i nci de nce of S O C a cc or di n g t o t ot al c ol u m n a n d P T wit hi n eac h S O C. If t h e 
fre q ue ncies tie, a n al p ha b eti c or der will be a p plie d.  
All c o nc o mita nt me dical or s ur gical pr o ce d ures will be prese nte d i n t he p atie nt listi n g. 
5. 2. 9.  
Effic ac y A n al yses 
T he safet y a nal ysis set will be use d f or all efficac y a nal ysis u nless ot her wise s pecifie d. N o 
f or mal h y p ot h esis testi n g is pla n ne d f or t his st u d y. T w o-si de d 9 5 % c o nfi de n ce i nter v als ( CIs) 
will b e calc ulate d i n t he a p pli ca ble s u m mar y, u nl ess ot h er wise s pecifie d. 


 
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5. 2. 9. 1.  
Pri m ar y Effic ac y A n al yses 
T he n u m ber a n d p erce nta ge of pati e nts i n eac h cate g or y of deri ve d B O R ( C R, P R, U nc o nfir me d 
C R, U nc o nfir me d P R, S D, P D, N E, or N A) will be s u m marize d f or t he safet y a nal ysis set. O R R 
a n d O R R U N C O N FI R M E D  will b e s u m m arize d b y c o h ort as defi n e d i n T a ble 9  .   
T he 9 5 % CIs of O R R a n d O R R U N C O N FI R M E D  will b e calc ulate d usi n g t he Cl o p per- Pears o n met h o d 
f or eac h c o h ort. 
T u m or e val uati o n data will be prese nte d i n listi n gs. 
5. 2. 9. 2.  
Sec o n d ar y Effic ac y A n al yses 
F or t he ti me t o e ve nt e n d p oi nts, s uc h as P F S, O S, a n d D o R, t he me dia n, 2 5 % a n d 7 5 % p erce ntile of 
ti me-t o-e ve nt will be esti mate d usi n g Ka pla n- Meier m et h o d wit h t heir c orres p o n di n g 9 5 % CI. F or P F S 
a n d O S, a d diti o nall y, esti mates will be pr o vi de d f or t h e s ur vi val pr o ba bilit y al o n g wit h t heir 9 5 % CIs 
w hic h are calc ulat e d usi n g li n ear tra nsf or mati o n ( Br o o k m e yer 1 9 8 2 
at selecte d la n d mar ks, f or e xa m ple, at 3, 6, 9, 1 2, a n d 1 8 m o nt hs. T he Ka pla n- Meier pl ots will be 
pr o d uce d f or P F S a n d O S. T he d urati o n of f oll o w- u p will be calc ulate d descri pti vel y usi n g t he Ka pla n-
Meier met h o d.  
I n or der t o assess d urati o n of f oll o w- u p f or P F S a n d O S, Ka pla n Meier esti mates will be calc ul ate d 
i n t h e sa me w a y as i n t heir a nal ysis, w hil e usi n g differe nt ce ns ori n g r ule w hi c h re verses ce ns ori n g 
i n dicat or i nstea d, i. e., patie nts w h o ha ve e ve nt will be ce ns ore d at t he d ate of e ve nt. Patie nts w h o 
are ce ns ore d will be assi g ne d as e v e nt
 
T he D C R a n d C B R will b e a nal yze d i n a si milar wa y as O R R descri be d i n Secti o n 5. 2. 9. 1 .  
5. 2. 9. 3.  
Se nsiti vit y A n al ysis f or Effic ac y E n d p oi nt 
A se nsiti vit y a nal ysis f or O R R, D C R, C B R a n d D o R will be c o n d u cte d usi n g t he res p o nse 
e val ua ble a nal ysis set. T he a nal ysis tec h ni q ues f oll o w t h ose descri be d i n Secti o n 5. 2. 9. 1 .  
5. 2. 1 0.  
E x p os ure of St u d y Tre at me nt 
E x p os ure of st u d y tr eat me nt descri b e d i n Secti o n 4. 3 ( d urati o n of e x p os ure, n u m b er of c ycles of 
treat me nt recei ve d, c u m ulati ve d ose, d ose i nte nsit y a n d relati ve d ose i nte nsit y f or e ac h st u d y dr u g,) 
will b e s u m m arize d b y c o h ort as defi ne d i n  T a ble 9 .   
N u m ber of c ycles recei ve d will be cat e g orize d as ( 1, 2, 3, 4, 5, 6, > 6, a n d t he n u m ber a n d 
perce nt a ge of p atie nts f or eac h cate g or y will be s u m marize d.  
T he f oll o wi n g s u m m ar y f or d ose m o dificati o n will b e s u m m arize d se p aratel y f or eac h dr u g 
(fr u q ui nti ni b a n d tisleliz u ma b) b y c o h ort. D ose re d ucti o n/i ncrease is n ot all o we d wit h tisleliz u ma b. 
 
N u m ber of p atie nts wit h a n y d ose m o dificati o n wit h fr u q ui nti ni b (i ncl u di n g b ot h dr u g 
i nterr u pti o n a n d d ose re d ucti o n, a n d fre q u e nc y of d ose m o dificati o n: 0, 1, 2, 3, 4, 5, 6, > 6 








 
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5. 2. 1 1. 5.  
E C G 
Descri pti ve statistics will be prese nt e d f or eac h E C G para meter f or t h e o bs er ve d val u es a n d 
c ha n ge fr o m baseli n e t o p ost baseli ne b y visit.  
A listi n g of all E C G data will be pr o vi de d.  
T he criteria f or p ote ntiall y cli nicall y si g nifica nt fi n di n gs are defi n e d i n Ta ble 7 . T he fre q ue nc y 
a n d perce nta ge of patie nts wit h a n y p ote ntiall y cli nicall y si g nifica nt fi n di n gs d uri n g t he 
treat me nt peri o d will be prese nte d. T h e s u p p orti ve data will be pr o vi d e d i n patie nt data listi n gs. 
5. 2. 1 1. 6.  
Vit al Si g ns 
F or vital si g n para meters ( S B P, D B P, h eart rate, te m perat ure, a n d wei g ht) t he o bser ve d v al ues 
a n d c ha n g e fr o m baseli ne will be s u m marize d usi n g descri pti ve statisti cs at eac h visit d uri n g t he 
treat me nt peri o d. 
A d diti o nall y, t he fre q u e nc y a n d p erce nta ge of patie nts wit h a n y p ote ntiall y cli nicall y si g nifi ca nt 
fi n di n gs ( defi ne d i n Ta bl e 8 ) d uri n g t he o verall treat me nt peri o d will be prese nte d. A listi n g of 
all vital si g n data will be pr o vi de d.  
M ore o v er, t h e mi ni m u m,  ma xi m u m, a n d t heir c orres p o n di n g c ha n g e fr o m baseli n e vit al si g n 
val ues will be s u m marize d descri pti v el y o verall treat m e nt peri o d. 
5. 2. 1 1. 7.  
Perf o r m a nce St at us 
T he fre q u e nc y a n d perce nta ge of patie nts f or eac h E C O G sc ore le v el will be s u m marize d b y 
visit. S hift i n gra de fr o m baseli ne t o t h e ma xi m u m p ost- baseli n e sc ore will be s u m marize d.  
A listi n g of E C O G sc ores f or all patie nts will be pr o vi de d. 
5. 2. 1 1. 8.  
Ec h oc ar di o gr a m 
Descri pti ve statistics f or E C H O/ M U G A will be s u m marize d b y visit. A b y- patie nt listi n g of 
E C H O/ M U G A v al ues at eac h ti m e p oi nt will be prese nte d. 
5. 2. 1 1. 9.  
P h ysic al E x a mi n ati o n 
A listi n g of p h ysical e xa mi n ati o n data f or all pati e nts will be pr o vi de d.   
5. 3.  S u b gr o u p A n al yses 
N ot a p plica ble. 
5. 4.  Ot her A n al yses 
5. 4. 1.  
P h ar m ac o ki n etic A n al ysis 
T he P K a nal ysis is use d f or listi n g a n d s u m maries of data s pecifie d i n t his secti o n. 


 
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5. 4. 1. 1.  
H a n dli n g of Missi n g D at a 
Missi n g c o nce ntrati o n data f or all patie nts w h o are a d mi nist ere d sc he d ul e d st u d y treat me nts is 
c o nsi dere d as n o n-i nf or mati v e missi n g a n d will n ot be i m p ute d. N o c o n ce ntr ati o n esti mates will 
be pr o vi de d f or missi n g sa m ple val ues. 
5. 4. 1. 2.  
H a n dli n g of D ose Re d ucti o n or I nterr u pti o n. 
A n y c o nce ntrati o n data ta ke n at or after t he ti m e of a d ose re d uce d or i nterr u pte d of fr u q ui nti ni b, 
or a d os e i nterr u pte d of tisleliz u ma b will be list e d wit h a fla g b ut e x cl u de d fr o m s u m m ar y statistics.  
5. 4. 1. 3.  
H a n dli n g of bel o w t he l o wer li mit of q u a ntific ati o n ( B L Q) D at a 
P K c o nce ntrati o n s u m mar y, t he f oll o wi n g r ules a p pl y: 
P K c o nce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n ( B L Q) will be set t o zer o. 
T he f oll o wi n g r ules will a p pl y f or listi n g a n d pres e nti n g i n di vi d ual P K data: 
All c o nce ntrati o ns are prese nte d i n ori gi nal u nits a n d t o t h e sa me deci m al place as 
re p orte d b y Bi oa nal ytical l a b, e. g., n g/ m L;  
Listi n g of P K s a m pli n g ti mes i ncl u di n g n o mi n al a n d act ual ti me ela pse d fr o m refere nce 
d ose wit h t he de vi ati o n fr o m t h e n o mi nal ti m e a n d meas ure d c o nce ntrati o ns of t he dr u g. 
If act u al ti m e is missi n g, ti me will be re p orte d as N R ( n ot rec or d e d) a n d act ual ti me will 
be re p ort e d as N C ( n ot calc ulate d). F or fr u q ui nti ni b, refere nce d ose will be t he 
fr u q ui nti ni b d ose o n t h e d a y of fr u q ui nti ni b P K sa m ple c oll ecti o n. F or tisleliz u ma b, 
refere nce d ose will be t h e tisleliz u ma b d ose d uri n g t he sa me c ycle of tisleliz u ma b P K 
sa m ple c ollecti o n or last tisleli z u ma b d ose f or E O T sa m ples. 
5. 4. 1. 4.  
S u m m ar y of P K c o nce ntr ati o n D at a 
C o nce ntrati o n d ata of fr u q ui nti ni b, 
meta b olite 
M 1 1, a n d tisleliz u ma b 
will be liste d a n d 
s u m marize d. Descri pti v e statisti cs will i ncl u de n u m ber of patie nts [ n], arit h metic mea n, sta n dar d 
de viati o n, c oefficie nt of variati o n [ C V %], me di a n, mi ni m u m, a n d ma xi m u m as a p pr o priate. 
T he c o n ve nti o ns pres e nte d i n Ta ble bel o w are use d f or t he pres e ntati o n of t he descri pti ve statisti cs 
of P K c o nce ntrati o ns. 
V ari a ble  
S u m m arize d wit h:  
Mi ni m u m, Ma xi m u m 
3 si g nifica nt di gits or as nee de d base d o n act ual 
meas ure d  val ues   
Mea n (arit h metic), Me dia n 
3 si g nifica nt di gits 
St d De v 
3 si g nifica nt di gits 
C V %  
 1 deci mal p oi nt 


 
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5. 4. 1. 5.  
H a n dli n g of t he Differe nce bet wee n t he Sc he d ule d ( n o mi n al ti me) a n d t he 
Act u al S a m pli n g Ti mes ( act u al ti me) 
F or all sa m pli n g ti m es, t he act ual s a m pli n g ti mes relati ve t o d osi n g will be calc ulate d as t he 
differe n ce bet w ee n t h e act ual cl oc k ti m e of sa m pli n g a n d t he act ual cl o c k ti me of d osi n g o n t he 
da y of P K visit. F or t h e visit w he n n o d ose a d mi nistrati o n is sc h e d ule d (e. g., n o tisleliz u ma b 
a d mi nistrati o n o n C 1 D 8 a n d C 1 D 1 5), t he act u al sa m pli n g ti mes will be calc ulate d as t h e differe nce 
bet wee n t h e act u al cl oc k ti me of sa m pli n g a n d t he act ual cl oc k ti m e of t he m ost rece nt d ose 
a d mi nistere d pri or t o t h e visit (e. g., C 1 D 1). If t he act ual ti me of s a m pli n g is missi n g, it will be 
re p orte d as N R ( n ot rec or de d) i n t he listi n g, t h e n o mi nal ti me will be use d f or s u m mar y st atisti cs. 
5. 4. 2.  
I m m u n o ge nicit y A n al ysis 
T he A nti dr u g A nti b o d y ( A D A) a nal ysis set are patie nts t hat ha ve o ne baseli n e A D A meas ure me nt 
a n d at least o ne p ost- b aseli ne A D A m eas ure me nt. 
T he i nci d e nces of p ositi v e A D As a n d n e utralizi n g A D As t o tisleliz u ma b will be re p orte d f or 
e val ua ble p ati e nts. W he n a vaila ble, titer will b e re p orte d. T he i m m u n o ge ni cit y res ults will be 
s u m marize d usi n g descri pti ve statistics b y t he n u m ber a n d perce nta ge of p atie nts w h o de vel o p 
detecta ble A D As t o tisleliz u ma b acc or di n g t o t he f oll o wi n g attri b utes a n d e n d p oi nts. 
A D A attri b utes: 
Tre at me nt- b o oste d A D A  is defi ne d as A D A p ositi ve at baseli n e t hat was b o oste d t o a 4- 
f ol d or hi g her-le v el f oll o wi n g dr u g a d mi nistrati o n.  
I n or der t o calc ulate f ol d c ha n ge, tit er 
val ue of 1. 
Tre at me nt-i n d uce d A D A  is defi ne d as A D A n e gati ve at baseli ne a n d A D A p ositi ve 
p ost- baseli n e. 
Tr a nsie nt A D A res p o nse  is defi ne d as treat me nt-i n d uce d A D A d etecte d o nl y at 1 ti me 
p oi nt d uri n g treat m e nt or f oll o w- u p, e xcl u di n g last ti m e p oi nt; or detecte d at 2 or m ore ti m e 
p oi nts d uri n g treat m e nt or f oll o w- u p, w here t h e first a n d last p ositi ve sa m ples are s e parate d 
b y less t ha n 1 6 wee ks a n d t he last ti me p oi nt is ne gati v e. 
Persiste nt A D A r es p o nse  is defi ne d as treat me nt-i n d uce d A D A d etecte d at 2 or m ore 
ti m e p oi nts d uri n g treat m e nt or f oll o w- u p, w h ere t he first a n d last A D A p ositi ve sa m pl es are 
se parat e d b y 1 6 wee ks or l o n ger; or detecte d o nl y i n t h e last ti me p oi nt. 
Ne utr alizi n g A D A  is defi ne d as A D A t hat i n hi bits or re d uces p har m ac ol o gi cal acti vit y. 
A D A res p o nse e n d p oi nts: 
A D A i n ci de nce (als o k n o w n as treat me nt-e mer g e nt A D A) is defi n e d as s u m of treat me nt-
i n d uce d a n d treat me nt- b o oste d A D A- p ositi ve patie nts as a pr o p orti o n of t h e A D A e val u a ble 
p o p ulati o n. 
A D A pre v ale nce is defi n e d as pr o p orti o n of all patie nts t hat are A D A p ositi ve, i n cl u di n g 
pre-e xisti n g A D A, at a n y ti me p oi nt. 
 


 
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T he f oll o wi n g r ules will a p pl y f or listi n g a n d pres e nti n g i n di vi d ual A D A data: 
All A D A res ults are pres e nt e d as re p orte d b y t he Bi oa nal yti cal la b, e. g., ne g ati v e or 
p ositi ve a n d titer val ue (if a p plica ble);  
Listi n g of A D A sa m pli n g ti m es i ncl u di n g n o mi nal a n d act ual ti me ela pse d fr o m 
tisleliz u ma b d ose wit h t he d e viati o n fr o m t he n o mi nal ti me a n d A D A res ults b y 
scree ni n g, c o nfir mat or y or titer (as a p pli ca ble). If act ual ti m e is missi n g, ti me will be 
re p orte d as N R ( n ot rec or de d) a n d act ual ti me will be re p ort e d as N C ( n ot calc ulate d). 
F or A D A, refere nce d os e will be t he tisleliz u ma b d ose d uri n g t he sa me c y cle of A D A 
sa m ple c ollecti o n or last tisleli z u ma b d ose f or E O T sa m ples. 
5. 4. 3.  
E x pl or at or y A n al yses 
Distri b uti o n of P D- L 1 e x pressi o n or M S S/ M SI stat us will be e xa mi n e d i n all patie nts. Ot h er 
p ote nti al pre dicti ve 
mar kers i n cl u di n g, b ut n ot li mite d t o, TI Ls, T M B, c yt o ki n e e x pressi o n, 
a n d ge ne si g nat ure pr ofili n g ma y be d etecte d a n d a nal yze d. 
E x pl orat or y bi o m ar ker a nal yses will be perf or me d i n a n eff ort t o u n dersta n d t h e ass ociati o n of 
t hese mar k ers wit h st u d y dr u g res p o nse, s uc h as efficac y a n d resista nce. 
T he bi o mar ker data a n d a nal ysis m a y be re p orte d se paratel y fr o m t he C S R. 


 
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6.  P L A N N E D A N A L Y SI S  
6. 1.  I n de pe n de nt S afet y D at a M o nit ori n g  
Safet y m o nit ori n g a n d e val uati o n of t he safet y lea d-i n ( Part 1) will be carrie d o ut b y t he Safet y 
Re vie w C o m mittee ( S R C). S afet y will be e val uate d t o deter mi ne or c o nfir m t he R P 2 D f or t h e 
c o m bi nati o n of fr u q ui nti ni b a n d tisleliz u ma b. 
After t h e R P 2 D has bee n deter mi ne d i n Part 1, t he S R C will c o nti n ue t o peri o dicall y re vie w 
t he c u m ulati ve safet y data d uri n g t h e c o n d uct of Part 2. 
6. 2.  I nteri m A n al ysis 
A n i nteri m a nal ysis fr o m Data base L oc k ( D B L) w as c o n d ucte d t o s u p p ort t h e safet y data re vie w 
a n d re g ul at or y i nteracti o n i n t he fr u q ui nti ni b ne w dr u g a p plicati o n ( N D A), t he data s na ps h ot was 
ta ke n o n 
 wit h data c ut off date o n 
. B y t he ti m e of t he sc he d ule d 
i nteri m a nal ysis, n o patie nts were e nr olle d i n t he Part 2, t heref ore, t he a nal ysis was carrie d o ut 
o nl y o n pati e nts fr o m Part 1. Ke y st u d y safet y data c ollecte d u p t hr o u g h t he ti me of defi ne d dat a 
c ut off were s u m marize d.  
6. 3.  Fi n al A n al ysis 
T he fi nal a n al ysis will b e c o n d ucte d after D B L f or t his st u d y. All st u d y data c ollecte d u p t hr o u g h 
t he ti me of t h e fi nal a nal ysis will be s u m mariz e d, u nless ot her wise s pecifie d.  
C CI
C CI


 
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7.  C H A N G E F R O M T H E P R O T O C O L 
A fe w n ote d c ha n g es fr o m t he pr ot o c ol are s u m m arize d as f oll o w: 
T he p har ma c o ki n etics a n al ysis set defi niti o n has b ee n u p date d c o m pare d t o t he pr ot o c ol 
as s o me patie nts ma y ha ve n o fr u q ui nti ni b sa m ples as t h e a p pr o priate bl o o d c ollecti o n 
t u bes were n ot a vaila ble.  H o w e ver, t he y will still ha ve tisleliz u ma b sa m ples. 
T h o u g h i n t he pr ot oc ol, it is state d t hat s u m mar y will o nl y be c o n d ucte d f or t hese c o h orts 
if t here are m ore t ha n 3 p atie nts e nr olle d a n d d ose d, i n t he act u al ta ble pr o d u cti o n, t he 
s u m mar y i nf or m ati o n will still be prese nte d f or a c o h ort re gar dl ess of t h e n u m ber of 
patie nts e nr oll e d f or t h e c o h ort. 
T he D L T- e val ua ble a nal ysis set defi niti o n i n t he pr ot oc ol is t o i ncl u de all patie nts 
e nr oll e d i nt o t he safet y lea d-i n p orti o n of t he st u d y  w h o meet at least o ne crit eria of (i) 
a n d (ii), a n d b ot h crit eria (iii) a n d (i v) as defi ne d as 
assess me nt wi n d o w; (ii) e x perie n ce d a D L T; (iii) di d n ot recei v e pr o p h ylactic s u p p orti ve 
care t h at c o nf o u n ds t he e val uati o n of D L Ts. T hat is, f or a patie nt, if t h ere is a rec or d i n 
c o nc o mita nt me di cati o n wit h cate g or y b ei n g ' P RI O R A N D C O N C O MI T A N T 
M E DI C A TI O N S', i n dicati o n bei n g ' P R O P H Y L A XI S', a n d t he me dicati o n is t a ke n wit hi n 
2 8 da ys (
 2 8) si nce t h e date of first st u d y dr u g a d mi nistr ati o n, t he n t he patie nt will be 
c o nsi dere d t o ha ve recei v e d pre ve nti ve treat me nt d uri n g t he D L T p eri o d; (i v) di d n ot ta ke 
a str o n g i n d ucer of e nz y me C Y P 3 A. H o we ver, t h ese criteria ha v e bee n i n c or p orate d i n 
t he S R C re vie w a n d it is ali g ne d wit h t h ose patie nts w h o t o o k at o ne d ose of st u d y dr u g 
fr u q ui nti ni b or tisleli z u ma b. T heref ore, t h e D L T-e val ua ble a nal ysis set will be base d o n 
t he decisi o n fr o m t he S R C re vie w a n d is defi ne d t o i ncl u de all pati e nts w h o t o o k at o ne 
d ose of st u d y dr u g fr u q ui nti ni b or tisleliz u ma b.  


 
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S A P Versi o n 2. 0  
 
C O N FI D E N TI A L  
Pa ge 5 5  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
 
 
R E F E R E N C E 
Allis o n 2 0 2 0 
Allis o n K H, H a m m o n d E H, D o wsett M, et al. Estr o ge n a n d pr o gester o ne rece pt or t esti n g i n 
breast ca ncer: A S C O/ C A P g ui deli ne u p date. J Cli n O nc ol. 2 0 2 0; 3 8: 1 3 4 6- 6 6. 
Br o o k me yer 1 9 8 2 
Br o o k me yer R., a n d Cr o wle y J. ( 1 9 8 2). A c o nfi de nce i nter val f or t he me dia n s ur vi val ti me. 
Bi o metrics, 2 9- 4 1. 
Eise n ha uer 2 0 0 9 
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: 
re vis e d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5: 2 2 8- 2 4 7.  
Ra k ha 2 0 1 4 
Ra k ha E A, St arcz y ns ki J, Lee A H S, Ellis I O. T he u p date d A S C O/ C A P g ui deli ne 
rec o m me n d ati o ns f or H E R 2 testi n g i n t he ma na ge me nt of i n vasi v e breast c a ncer: a criti cal 
re vie w of t h eir i m pli cati o ns f or r o uti ne practice. Hist o pat h ol o g y. 2 0 1 4; 6 4: 6 0 9 6 1 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






H U T C H M E D Li mit e d
St u d y Pr ot oc ol: 2 0 2 0- 0 1 3- 0 0 U S 3 
 
S A P Versi o n 2. 0  
 
C O N FI D E N TI A L  
Pa ge 5 8  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
A E =a d verse e ve nt; A L P =al k ali n e p h os p h atase; A L T =ala ni n e a mi n otra nsferase; a P T T = a cti v ate d p artial t hr o m b o plasti n ti me; A S T =as partate a mi n otra nsferase; C =c ycle; 
C K =creati n e ki nase; C K M B = creati n e ki n ase- M B; Cr Cl =creati ni n e cleara n ce;  D = da y; D N A = d e o x yri b o n u cleic aci d; E C G =electr o car di o gra m; E C H O =ec h ocar di o gra m; 
E C O G =easter n c o o perati ve o n c ol o g y gr o u p; e C R F =electr o nic case re p ort f or m; E O T =e n d of treat me nt; H B V = he patitis B vir us; H Bs A g = he patitis B s urface a nti g e n; 
H C V = he p atitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us; I C F =i nf or me d c o nse nt f or m; I N R =i nter nati o nal n or malize d rati o; I V =i ntra v e n o us; M SI = micr osatellite 
i nsta bilit y; M S S = micr osatellite sta bilit y sta ble; M U G A = m ulti g ate d ac q uisiti o n; P C R = p ol y merase c hai n reacti o n; P D = pr o gressi v e dis ease; P D- L 1 = pr o gra m me d d eat h-li ga n d 
1; P K = p h ar mac o ki n etics; P O = orall y; Q D = o n ce dail y; Q 3 W =e ver y 3 wee ks; Q 4 W = e ver y 4 wee ks; Q Tc F = Q T i nter v al c orrecte d b y t h e met h o d of Fre dericia; 
R N A =ri b o n u cleic aci d; R P 2 D =rec o m me n d e d p hase 2 d ose; S A E =seri o us a d v erse e ve nt; S O P =sta n dar d o perati n g pr oce d ure. 
a
Writt e n i nf or me d c o ns e nt m ust be o btai n e d bef ore a n y st u d y-relate d e xa mi n ati o ns or pr oce d ures are perf or me d.  H o we ver, b ef ore i nf or me d c o nse nt is o btai ne d, if t h e 
e xa mi n ati o ns f or sta n dar d treat m e nt are perf or me d wit hi n 2 8 d a ys bef ore t h e pl a n ne d C 1 D 1, t h e y ca n b e use d t o re place t he e x a mi n ati o ns d uri n g t he scree ni n g p eri o d wit h o ut 
re peati n g t he e xa mi n ati o ns, e x ce pt f or e xa mi n ati o ns t h at n ee d t o b e p erf or me d 7 d a ys bef ore t h e start of t h e st u d y dr u g a d mi nistrati o n.   
b
P D- L 1 e x pressi o n as d eter mi ne d l o call y, f or C o h orts A, B, a n d C.  T h e res ults s h o ul d be a v ail a ble i n t h e s o urce d oc u me nts a n d b e t h ose use d t o ma ke treat me nt d ecisi o ns f or 
t h e patie nt.  A re d acte d c o p y of t he l o cal res ults s h o ul d acc o m pa n y t h e arc hi v al t u m or s a m ples s u b mitte d as p art of t h e pr ot o c ol. 
c
M S S/ M SI stat us as deter mi n e d l ocall y, f or C o h orts C a n d D o nl y.  T he res ults s h o ul d be a vaila ble i n t h e s o urce d oc u me nts a n d b e t h ose use d t o ma ke treat me nt d ecisi o ns f or 
t h e patie nt.  A re d acte d c o p y of t he l o cal res ults s h o ul d acc o m pa n y t h e arc hi v al t u m or s a m ples s u b mitte d as p art of t h e pr ot o c ol. 
d
Me dical hist or y a n d diseas e hist or y data i ncl u d e si g nifica nt cli nic al disease or s y m pt o m, s ur gical hist or y, hist or y of mali g n a nc y (i ncl u di n g date of dia g n osis, classificati o n a n d 
pr o g n osis e v al uati o n of t he st u d y diseas e, a n d t h e treat me nt p erf or me d a n d t h e o utc o me; t h e t u m or s pecies a n d o ut c o mes of a n y ot h er pre vi o us mali g n a ncies), s m o ki n g 
hist or y, hist or y of alc o h ol c o ns u m pti o n, hist or y of dr u g a b use, a n d ot her me dic al-relate d hist or y.  
e
De m o gra p hic i nf or mati o n i ncl u des se x, race, a n d i n s o me c o u ntries, y ear of birt h. 
f
C o nc o mita nt me dicati o ns i ncl u d e a n y prescri pti o n a n d o ver-t h e-c o u nter me dicati o ns starte d after si g ni n g of I C F.  D uri n g t h e s cree ni n g peri o d, all dr u gs use d f or t h e patie nt 
wit hi n 2 8 da ys pri or t o t h e start of st u d y dr u g s h o ul d b e rec or de d.  I n s u bse q ue nt visits, t h e dr u gs use d i n t he p atie nt after t he last rec or d, as well as dr u gs 3 0 da ys after t he last 
d ose of st u d y dr u g(s), s h o ul d be rec or d e d i n e C R F.  S u bse q u e nt n e w a nti-t u m or treat me nt re gi m e ns d uri n g t h e Safet y a n d S ur vi val F oll o w- u p Peri o ds will als o b e rec or de d. 
g
A c o m pre h e nsi v e p h ysical e x a mi n ati o n i n cl u d es p atie nt hei g ht, wei g ht, a n d ge n eral c o n diti o n, as well as a n e xa mi n ati o n of t he h ea d, heart, c h est (i n cl u di n g t h e l u n gs), 
a b d o me n, e xtre mities, s ki n, l y m p h n o des, n er v o us s yste m, a n d a d diti o n al areas/s yste ms as cli nicall y i n dic ate d. 
h
Li mite d p h ysical e x a mi n ati o n i n cl u d es vit al si g ns a n d a n y c ha n ge fr o m b aseli n e; a n y n e w a b n or maliti es; e x a mi n ati o n of wei g ht, t h ora x, a b d o me n; a n d a d diti o nal 
areas/s yste ms as cli nicall y i n dicate d.  I n or der t o assess c h a n g es fr o m b aseli n e a n d t o e v al u ate f or ne w a b n or maliti es, t h e li mite d p h ysical e xa mi n ati o n s h o ul d assess f or ne w 
or c ha n g e d s ki n lesi o ns, e nlar ge d l y m p h n o d es, p al p a ble masses, a n d a p pr o priate e xa mi n ati o n t o a d dress a n y p atie nt-re p orte d s y m pt o ms. 
i
Assess me nts ca n b e perf or me d u p t o a n d i ncl u di n g C 1 D 1.  Details f or E C O G assess me nt ca n b e f o u n d i n Secti o n 6. 1. 1 1 of t he pr ot o c ol a n d f or vital si g n c oll ecti o n i n Secti o n 
6. 1. 1 2 of t he pr ot o c ol. 
j
He mat ol o g y i ncl u des re d bl o o d cell c o u nt, h e m o gl o bi n, h e mat o crit, a bs ol ute retic ul o c yte c o u nt, w hite bl o o d cell c o u nt a n d classificati o ns ( ne utr o p hils, l y m p h oc ytes, 
e osi n o p hils, m o n o c ytes, a n d b as o p hils), a n d platelet c o u nt.  If a b n or mal or pri miti v e i m mat ure cells are see n, t he y m ust als o b e rec or de d.  A n y a d diti o nal r o uti ne bl o o d tests 
d uri n g t h e st u d y s hall be arra n g e d b y t h e i n v esti gat or as n ee d e d.  
k
Bl o o d c he mistr y i n cl u des A L T, A S T, al k ali n e p h os p hatase ( A L P), bicar b o n ate, bilir u bi n/t otal bilir u bi n, lactic de h y dr o g e n ase, n o n-fasti n g t otal c h olester ol, tri gl y ceri d es, uric 
aci d, t otal pr otei n, al b u mi n, bl o o d urea nitr o ge n or urea, creati ni n e, Cr Cl rate, s o di u m, p otassi u m, ma g nesi u m, c hl ori de, c orrecte d calci u m (f or p atie nts wit h 
h y p o pr otei ne mia), p h os p h or us, bl o o d gl uc ose, creati n e p h os p h o ki nase, a n d creati n e ki n as e- M B ( C K- M B).  If C K- M B fracti o n ati o n is n ot a vaila ble, tr o p o ni n I a n d/ or tr o p o ni n 
T s h o ul d b e teste d i nstea d.  Ser u m tr o p o ni ns ma y b e s u bstit ute d per l o cal g ui d eli n es if us e d c o nsiste ntl y t hr o u g h o ut t h e st u d y.  If tisleliz u ma b h as bee n p er ma ne ntl y 
disc o nti n ue d, C K a n d C K- M B testi n g will b e d o ne as cli nicall y i n dicate d.  
l
Fasti n g li pi d p a nel i n cl u d es t otal c h olester ol, hi g h- d e nsit y li p o pr otei n, l o w- d e nsit y li p o pr otei n, a n d tri gl y ceri d es.  
m
C o a g ulati o n i n dicat ors i ncl u de pr ot hr o m bi n ti me, a P T T, a n d I N R. 
n
Fe male p ati e nts of c hil d b eari n g p ote ntial (i ncl u di n g t h ose w h o h a ve u n d er g o n e t u b al li g ati o n) m ust u n d er g o a ser u m pre g na n c y 
7 da ys b ef ore t he first d ose a n d rec or d a 
n e g ati v e res ult.  If ser u m pre g n a nc y test was dra w n wit hi n 7 2 h o urs of C 1 D 1, t h e n uri n e pre g na nc y test is n ot re q uire d o n C 1 D 1.  After e nr oll me nt, uri n e pre g na n c y test 
s h o ul d be c o n d ucte d o n Da y 1 of e v er y treat m e nt c ycle starti n g fr o m C y cle 1, a n d at t h e E O T visit.  A ser u m pre g n a nc y test s h o ul d b e p erf or me d at t h e Safet y F oll o w- u p 
Visit.  If t h e res ult of uri n e pre g na nc y testi n g is e q ui v o cal, a s er u m test s h o ul d be p erf or me d.  U nsc he d ule d testi n g via eit h er met h o d ca n be p erf or me d if t h ere is a n i n dicati o n, 
h o we ver, a n y e q ui v o cal uri n e pre g n a nc y tests s h o ul d b e re peate d via ser u m pre g n a nc y testi n g. 


H U T C H M E D Li mit e d
St u d y Pr ot oc ol: 2 0 2 0- 0 1 3- 0 0 U S 3 
 
S A P Versi o n 2. 0  
 
C O N FI D E N TI A L  
Pa ge 5 9  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
o 
T h yr oi d f u n cti o n tests i n cl u de ser u m free tri-i o d ot h yr o ni ne, s er u m free t h yr o xi n e, a n d t h yr oi d sti m ulati n g h or m o n e.  
p
Uri n al ysis i n cl u des uri n e p H, pr otei n, gl u c ose, bl o o d a n d k et o nes; micr osc o pic f or w hit e bl o o d cell a n d re d bl o o d cell c o u nt.  A 2 4- h o ur uri n e f or q u a ntitati v e pr otei n m ust be 
c ollecte d fr o m all p ati e nts wit h 1 + pr otei n uria. 
q
Testi n g will b e p erf or me d b y t h e l ocal la b orat or y at scree ni n g a n d will i ncl u d e H B V/ H C V ser ol o g y ( H Bs A g a n d H C V a nti b o d y) a n d viral l o a d assess me nt ( H B V D N A a n d 
H C V R N A), w hic h will be assesse d o nl y w h e n H Bs A g or H C V a nti b o d y is p ositi v e, res p ecti vel y.  A d diti o nall y, f or patie nts w h o h a ve d etecta ble H B V D N A at scree ni n g, t he 
res p ecti ve viral l o a d test will be perf or me d e v er y 4 c ycles starti n g at C y cle 5 (ie, Da y 1 of C ycles 5, 9, 1 3, etc) a n d at t h e E O T visit. 
r
E C G i n dicat ors i ncl u de P R i nter val, Q R S i nter v al, R R i nter v al, Q T/ Q Tc F i nter v al a n d h eart rate.  U nsc h e d ule d E C G or ot h er car diac e xa mi n ati o ns ca n be perf or me d if 
cli nicall y i n dicate d.  All E C Gs s h o ul d be d o ne pri or t o d osi n g of st u d y dr u gs. 
s  
If a patie nt dis c o nti n ues st u d y dr u g(s) d u e t o reas o ns ot h er t h a n P D or deat h, t u m or assess me nts s h o ul d c o nti n ue t o b e p erf or me d f oll o wi n g t h e s c he d ule d assess me nt pla n 
u ntil t he start of ne w a ntica ncer t hera p y, P D, d eat h, l ost t o f oll o w- u p, or wit h dra wal of c o nse nt.. 
t
Tisleliz u ma b 3 0 0 m g I V will b e a d mi nistere d o n Da y 1 of eac h 2 8- da y c ycle ( o n ce e ver y 4 wee ks).  E ver y 3 wee ks ( Q 3 W)  d osi n g of tisleliz u ma b ma y b e e x pl ore d d e pe n di n g 
o n t h e t olera bilit y of t h e Q 4 W d osi n g sc he d ule. 
u
After si g ni n g t h e i nf or me d c o nse nt f or m, all A Es i n cl u di n g S A Es re gar dless of attri b uti o n will be c ollecte d u ntil 3 0 da ys aft er t he last d ose of st u d y dr u g or i nitiati o n of a n e w 
treat me nt t h era p y, w hic he v er is earlier.  After t his peri o d, i n v esti gat ors s h o ul d re p ort o nl y S A Es t h at are c o nsi d ere d t o b e relate d t o t h e st u d y dr u g.  I m m u n e- me diate d A Es 
(seri o us or n o nseri o us) s h o ul d b e re p orte d u ntil 9 0 da ys after t he last d os e of tisleliz u ma b re gar dl ess of w h et h er or n ot t he patie nt starts a n e w a ntica n cer t h era p y.  
v
F oll o wi n g E O T, p atie nts will b e f oll o we d e ver y 8 wee ks ( ± 1 4 d a ys) via tele p h o n e or i n ma n ner t h at f oll o ws l ocal site S O Ps. 












H U T C H M E D Li mit e d 
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S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 6 5  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
A b n or mal ut eri n e blee di n g 
Hae m orr h a g e 
Petec hiae 
A b n or mal wit h dra wal blee di n g 
Hae m orr ha g e c or o n ar y arter y 
P h ar y n geal c o nt usi o n 
Ac he n b ac h s y n dr o me 
Hae m orr ha g e f oetal 
P h ar y n geal hae mat o ma 
Ac ute hae m orr ha gic le u k oe n ce p h alitis 
Hae m orr h a g e i n pre g na n c y 
P h ar y n geal hae m orr ha ge 
Ac ute hae m orr ha gic ulcerati ve c olitis 
Hae m orr ha ge i ntracra nial 
Pit uitar y a p o ple x y 
A d mi nistrati o n site br uise 
Hae m orr h a g e n e o n atal 
Pit uitar y hae m orr ha ge 
A d mi nistrati o n site h ae mat o ma 
Hae m orr h a ge s u b c uta ne o us 
Place nta prae via hae m orr ha ge 
A d mi nistrati o n site h ae m orr ha g e 
Hae m orr ha g e s u b e pi d er mal 
Plas mi n i n crease d 
A dre nal hae mat o ma 
Hae m orr ha g e uri n ar y tract 
P ol y me n orr ha gia 
A dre nal hae m orr ha ge 
Hae m orr h a gic a dre n al i nfarcti o n 
P ost a b orti o n h ae m orr h a g e 
A n al fiss ure hae m orr h a ge 
Hae m orr h a gic arteri o v e n o us malf or mati o n  
P ost pr oce d ural c o nt usi o n 
A n al hae m orr ha ge 
H ae m orr h a gic ascites 
P ost pr o ce d ural h ae mat o ma 
A n al ulcer hae m orr ha g e 
Hae m orr h a gic breast c yst 
P ost pr o ce d ural h ae mat uria 
A n ast o m otic hae m orr ha ge 
Hae m orr ha gic cere bellar i nfarcti o n 
P ost pr oce d ural hae m orr ha ge 
A n ast o m otic ul cer h ae m orr h a g e 
Hae m orr h a gic cere bral i nfar cti o n 
P ost tra nsf usi o n p ur p ura 
A n e ur ys m r u pt ure d 
Hae m orr ha gic c yst 
P ost-tra u matic p u nctate i ntrae pi d er mal 
h ae m orr ha ge 
A n gi n a b ull osa h ae m orr ha gica 
Hae m orr h a gic diat hesis 
P ost me n o p a usal hae m orr ha ge 
A n orectal varices hae m orr ha ge 
Hae m orr h a gic disease of n e w b or n 
P ost p art u m hae m orr ha ge 
A ntic oa g ula nt-relate d n e p hr o pat h y 
Hae m orr h a gic dis or d er 
Pre k alli krei n i ncrease d 
A nti platelet re v ers al t hera p y  
Hae m orr ha gic er osi v e g astritis  
Pre mat ure se p arati o n of place nta  
A ortic a ne ur ys m r u pt ure  
Hae m orr ha gic g astr o e nteritis  
Pr oce d ural h ae m orr h a ge  
A ortic dissecti o n r u pt ure  
Hae m orr ha gic h e patic c yst  
Pr octitis hae m orr ha gic  
A ortic i ntra m ural h ae mat o m a  
Hae m orr ha gic i nfarcti o n  
Pr ostatic h ae m orr h a ge  
A ortic p erf orati o n  
Hae m orr ha gic n ecr otic pa ncreatitis  
P ul m o n ar y al v e olar hae m orr ha ge  
A ortic r u pt ure  
Hae m orr ha gic o ccl usi v e reti n al v as c ulitis  
P ul m o n ar y c o nt usi o n  
A p o n e ur osis c o nt usi o n  
Hae m orr ha gic o varia n c yst  
P ul m o n ar y h ae mat o ma  
A p plicati o n site br uise  
Hae m orr ha gic str o k e  
P ul m o n ar y h ae m orr h a ge  
A p plicati o n site hae mat o ma  
Hae m orr ha gic t h yr oi d c yst  
P ul m o n ar y h ae m orr h a ge ne o natal  
A p plicati o n site hae m orr ha ge  
Hae m orr ha gic tra nsf or mati o n str o ke  
P u nct ure site br uise  
A p plicati o n site p ur p ura  
Hae m orr ha gic t u m o ur n ecr osis  
P u nct ure site hae mat o m a  
Arterial hae m orr ha g e  
Hae m orr ha gic urticaria  
P u nct ure site hae m orr h a ge  
Arterial i ntra m ural hae mat o ma  
Hae m orr ha gic v asc ulitis  
P ur p ura  
Arterial perf orati o n  
Hae m orr h oi d al hae m orr ha ge  
P ur p ura f ul mi n a ns  
Arterial r u pt ure  
Hae m ostasis  
P ur p ura ne o natal  
Arteri o ve n o us fist ula site h ae mat o m a  
Hae m ot h ora x  
P ur p ura n o n -t hr o m b o c yt o pe nic 
Arteri o ve n o us fist ula site h ae m orr ha ge  
Hea v y me nstr u al blee di n g  
P ur p ura se nil e  
Arteri o ve n o us graft site hae mat o ma  
He n o c h -Sc h o nlei n p ur p ura  
P uta me n hae m orr ha ge  


H U T C H M E D Li mit e d 
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S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 6 6  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
Arteri o ve n o us graft site hae m orr ha ge 
He patic arter y hae m orr ha g e 
Ra diati o n ass o ci ate d h ae m orr h a g e 
Astri n g e nt t h era p y 
He patic h ae ma n gi o ma r u pt ure 
Rectal h ae m orr ha ge 
Atrial r u pt ure 
He p atic h ae mat o ma 
Rectal ulcer h ae m orr h a ge 
A uric ular hae mat o ma 
He patic h ae m orr ha g e 
Re n al arter y perf orati o n 
Basal ga n glia h ae mat o ma 
Here ditar y hae m orr ha gic tela n giectasia 
Re n al c yst h ae m orr h a ge 
Basal ga n glia h ae m orr h a g e 
H y p erfi bri n ol ysis 
Re nal h ae mat o ma 
Basilar arter y perf orati o n 
H y per g a m ma gl o b uli n ae mic p ur p ura of 
Wal d e nstr o m 
Re n al h ae m orr h a ge 
Bla d d er ta m p o na d e 
H y p h ae ma 
Res pirat or y tract hae m orr ha ge 
Blee di n g varic ose v ei n 
Iliac arter y perf orati o n 
Res pirat or y tract hae m orr ha ge ne o n atal 
Bl o o d blister 
Iliac arter y r u pt ure 
Reti nal a ne ur ys m r u pt ure 
Bl o o d l oss a n ae mia 
Iliac vei n perf orati o n 
Reti n al h ae m orr ha ge 
Bl o o d uri ne 
I m m u n e t hr o m b o c yt o pe nia 
Reti n o p at h y hae m orr ha gic 
Bl o o d uri ne prese nt 
I m pla nt site br uisi n g 
Retr o p erit o neal hae mat o ma 
Bl o o d y disc h ar g e 
I m pla nt site hae mat o ma 
Retr o p erit o neal hae m orr ha g e 
Bl o o d y perit o neal effl u e nt 
I m pla nt site hae m orr ha ge 
Retr o place ntal h ae mat o ma 
B o ne c o nt usi o n 
I n cisi o n site hae mat o ma 
R u pt ure d cere bral a ne ur ys m 
B o ne marr o w hae m orr ha ge 
I ncisi o n site hae m orr h a g e 
Scleral hae mat o ma 
Brai n c o nt usi o n 
I ncrease d te n d e nc y t o br uise 
Scleral hae m orr h a ge 
Brai n ste m h ae mat o ma 
I n d u ce d a b orti o n h ae m orr ha g e 
Scr otal hae mat o c oele 
Brai n ste m h ae m orr ha ge  
I nferi or ve na ca va p erf orati o n 
Scr otal h ae mat o ma  
Brai n ste m micr o h ae m orr ha ge  
I nf usi o n sit e br uisi n g 
Scr otal h ae m orr h a g e  
Breast hae mat o m a  
I nf usi o n sit e h ae mat o ma 
S h oc k hae m orr ha gic  
Breast hae m orr ha ge  
I nf usi o n sit e h ae m orr ha g e 
S ki n h ae m orr h a ge  
Br oa d li g a m e nt h ae mat o ma  
I njecti o n site br uisi n g 
S ki n n e o pl as m blee di n g  
Br o n c hial hae m orr ha ge  
I njecti o n site hae mat o m a 
S ki n ulcer h ae m orr h a g e  
Br o n c hial varices h ae m orr ha ge  
I njecti o n site hae m orr h a ge 
S mall i ntesti n al hae m orr h a ge  
B ull o us h ae m orr h a gic d er mat osis  
I nstillati o n site br uise 
S mall i ntesti n al ulcer hae m orr h a g e  
B ursal h ae mat o ma  
I nstillati o n site hae mat o m a 
S oft tiss u e h ae m orr ha ge  
Car diac c o nt usi o n 
I nstillati o n site hae m orr h a ge 
S p er matic c or d hae m orr ha ge  
Car oti d a n e ur ys m r u pt ure  
I nter me nstr u al blee di n g 
S pi n al c or d hae mat o m a  
Car oti d arter y perf orati o n  
I nter n al hae m orr h a g e 
S pi n al c or d hae m orr h a ge  
Cat h eter site br uise  
I ntesti n al h ae mat o m a  
S pi n al e pi d ural h ae mat o m a  
Cat h eter site h ae mat o ma  
I ntesti n al hae m orr ha g e 
S pi n al e pi d ural h ae m orr h a ge  
Cat h eter site h ae m orr h a ge  
I ntesti n al vari ces hae m orr ha ge 
S pi n al s u bar ac h n oi d hae m orr ha ge  
Ce ntral n er v o us s yste m hae m orr h a g e  
I ntra-a b d o mi nal h ae mat o m a 
S pi n al s u b d ural hae mat o m a  
Ce p h al hae mat o ma  
I ntra-a b d o mi nal h ae m orr h a ge  
S pi n al s u b d ural hae m orr h a ge  
Cere bellar h ae mat o ma  
I ntracer e bral h ae mat o ma e vac u ati o n 
S plee n c o nt usi o n  


H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 6 7  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
Cere bellar h ae m orr ha ge 
I ntracra ni al h ae mat o ma 
S ple nic arter y p erf orati o n 
Cere bellar micr o hae m orr ha ge 
I ntracra ni al h ae m orr h a g e ne o natal 
S ple nic h ae mat o ma 
Cere bral a ne ur ys m perf orati o n 
I ntracra ni al t u m o ur h ae m orr ha g e 
S ple nic h ae m orr h a ge 
Cere bral a ne ur ys m r u pt ure d s y p hilitic 
I ntra oc ular hae mat o m a 
S ple nic v arices hae m orr ha g e 
Cere bral arteri o v e n o us malf or mati o n hae m orr h a gic 
I ntra p art u m h ae m orr ha ge 
S pli nter h ae m orr ha ges 
Cere bral arter y perf orati o n 
I ntrat u m o ural h ae mat o ma 
S p o nta ne o us hae mat o ma 
Cere bral c yst h ae m orr ha ge 
I ntra ve ntric ular h ae m orr ha g e 
S p o nta ne o us hae m orr ha ge 
Cere bral h ae mat o m a 
I ntra ve ntric ular hae m orr h a ge n e o natal 
St o m a site h ae m orr ha ge 
Cere bral h ae m orr ha g e 
Iris hae m orr ha ge 
St o matitis hae m orr h a gic 
Cere bral h ae m orr ha g e f o etal 
J oi nt micr o hae m orr h a g e 
S u barac h n oi d h ae mat o ma 
Cere bral h ae m orr ha g e ne o n atal 
J u g ular vei n hae m orr h a ge 
S u barac h n oi d h ae m orr h a g e 
Cere bral micr o h ae m orr ha g e 
Ki d n e y c o nt usi o n 
S u barac h n oi d h ae m orr ha ge ne o n atal 
Cer vi x h ae mat o m a uteri n e 
Lacri mal hae m orr ha g e 
S u bca ps ular he patic hae mat o m a 
Cer vi x h ae m orr h a ge uteri n e 
Lar ge i ntesti nal h ae m orr h a ge 
S u bca ps ular re n al hae mat o ma 
C h est wall hae mat o ma 
Lar ge i ntesti nal ulcer hae m orr ha g e 
S u bca ps ular s ple nic h ae mat o ma 
C h or oi d al h ae mat o ma 
Lar y n g eal hae mat o ma 
S u bc h ori o ni c h ae mat o ma 
C h or oi d al h ae m orr h a g e 
Lar y n geal h ae m orr ha ge 
S u b c h ori o ni c h ae m orr ha ge 
C hr o nic gastr oi ntesti nal blee di n g 
Li p hae mat o ma 
S u bcla via n art er y p erf orati o n 
C hr o nic pi g me nte d p ur p ura 
Li p h ae m orr ha g e 
S u bcla via n vei n perf orati o n 
Ciliar y b o d y hae m orr h a ge 
Li v er c o nt usi o n 
S u bc uta ne o us hae mat o ma 
C oital blee di n g  
L o wer g astr oi ntesti nal h ae m orr ha ge  
S u b d ural hae mat o ma  
C ol o nic h ae mat o ma  
L o wer li m b arter y perf orati o n  
S u b d ural hae mat o ma e v ac uati o n  
C o nj u ncti v al hae m orr h a ge  
L y m p h n o d e hae m orr ha ge  
S u b d ural hae m orr ha ge  
C o nt usi o n  
Mall or y -Weiss s y n dr o me  
S u b d ural hae m orr ha ge n e o n atal  
C or n eal blee di n g  
Me diasti n al hae mat o ma  
S u be n d o car dial h ae m orr h a ge  
C ulle n's si g n  
Me diasti n al hae m orr ha ge  
S u b g aleal h ae mat o m a  
C ystitis hae m orr ha gic  
Me dical d e vice site br uise  
S u b g aleal h ae m orr ha ge  
Dee p dissecti n g h ae mat o m a  
Me dical d e vice site h ae mat o ma  
S u breti n al hae mat o ma  
Diarr h o ea hae m orr h a gic  
Me dical d e vice site h ae m orr ha ge  
S u peri or v e n a ca va perf orati o n  
Disse mi n ate d i ntra vas c ular c oa g ulati o n  
Melae n a  
Testic ular h ae m orr ha g e  
Di v ertic ulitis i ntesti nal h ae m orr ha gic  
Melae n a n e o n atal  
T h ala m us h ae m orr h a ge  
Di v ertic ul u m i ntesti nal h ae m orr h a gic  
Me ni n g orr ha gia  
T hir d sta ge p ost part u m hae m orr ha ge  
D u o d e nal ulcer h ae m orr h a ge  
Me n o metr orr h a gia  
T h oracic hae m orr h a ge  
D u o d e nitis h ae m orr ha gic  
Mese nteric hae mat o ma  
T hr o m b oc yt o pe nic p ur p ura  
Ear hae m orr ha ge  
Mese nteric hae m orr ha g e  
T hr o m b o m o d uli n i n crease d  
Ecc h y m osis  
M o ut h h ae m orr ha g e  
T hr o m b oti c t hr o m b o c yt o pe nic p ur p ura  
E n ce p h alitis hae m orr ha gic  
M u c oc uta ne o us h ae m orr ha ge  
T h yr oi d hae m orr ha ge  
E nter oc olitis h ae m orr h a gic  
M u c osal hae m orr ha ge  
T o n g ue hae mat o m a  


H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 6 8  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
E pi d ural hae m orr ha ge 
M uscle c o nt usi o n 
T o n g ue hae m orr ha ge 
E pista xis 
M uscle h ae m orr ha ge 
T o nsillar hae m orr ha ge 
E xsa n g ui n ati o n 
M y o car dial hae m orr h a g e 
T o ot h p ul p h ae m orr h a g e 
E xtra-a xial hae m orr ha g e 
M y ocar dial r u pt ure 
T o ot h s oc ket h ae m orr ha ge 
E xtra d ural hae mat o m a 
Nae v us hae m orr h a ge 
Trac heal h ae m orr ha ge 
E xtra d ural hae mat o m a e vac uati o n 
Nail be d blee di n g 
Tra u m atic hae mat o ma 
E xtra vasati o n bl o o d 
Nasal se pt u m h ae mat o m a 
Tra u matic hae m orr ha ge 
E y e c o nt usi o n 
Ne o n atal g astr oi ntesti nal h ae m orr h a g e 
Tra u matic hae m ot h ora x 
E y e h ae mat o ma 
Ne p hritis h ae m orr ha gic 
Tra u matic i ntracra nial hae mat o ma 
E y e h ae m orr ha ge 
Ni p ple e x u date bl o o d y 
Tra u m atic i ntracra nial hae m orr h a g e 
E y eli d blee di n g 
Occ ult bl o o d p ositi ve 
T u m o ur hae m orr ha ge 
E y eli d c o nt usi o n 
O c ular retr o b ul bar hae m orr h a ge 
Ulcer h ae m orr ha g e 
E y eli d hae mat o ma 
Oes o p h a g eal h ae m orr h a g e 
U m bilical c or d hae m orr ha g e 
Fe m oral arter y perf orati o n 
Oes o p h a g eal i ntra m ural h ae mat o ma 
U m bilical h ae mat o ma 
Fe m oral vei n perf orati o n 
Oes o p h a g eal ulcer h ae m orr h a ge 
U m bilical hae m orr h a ge 
F o etal- mater nal hae m orr ha ge 
Oes o p h a geal v arices hae m orr ha g e 
U p per g astr oi ntesti nal hae m orr h a ge 
F ot h er gill si g n p ositi v e 
Oes o p h a gitis h ae m orr ha gic 
Ureteric hae m orr ha ge 
Gall bla d d er hae mat o ma 
O me ntal h ae m orr ha ge 
Uret hral hae m orr ha ge 
Gastric h ae m orr h a ge 
O ptic disc h ae m orr ha g e 
Uri n ar y bl a d d er h ae mat o m a 
Gastric o cc ult bl o o d p ositi v e 
O ptic n er ve s heat h hae m orr h a ge 
Uri n ar y bl a d d er h ae m orr ha ge 
Gastric ulcer hae m orr ha ge  
Oral bl o o d blister  
Uri n ar y occ ult bl o o d  
Gastric ulcer hae m orr ha ge, o bstr u cti v e  
Oral c o nt usi o n  
Uri n ar y occ ult bl o o d p ositi ve  
Gastric v arices hae m orr ha ge  
Oral m u c osa hae mat o ma  
Ur o g e nital h ae m orr ha ge  
Gastritis alc o h olic h ae m orr ha gic  
Oral p ur p ura  
Uteri ne h ae mat o ma  
Gastritis h ae m orr h a gic  
Or bital hae mat o ma  
Uteri ne h ae m orr h a ge  
Gastr o d u o de n al hae m orr ha ge  
Or bital hae m orr ha ge  
Vacci nati o n site br uisi n g  
Gastr oi ntesti n al a nast o m otic hae m orr h a g e  
Oste orr ha gia  
Vacci nati o n site hae mat o ma  
Gastr oi ntesti n al h ae m orr h a ge  
O v aria n h ae mat o m a  
Vacci nati o n site hae m orr h a ge  
Gastr oi ntesti n al p ol y p h ae m orr ha ge  
O v aria n h ae m orr ha ge  
Va gi n al hae mat o ma  
Gastr oi ntesti n al ulcer hae m orr h a ge  
Pal p a ble p ur p ura  
Va gi n al hae m orr h a ge  
Gastr oi ntesti n al v as c ular malf or mati o n 
h ae m orr ha gic  
Pa ncreatic h ae m orr ha g e  
Varic ose vei n r u pt ure d  
Ge nital c o nt usi o n  
Pa ncreatic pse u d o c yst h ae m orr ha ge  
Vasc ular access site br uisi n g  
Ge nital h ae m orr h a g e  
Pa ncreatitis h ae m orr ha gic  
Vasc ular access site h ae mat o ma  
Gi n gi v al blee di n g  
Pa pillar y m uscle h ae m orr ha ge  
Vasc ular access site hae m orr h a ge  
Graft hae m orr ha ge  
Para nasal si n us h ae mat o ma  
Vasc ular access site r u pt ure  
Gre y T ur ner's si g n  
Para nasal si n us h ae m orr ha g e  
Vasc ular a nast o m oti c hae m orr h a ge  
Hae ma n gi o ma r u pt ure  
Parat h yr oi d hae m orr ha ge  
Vasc ular graft hae m orr ha g e  






H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 7 1  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
Arterect o m y wit h graft re place me nt 
He p atic arter y t hr o m b osis 
Re n al e m b olis m 
Arterial a n gi o plast y 
He p atic i nfarcti o n 
Re n al i nfarct 
Arterial b y pass o p erati o n 
He patic v asc ular t hr o m b osis 
Re nal v asc ular t hr o m b osis 
Arterial graft 
He patic vei n e m b olis m 
Re nal v ei n e m b olis m 
Arterial occl usi ve disease 
H e patic v ei n occl usi o n 
Re nal v ei n occl usi o n 
Arterial re v as c ul arisati o n 
He p atic v ei n t hr o m b osis 
Re nal v ei n t hr o m b osis 
Arterial ste nt i nserti o n 
H o m a ns' si g n p ositi ve 
Re nal-li mite d t hr o m b otic micr oa n gi o pat h y 
Arterial t h er a p e uti c pr oce d ure 
H y p ot h e nar h a m mer s y n dr o me 
Reti nal arter y e m b olis m 
Arterial t hr o m b osis 
Iliac arter y e m b olis m 
Reti nal arter y occl usi o n 
Arteri o gra m a b n or mal 
Iliac arter y o ccl usi o n 
Reti nal arter y t hr o m b osis 
Arteri o gra m car oti d a b n or mal 
Iliac vei n occl usi o n 
Reti nal i nfarcti o n 
Arteri ot o m y 
I m pla nt site t hr o m b osis 
Reti n al v asc ular t hr o m b osis 
Arteri o ve n o us fist ula o ccl usi o n 
I ncisi o n site vessel o ccl usi o n 
Reti nal v ei n o ccl usi o n 
Arteri o ve n o us fist ula t hr o m b osis 
I nfarcti o n 
Reti nal v ei n t hr o m b osis 
Arteri o ve n o us graft t hr o m b osis 
I nferi or ve na ca v a s y n dr o me 
Re v asc ularisati o n pr o ce d ure 
Artificial bl o o d vessel o ccl usi o n 
I nferi or ve na ca val o ccl usi o n 
SI QIII TIII p atter n 
Ase ptic ca ver n o us si n us t hr o m b osis 
I nf usi o n sit e t hr o m b osis 
Se g me ntal arterial m e di ol ysis 
At h erect o m y 
I njecti o n site t hr o m b osis 
S h u nt occl usi o n 
At h er oscler otic pl a q ue r u pt ure 
I n n er ear i nfarcti o n 
S h u nt t hr o m b osis 
Atrial a p p e n da ge cl os ure 
I nstillati o n site t hr o m b osis 
Si g m oi d si n us t hr o m b osis 
Atrial a p p e n da ge resecti o n  
I nter n al ca ps ule i nfarcti o n 
Sile nt m y o car dial i nfarcti o n  
Atrial t hr o m b osis  
I ntesti n al i nfarcti o n 
S pi n al arter y e m b olis m  
A ut oi m m u ne h e pari n -i n d uce d t hr o m b o c yt o pe nia 
I ntra-a ortic ball o o n place me nt  
S pi n al arter y t hr o m b osis  
A xillar y vei n t hr o m b osis  
I ntracar di ac mass 
S pi n al c or d i nfarcti o n  
Basal ga n glia i nfarcti o n  
I ntracar di ac t hr o m b us 
S pi n al str o ke  
Basal ga n glia str o ke  
I ntra o perati v e cere bral arter y occl usi o n 
S ple nic arter y t hr o m b osis  
Basilar arter y occl usi o n  
Isc hae mic cere bral i nfarcti o n 
S ple nic e m b olis m  
Basilar arter y t hr o m b osis  
Isc hae mic str o k e 
S ple nic i nfarcti o n  
Bli n d n ess tra nsie nt  
J u g ular v ei n e m b olis m 
S ple nic t hr o m b osis  
B o ne i nfarcti o n  
J u g ular v ei n occl usi o n 
S ple nic v ei n occl usi o n  
Brac hi o ce p halic arter y occl usi o n  
J u g ular v ei n t hr o m b osis 
S ple nic v ei n t hr o m b osis  
Brac hi o ce p halic v ei n occl usi o n  
Lac u nar i nfarcti o n  
S p o nta n e o us he p ari n-i n d u ce d t hr o m b oc yt o pe nia 
s y n dr o me 
Brac hi o ce p halic v ei n t hr o m b osis  
La m bl's e xcresce n ces  
St o ma site t hr o m b osis 
Brai n ste m e m b olis m  
Left atrial a p p e n da ge cl os ure i m pla nt  
Stress car di o m y o p at h y  
Brai n ste m i nfarcti o n  
Leric he s y n dr o me  
Str o k e i n e v ol uti o n  
Brai n ste m str o k e  
Ma hler si g n  
Str o k ect o m y  
Brai n ste m t hr o m b osis  
Ma y -T h ur ner s y n dr o m e  
S u bcla via n arter y e m b olis m  


H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 7 2  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
B u d d- C hiari s y n dr o me 
Me dical d e vice site t hr o m b osis 
S u bcla via n art er y o ccl usi o n 
Ca ps ular war ni n g s y n dr o me 
Mese nteric arteri al occl usi o n 
S u bcla via n art er y t hr o m b osis 
Car diac v e ntric ul ar t hr o m b osis 
Mese nteric arteri oscler osis 
S u bcla via n vei n occl usi o n 
Car oti d a n gi o plast y 
Mese nteric arter y e m b olis m 
S u bcla via n vei n t hr o m b osis 
Car oti d arteri al e m b ol us 
Mese nteric arter y ste n osis 
S u perficial vei n t hr o m b osis 
Car oti d arter y b y pass 
Mese nteric arter y ste nt i nserti o n 
S u peri or sa gittal si n us t hr o m b osis 
Car oti d arter y occl usi o n 
Mese nteric arter y t hr o m b osis 
S u peri or ve na ca va occl usi o n 
Car oti d arter y ste nt i nserti o n 
Mese nteric v asc ular i ns ufficie n c y 
S u peri or v e n a ca va s y n dr o me 
Car oti d arter y t hr o m b osis 
Mese nteric vasc ular occl usi o n 
S ur gical v as c ul ar s h u nt 
Car oti d e n darterect o m y 
Mese nteric vei n t hr o m b osis 
Testic ular i nfarcti o n 
Cat h eter directe d t hr o m b ol ysis 
Mese nteric v e n o us o ccl usi o n 
T h ala mic i nfarcti o n 
Cat h eter site t hr o m b osis 
Meta b olic str o k e 
T hr o m bect o m y 
Cat h eterisati o n ve n o us 
Micr oe m b olis m 
T hr o m b oa n giitis o blitera ns 
Ca ver n o us si n us t hr o m b osis 
M o n o p aresis 
T hr o m b oe m b olect o m y 
Ce ntral v e n o us cat heterisati o n 
M o n o ple gia 
T hr o m b ol ysis 
Cere bellar arter y o ccl usi o n 
M uscle i nfarcti o n 
T hr o m b o p hle bitis 
Cere bellar arter y t hr o m b osis 
M y o car dial i nfarcti o n 
T hr o m b o p hle bitis mi gra ns 
Cere bellar e m b olis m 
M y ocar dial necr osis 
T hr o m b o p hle bitis ne o n atal 
Cere bellar i nfarcti o n 
O bstetrical p ul m o n ar y e m b olis m 
T hr o m b ose d v aric ose vei n 
Cere bral arter y e m b olis m 
O bstr ucti v e s h oc k 
T hr o m b osis 
Cere bral arter y occl usi o n  
O p ht h al mic art er y o ccl usi o n  
T hr o m b osis c or p ora ca v er n osa  
Cere bral arter y ste nt i nserti o n  
O p ht h al mic art er y t hr o m b osis  
T hr o m b osis i n d e vice  
Cere bral arter y t hr o m b osis 
O p ht h al mic v ei n t hr o m b osis  
T hr o m b osis mese nteric vessel  
Cere bral c o n gesti o n  
O ptic ner ve i nfarcti o n  
T hr o m b osis pr o p h yla xis  
Cere bral h y p o p erf usi o n  
O v aria n v ei n t hr o m b osis  
T hr o m b osis wit h t hr o m b oc yt o pe nia s y n dr o me  
Cere bral i nfarcti o n  
Pa get -Sc hr o etter s y n dr o me  
T hr o m b oti c cere bral i nfarcti o n  
Cere bral i nfarcti o n f o etal  
Pa ncreatic i nfarcti o n  
T hr o m b oti c micr oa n gi o pat h y  
Cere bral isc h ae mia  
Pa pillar y m uscle i nfarcti o n  
T hr o m b oti c str o k e  
Cere bral micr oe m b olis m  
Para d o xical e m b olis m  
T hr o m b oti c t hr o m b o c yt o pe nic p ur p ura  
Cere bral micr oi nfarcti o n  
Para ne o plastic t hr o m b osis  
T h yr oi d i nfarcti o n  
Cere bral se ptic i nfarct  
Para paresis  
Tra nsie nt isc h ae mi c attac k  
Cere bral t hr o m b osis  
Para ple gia  
Tra ns verse si n us t hr o m b osis  
Cere bral v as c ular o ccl usi o n  
Paresis  
Tr u nc us c o eliac us t hr o m b osis  
Cere bral v e n o us si n us t hr o m b osis  
Pel vic v e n o us t hr o m b osis  
T u m o ur e m b olis m  
Cere bral v e n o us t hr o m b osis  
Pe nile arter y o ccl usi o n  
T u m o ur t hr o m bect o m y  
Cere br os pi n al t hr o m b otic ta m p o n a de  
Pe nile v ei n t hr o m b osis 
T u m o ur t hr o m b osis  
Cere br o v as c ul ar acci de nt  
Perc uta ne o us c or o n ar y i nter ve nti o n  
Ultras o nic a n gi o gra m a b n or mal  
Cere br o v as c ul ar acci de nt pr o p h yla xis  
Peri p heral arterial o ccl usi v e disease  
Ultras o u n d D o p pler a b n or mal  


H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 7 3  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
Cere br o v as c ul ar dis or der 
Peri p h eral art erial re o ccl usi o n 
U m bilical c or d occl usi o n 
Cere br o v as c ul ar i ns ufficie n c y 
Peri p heral art er y a n gi o plast y 
U m bilical c or d t hr o m b osis 
Cere br o v as c ul ar o p erati o n 
Peri p heral art er y b y p ass 
Vacci nati o n site t hr o m b osis 
Cere br o v as c ul ar ste n osis 
Peri p heral arter y occl usi o n 
Vasc ular access site t hr o m b osis 
C h or oi d al i nfarcti o n 
Peri p h eral art er y ste nt i nserti o n 
Vasc ular de vice occl usi o n 
C o eliac arter y occl usi o n 
Peri p h eral art er y s ur g er y 
Vasc ular graft 
C ollateral circ ulati o n 
Peri p heral arter y t hr o m b osis 
Vasc ular graft occl usi o n 
C o m pressi o n g ar me nt a p plicati o n 
Peri p heral e m b olis m 
Vasc ular graft t hr o m b osis 
C or o nar y a n gi o plast y 
Peri p heral e n d arterect o m y 
Vasc ular o perati o n 
C or o nar y arterial ste nt i nserti o n 
Peri p heral re v asc ularisati o n 
Vasc ular pse u d oa ne ur ys m t hr o m b osis 
C or o nar y arter y b y pass 
Peri p h eral vei n o ccl usi o n 
Vasc ular ste nt i nserti o n 
C or o nar y arter y e m b olis m 
Peri p h eral vei n t hr o m b osis 
V asc ular ste nt o ccl usi o n 
C or o nar y arter y occl usi o n 
Peri p h eral vei n t hr o m b us e xte nsi o n 
V asc ular ste nt t hr o m b osis 
C or o nar y arter y re occl usi o n 
P hle bect o m y 
Vas o dilati o n pr oce d ure 
C or o nar y arter y s ur ger y 
Pit uitar y i nfarcti o n 
Ve n a ca va e m b olis m 
C or o nar y arter y t hr o m b osis 
Place ntal i nfarcti o n 
Ve na ca va filter i nserti o n 
C or o nar y b y p ass t hr o m b osis 
P n e u matic c o m pressi o n t h era p y 
Ve n a ca va filter re m o val 
C or o nar y e n d arterect o m y 
P o pliteal arter y e ntra p me nt s y n dr o m e 
Ve na ca va t hr o m b osis 
C or o nar y re vasc ularisati o n 
P ortal s h u nt pr o ce d ure 
V e n o gra m a b n or mal 
C or o nar y vasc ular graft occl usi o n 
P ortal vei n ca ver n o us tra nsf or mati o n 
Ve n o o ccl usi v e disease 
Dee p vei n t hr o m b osis  
P ortal vei n e m b olis m  
Ve n o occl usi v e li ver disease  
Dee p vei n t hr o m b osis p ost o perati v e  
P ortal vei n occl usi o n  
Ve n o us a n gi o pl ast y  
De vice e m b olisati o n  
P ortal vei n t hr o m b osis  
Ve n o us o ccl usi o n  
De vice o ccl usi o n  
P ort os ple n o mes e nteric ve n o us t hr o m b osis  
Ve n o us o perati o n  
De vice relate d t hr o m b osis  
P ost pr oce d ural m y o car dial i nfarcti o n  
Ve n o us rec a n alisati o n  
Di ple gia  
P ost pr oce d ural p ul m o nar y e m b olis m  
Ve n o us re pair 
Directi o n al D o p pler fl o w tests a b n or mal  
P ost pr oce d ural str o k e  
Ve n o us ste nt i nserti o n  
Disse mi n ate d i ntra vas c ular c oa g ulati o n  
P ost t hr o m b oti c s y n dr o m e  
Ve n o us t hr o m b osis  
Disse mi n ate d i ntra vas c ular c oa g ulati o n i n ne w b or n  
P osti nfarcti o n a n gi n a  
Ve n o us t hr o m b osis i n pre g na nc y  
E m b olia c utis me dica me nt osa  
P ost o perati v e t hr o m b osis  
Ve n o us t hr o m b osis li m b  
E m b olic cere bellar i nfarcti o n  
P ost p art u m t hr o m b osis  
Ve n o us t hr o m b osis ne o natal  
E m b olic cere bral i nfarcti o n  
P ost p art u m v e n o us t hr o m b osis  
Verte bral arter y o ccl usi o n  
E m b olic p n e u m o nia  
Precere bral arter y e m b olis m  
Verte bral arter y t hr o m b osis  
E m b olic str o k e  
Precere bral arter y o ccl usi o n  
Vessel p u n ct ure site o ccl usi o n  
E m b olis m  
Precere bral arter y t hr o m b osis  
Vessel p u n ct ure site t hr o m b osis 
E m b olis m arterial  
Pr of u n d a plast y  
Visceral v e n o us t hr o m b osis  
 
Vis u al ac uit y re d u ce d tra nsie ntl y  
 
Vis u al mi dli n e s hift s y n dr o me  




H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 7 5  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
Biliar y cirr h osis 
He patic fi br osis 
Ma g n etic res o n a n ce pr ot o n de nsit y fat fracti o n 
meas ure me nt 
Biliar y fi br osis 
He p atic f u n cti o n a b n or mal 
Mit o c h o n dri al as partate a mi n otra nsferas e 
i ncrease d 
Bilir u bi n c o nj u gate d a b n or mal 
He patic h ae ma n gi o m a r u pt ure 
Mi xe d he pat o cell ular c h ola n gi o carci n o ma 
Bilir u bi n c o nj u gate d i ncrease d 
He p atic h a mart o ma 
Mi xe d li v er i nj ur y 
Bilir u bi n e xcreti o n dis or d er 
He patic h y dr ot h ora x 
M olar rati o of t otal bra n c h e d-c hai n a mi n o aci d 
t o t yr osi ne 
Bilir u bi n uri ne prese nt 
He p atic h y p ertr o p h y 
N o d ular re ge n erati v e h y p er plasia 
Bi o ps y li v er a b n or mal 
He p atic h y p o p erf usi o n 
N o n-alc o h olic fatt y li ver 
Bl o o d bilir u bi n a b n or mal 
He patic i nfiltrati o n e osi n o p hilic 
N o n-alc o h olic steat o he patitis 
Bl o o d bilir u bi n i ncrease d 
He patic lesi o n 
N o n-cirr h otic p ortal h y perte nsi o n 
Bl o o d bilir u bi n u n c o nj u gate d i n crease d 
He patic li p o ma 
Oc ular icter us 
Bl o o d fi bri n o ge n a b n or mal 
He patic mass 
O e de ma d ue t o h e patic disease 
Bl o o d fi bri n o ge n decrease d 
He patic n ecr osis 
Oes o p h a geal v arices h ae m orr ha g e 
Bl o o d t hr o m bi n a b n or mal 
He patic n e o plas m 
O me ntal o e de m a 
Bl o o d t hr o m bi n d ecrease d 
He p atic n e ur o e n d ocri n e t u m o ur 
Pare nteral n utriti o n ass o ciate d li v er disease 
Bl o o d t hr o m b o plasti n a b n or mal 
He patic p ai n 
Peri h e patic disc o mf ort 
Bl o o d t hr o m b o plasti n d ecrease d 
He p atic sarc o m a 
Peri pa ncreatic varices 
Br o m os ul p ht halei n test a b n or mal 
H e patic se q uestrati o n 
P ortal fi br osis 
Car di o he patic s y n dr o me  
He patic steat o -fi br osis 
P ortal h y perte nsi o n  
C hil d -P u g h -T urc otte sc ore a b n or mal  
He patic steat osis  
P ortal h y perte nsi v e c ol o pat h y  
C hil d -P u g h -T urc otte sc ore i n crease d  
He patic v asc ular resista nce i n crease d  
P ortal h y perte nsi v e e nter o pat h y  
C h olae mia  
He patic v e n o us press ure gra die nt a b n or mal  
P ortal h y perte nsi v e g astr o p at h y  
C h ola n gi osarc o ma  
He patic v e n o us press ure gra die nt i n crease d  
P ortal vei n ca ver n o us tra nsf or mati o n  
C h olestasis  
He patitis  
P ortal vei n dil atati o n  
C h olestatic li ver i nj ur y  
He patitis ac ute  
P ort o p ul m o nar y h y p erte nsi o n  
C h olestatic pr urit us  
He patitis c h olestatic  
Pri mar y biliar y c h ola n gitis  
C hr o nic graft vers us h ost disease i n li ver  
He patitis c hr o nic acti ve  
Pr otei n C d ecrease d  
C hr o nic he patic fail ure  
He patitis c hr o nic p ersiste nt  
Pr otei n S a b n or mal 
C hr o nic he patitis  
He patitis f ul mi na nt  
Pr otei n S d ecreas e d  
C o a g ulati o n fact or I X le v el a b n or mal  
He patitis t o xic  
Pr ot hr o m bi n le vel a b n or mal  
C o a g ulati o n fact or I X le v el d ecrease d  
He pat o biliar y ca n cer  
Pr ot hr o m bi n le vel decrease d  
C o a g ulati o n fact or V le vel a b n or mal  
He pat o biliar y ca n cer i n sit u  
Pr ot hr o m bi n ti me a b n or mal  
C o a g ulati o n fact or V le vel d ecrease d  
He pat o biliar y c yst  
Pr ot hr o m bi n ti me pr ol o n ge d  
C o a g ulati o n fact or VII le vel a b n or mal  
He pat o biliar y disease  
Pr ot hr o m bi n ti me rati o a b n or mal  
C o a g ulati o n fact or VII le vel decrease d  
He pat o biliar y ne o plas m  
Pr ot hr o m bi n ti me rati o i ncrease d  
C o a g ulati o n fact or X le vel a b n or mal  
He pat o biliar y sca n a b n or mal  
Ra diati o n he p atitis  






H U T C H M E D Li mit e d 
St u d y Pr ot oc ol: 2 0 2 0 -0 1 3 -0 0 U S 3
 
S A P Versi o n 2. 0
 
C O N FI D E N TI A L  
Pa ge 7 8  of 7 9  
Date: 2 9  J ul y 2 0 2 4 
 
 
A p pe n di x 5 : Me d D R A ( Versi o n 2 5. 0) Preferre d Ter m List f or C O VI D- 1 9 Rel ate d A E  
As y m pt o mati c C O VI D- 1 9 
Occ u pati o nal e x p os ure t o S A R S- C o V- 2 
Brea kt hr o u g h C O VI D- 1 9 
P ost-ac ute C O VI D- 1 9 s y n dr o me 
C o n ge nital C O VI D- 1 9 
S A R S- C o V- 2 a nti b o d y test p ositi ve 
C or o na vir us i nfecti o n 
S A R S- C o V- 2 carrier 
C or o na vir us p ne u m o nia 
S A R S- C o V- 2 R N A decrease d 
C or o na vir us test p ositi ve 
S A R S- C o V- 2 R N A fl uct uati o n 
C O VI D- 1 9 
S A R S- C o V- 2 R N A i ncrease d 
C O VI D- 1 9 i m m u nisati o n 
S A R S- C o V- 2 s e psis 
C O VI D- 1 9 p ne u m o nia 
S A R S- C o V- 2 test false ne gati ve 
C O VI D- 1 9 pr o p h yla xis 
S A R S- C o V- 2 t est p ositi ve 
C O VI D- 1 9 treat me nt 
S A R S- C o V- 2 virae mi a 
E x p os ure t o S A R S- C o V- 2 
S us pecte d C O VI D- 1 9 
M ultis yste m i nfla m mat or y s y n dr o me 
T hr o m b osis wit h t hr o m b oc yt o pe nia s y n dr o me 
M ultis yste m i nfla m mat or y s y n dr o me i n a d ults  
Vacci ne deri ve d S A R S- C o V- 2 i nfecti o n 
M ultis yste m i nfla m mat or y s y n dr o me i n c hil dre n