Clinical trial NCT04579757
Conditions: Metastatic Solid Tumor Colorectal Cancer Neuroendocrine Tumors Small Cell Lung Cancer Gastric Cancer Soft Tissue Sarcoma Anaplastic Thyroid Cancer
Keywords: VEGF PD-1
Sponsor: Hutchmed
Start date: 2021-03-05; Completion date: 2024-08-27
Enrollment: 87 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2).

Detailed description:
This open-label, phase Ib/II study of surufatinib in combination with tislelizumab will evaluate the safety, tolerability, PK and efficacy in patients with advanced solid tumors. The study consists of 2 parts - dose finding (Part 1) and dose expansion (Part 2).

Part 1 will be conducted to determine the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab in patients with advanced or metastatic solid tumors who have progressed on, or are intolerant to standard therapies.

Part 2 will be an open-label, multi-cohort design to evaluate the anti-tumor activity of surufatinib in combination with tislelizumab in patients with specific types of advanced or metastatic solid tumors. Patients will receive the RP2D determined in part 1 of this study.

Arms: arm 1: In Part 1 (dose escalation), surufatinib and will be administered orally (PO) once daily (QD) and tislelizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). arm 2: In Part 2, the indication-specific expansion portion of the study, patients will receive surufatinib at the Recommended Phase 2 Dose (RP2D) dose selected in Part 1 with 200 mg tislelizumab IV, Q3W
Interventions: intervention 1: Surufatinib and Tislelizumab _ Part 1 intervention 2: Surufatinib and Tislelizumab _ Part 2
Intervention descriptions: intervention 1: Part 1 (all cohorts): oral surufatinib at a dose based on cohort level and intravenous tislelizumab at a 200-mg dose intervention 2: Part 2 (all cohorts): oral surufatinib at the RP2D dose selected in Part 1 and intravenous tislelizumab at a 200-mg dose

Protocol documents:
Prot_000.pdf: 
Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa 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 pe n -L a bel P h ase I b /II St u d y of S ur uf ati ni b i n C o m bi n ati o n 
wit h Tisleliz u m a b i n S u bjects  W it h A d v a nce d S oli d T u m ors 
 
S h ort Title  
S ur ufati ni b i n C o m bi nati o n W it 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): 
S ur ufati ni b ( H M P L -0 1 2)  
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 2 -G L O B 1  
Cli nic al P h ase:  
1 b /2  
A me n d me nt:  
5  
S p o ns or:  
H U T C H M E D  Li mite d  
N O. 4, La ne 7 2 0, Cail u n R oa d  
C hi na ( S ha n g hai) Pil ot Free Tra de Z o n e  
S ha n g hai, C hi na 2 0 1 2 0 3  
Re g ul at or y A ge nc y I de ntifier 
N u m ber(s):  
 
E u dra C T n u m ber 2 0 2 0 -0 0 4 1 6 3 -1 2  
D ate  of Iss ue : 
2 9  N o ve m ber  2 0 2 3  
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 prietar 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 fe deral, state, or l ocal la ws or 
re g ulati o n, ma y n ot be discl ose d t o a n y o ne ot her t ha n desi g nees of H U T C H M E D  Li mite d f or 
t he c o n d uct of t he st u d y wit h o ut pri or writte n per missi o n of H U T C H M E D Li mite d.  
 
C CI


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STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with this clinical study protocol, Good Clinical Practice 
(GCP) as outlined by the International Council for Harmonisation (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 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa 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 bel P hase I b /II St u d y of S ur ufati ni b i n C o m bi nati o n wit h 
Tisleliz u ma b i n S u bjects  W it 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 2 -G L O B 1  
A m e n d m e nt  
5  
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 h e 
S p o ns or’s res p o nsi ble pers o n nel as i n dicate d i n t h e si g nat ure ta ble b el o w.  
N a m e:  [last na me, first n a me] 
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 m m Y Y Y Y]  
 
P P D
P P D


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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2020-012-GLOB1 
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 GCP 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: 
 
 
 


Clinical Study Protocol 2020-012-GLOB1 
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DOCUMENT HISTORY  
Amendment 
Date of Issue 
Original 
30 September 2020 
1 
19 March 2021 
2 
10 October 2021 
3 
16 March 2022 
4 
30 November 2022 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 6  
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 2 -G L O B 1  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 2 -G L O B 1 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 me 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 t he ter mi nati o n of t his st u d y 
base d o n t he strate gic ree val uati o n of t he cli nical de vel o p me nt of s ur ufati ni b i n t he U nite d States 
a n d E ur o pe.  T his c ha 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 
s ur ufati ni b a n d/ or tisleliz u ma b treat me nt.  
 
  T he st u d y will be ter mi nate d eit her 9 0 d a ys aft er 
t he last patie nt has recei v e d tisleliz u ma b, or t he p oi nt at w hic h all i m m u ne-me diate d a d verse e v e nts 
(i m A Es) ha ve res ol ve d or are n o l o n g er bei n g f oll o we d , w hic he v er o cc urs  earlier. 
T he maj or c ha n g es i nc 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.   
Details of c ha n g es ma de i n pri or a me n d me nts are s u m marize d i n  A p pe n di x 1 1 . 
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. 
S y n o psis, Secti o n 1. 2 –  
Sc he d ule of E ve nts, Ta ble 1;  
Secti o n 4. 1. 3  –  Part 2 ( D ose 
E x pa nsi o n); Secti o n 5. 1 –  
Recr uit me nt; Secti o n 6. 1. 1 8  –  
Treat me nt  Peri o d ; Secti o n 
6. 1. 2 0 –  Efficac y F oll o w -u p 
Peri o d; Secti o n 6. 1. 2 1 S ur vi val 
F oll o w -u p Peri o d; Secti o n 
6. 2. 1. 1 –  Per ma n e nt 
Disc o nti n uati o n of Treat me nt; 
Secti o n 6. 3 –  St u d y 
Ter mi nati o n.  
La n g ua g e 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 T reat 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. 
S y n o psis, Secti o n 1. 2 –  
Sc he d ule of E ve nts, Ta ble 2 ; 
Secti o n 6. 1. 1 6 . 1 –  Sa m ple 
C ollecti o n a n d Ha n dli n g   
La n g ua g e was a d de d t o i n dicate 
ter mi nati o n of p har mac o ki netic ( P K ) 
sa m ples after C ycle 1 7.  
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.  
 
 
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
AMENDMENT SUMMARY ........................................................................................................ 6 
TABLE OF CONTENTS ............................................................................................................... 7 
LIST OF TABLES ....................................................................................................................... 12 
LIST OF FIGURES ..................................................................................................................... 13 
LIST OF APPENDICES .............................................................................................................. 13 
LIST OF ABBREVIATIONS ...................................................................................................... 15 
1 
SYNOPSIS ....................................................................................................................... 18 
1.1 
Study Schematic............................................................................................................ 21 
1.2 
Schedule of Events ........................................................................................................ 21 
2 
INTRODUCTION ........................................................................................................... 26 
2.1 
Study Rationale ............................................................................................................. 26 
2.2 
Background ................................................................................................................... 27 
2.2.1 
Target Indication and Population ............................................................................... 27 
2.2.1.1 
Colorectal Cancer.................................................................................................... 27 
2.2.1.2 
Neuroendocrine Tumors ......................................................................................... 27 
2.2.1.3 
Small-Cell Lung Cancer ......................................................................................... 28 
2.2.1.4 
Gastric Adenocarcinoma ......................................................................................... 29 
2.2.1.5 
Soft Tissue Sarcoma ............................................................................................... 29 
2.2.1.6 
Anaplastic Thyroid Cancer ..................................................................................... 30 
2.2.2 
Study Treatments ....................................................................................................... 31 
2.2.2.1 
Surufatinib............................................................................................................... 31 
2.2.2.2 
Tislelizumab ............................................................................................................ 31 
2.2.2.3 
Justification of Dosing Strategy .............................................................................. 31 
2.2.3 
Supportive Nonclinical Data ...................................................................................... 33 
2.2.3.1 
Pharmacology ......................................................................................................... 33 
2.2.3.2 
Toxicology .............................................................................................................. 33 
2.2.4 
Supportive Clinical Data ............................................................................................ 34 


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2.2.4.1 
Clinical Pharmacology and Pharmacokinetics........................................................ 34 
2.2.4.2 
Clinical Safety ......................................................................................................... 35 
2.2.4.3 
Clinical Efficacy ..................................................................................................... 36 
2.2.5 
Benefit:Risk Assessment ........................................................................................... 37 
2.2.5.1 
Risk Assessment ..................................................................................................... 37 
2.2.5.2 
Benefit Assessment ................................................................................................. 37 
2.2.5.3 
Overall Benefit:Risk Conclusion ............................................................................ 38 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 39 
4 
STUDY DESIGN............................................................................................................. 40 
4.1 
Overall Design .............................................................................................................. 40 
4.1.1 
Part 1 (Dose Escalation)............................................................................................. 40 
4.1.2 
Assessment of Dose-limiting Toxicities .................................................................... 41 
4.1.2.1 
Recommended Phase 2 Dose and Maximum Tolerated Dose ................................ 42 
4.1.3 
Part 2 (Dose Expansion) ............................................................................................ 42 
4.2 
Design Rationale ........................................................................................................... 44 
5 
POPULATION ................................................................................................................ 45 
5.1 
Recruitment ................................................................................................................... 45 
5.2 
Definitions..................................................................................................................... 45 
5.3 
Inclusion Criteria .......................................................................................................... 45 
5.4 
Exclusion Criteria ......................................................................................................... 47 
5.5 
Lifestyle Restrictions .................................................................................................... 49 
5.5.1 
Contraception ............................................................................................................. 49 
5.5.2 
Pregnancy and Lactation ............................................................................................ 50 
6 
STUDY CONDUCT ........................................................................................................ 51 
6.1 
Study Procedures .......................................................................................................... 51 
6.1.1 
Informed Consent....................................................................................................... 51 
6.1.2 
Medical History ......................................................................................................... 51 
6.1.3 
Tumor Diagnosis and Treatment History .................................................................. 51 
6.1.4 
Demographics ............................................................................................................ 51 
6.1.5 
Concomitant Medication and Procedures .................................................................. 51 
6.1.6 
Comprehensive Physical Examination ...................................................................... 51 
6.1.7 
Limited Physical Examination ................................................................................... 52 


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6.1.8 
Eastern Cooperative Oncology Group Performance Status ....................................... 52 
6.1.9 
Vital Signs .................................................................................................................. 52 
6.1.10 
Laboratory Evaluations .............................................................................................. 52 
6.1.10.1 
Hematology ............................................................................................................. 52 
6.1.10.2 
Blood Chemistry ..................................................................................................... 52 
6.1.10.3 
Coagulation Indicators ............................................................................................ 53 
6.1.10.4 
CK and CK-MB ...................................................................................................... 53 
6.1.10.5 
Thyroid Function .................................................................................................... 53 
6.1.10.6 
Pregnancy Test ........................................................................................................ 53 
6.1.10.7 
Urinalysis ................................................................................................................ 53 
6.1.10.8 
Virological Screening ............................................................................................. 53 
6.1.11 
Electrocardiogram Monitoring................................................................................... 53 
6.1.12 
Echocardiogram ......................................................................................................... 54 
6.1.13 
Tumor Evaluation/Imaging ........................................................................................ 54 
6.1.14 
Archived Tumor Sample ............................................................................................ 54 
6.1.14.1 
Core Needle Biopsy (Cohort F) .............................................................................. 54 
6.1.15 
Patient Enrollment Process ........................................................................................ 55 
6.1.16 
Pharmacokinetics Evaluations ................................................................................... 55 
6.1.16.1 
Sample Collection and Handling ............................................................................ 55 
6.1.16.2 
Analytical Procedures ............................................................................................. 55 
6.1.17 
Screening Period ........................................................................................................ 55 
6.1.18 
Treatment Period ........................................................................................................ 56 
6.1.19 
End of Treatment Visit............................................................................................... 56 
6.1.20 
Efficacy Follow-up Period ......................................................................................... 56 
6.1.21 
Survival Follow-up Period ......................................................................................... 56 
6.1.22 
End of Study .............................................................................................................. 56 
6.2 
Discontinuation or Withdrawal ..................................................................................... 56 
6.2.1 
Individual Patients ..................................................................................................... 56 
6.2.1.1 
Permanent Discontinuation of Treatment ............................................................... 56 
6.2.1.2 
Withdrawal from Study........................................................................................... 57 
6.2.1.3 
Replacement of Patients .......................................................................................... 58 
6.2.1.4 
Patients Lost to Follow-up ...................................................................................... 58 


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6.2.2 
Stopping Rules ........................................................................................................... 58 
6.2.2.1 
Individual Patients .................................................................................................. 58 
6.2.2.2 
Part 1 (Dose Escalation).......................................................................................... 58 
6.2.2.3 
Part 2 (Dose Expansion) ......................................................................................... 58 
6.3 
Study Termination ........................................................................................................ 59 
7 
STUDY INTERVENTIONS ........................................................................................... 60 
7.1 
Description of Products................................................................................................. 60 
7.1.1 
Surufatinib (HMP-012) .............................................................................................. 60 
7.1.1.1 
Formulation, Storage, Preparation, and Handling .................................................. 60 
7.1.1.2 
Dosing and Administration ..................................................................................... 60 
7.1.2 
Tislelizumab ............................................................................................................... 60 
7.1.2.1 
Formulation, Storage, Preparation and Handling ................................................... 60 
7.1.2.2 
Dosing and Administration ..................................................................................... 61 
7.1.3 
Dose Modifications .................................................................................................... 61 
7.1.4 
Dose Modification of Surufatinib for Adverse Events of Special Interest ................ 63 
7.2 
Treatment Assignment and Bias Minimization ............................................................ 66 
7.2.1 
Treatment Allocation ................................................................................................. 66 
7.3 
Assessment and Verification of Compliance ................................................................ 66 
7.4 
Prior and Concomitant Therapies ................................................................................. 67 
7.4.1 
Prohibited Therapies .................................................................................................. 67 
7.4.2 
Permitted Therapies ................................................................................................... 67 
7.4.3 
Drug-Drug Interactions .............................................................................................. 68 
8 
SAFETY MONITORING ................................................................................................ 69 
8.1 
Definitions..................................................................................................................... 69 
8.1.1 
Adverse Event ............................................................................................................ 69 
8.1.2 
Serious Adverse Event ............................................................................................... 69 
8.1.3 
Adverse Events of Special Interest ............................................................................ 70 
8.2 
Adverse Event Reporting .............................................................................................. 70 
8.2.1 
Timeframe for Collection of Adverse Events ............................................................ 70 
8.2.2 
Expedited Reporting .................................................................................................. 70 
8.3 
Eliciting Adverse Events............................................................................................... 71 
8.4 
Assessment of Severity ................................................................................................. 71 


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8.5 
Causality Assessment.................................................................................................... 71 
8.6 
Documenting Adverse Events....................................................................................... 72 
8.6.1 
Diagnosis Versus Symptoms and Signs ..................................................................... 72 
8.6.2 
Adverse Event Occurring Secondary to Other Events ............................................... 72 
8.6.3 
Persistent or Recurrent Adverse Events ..................................................................... 73 
8.6.4 
Abnormal Laboratory Values or Abnormal Vital Signs ............................................ 73 
8.6.5 
Preexisting Medical Condition .................................................................................. 73 
8.6.6 
Pregnancy ................................................................................................................... 74 
8.6.7 
Worsening of Solid Tumor ........................................................................................ 74 
8.6.8 
Death .......................................................................................................................... 74 
8.6.9 
Overdose .................................................................................................................... 74 
8.7 
Duration of Safety Follow-up for Adverse Events ....................................................... 75 
9 
ANALYSIS ...................................................................................................................... 76 
9.1 
Hypothesis..................................................................................................................... 76 
9.2 
Population ..................................................................................................................... 76 
9.2.1 
Sample Size Rationale ............................................................................................... 76 
9.2.1.1 
Part 1 ....................................................................................................................... 76 
9.2.1.2 
Part 2 ....................................................................................................................... 76 
9.2.2 
Analysis Populations .................................................................................................. 77 
9.3 
Statistical Analysis ........................................................................................................ 78 
9.3.1 
Patient Disposition ..................................................................................................... 78 
9.3.2 
Demographic and Other Baseline Characteristics ..................................................... 78 
9.3.3 
Prior and Concomitant Medications .......................................................................... 78 
9.3.4 
Safety Analysis .......................................................................................................... 78 
9.3.5 
Efficacy Analysis ....................................................................................................... 79 
9.3.5.1 
Primary Efficacy Analysis ...................................................................................... 79 
9.3.5.2 
Secondary Efficacy Analysis .................................................................................. 80 
9.3.6 
Pharmacokinetic Analysis .......................................................................................... 81 
9.3.7 
Immunogenicity Analysis .......................................................................................... 81 
9.3.8 
Other Exploratory Analyses ....................................................................................... 81 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 82 
10.1 
Good Clinical Practice .................................................................................................. 82 


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10.2 
Ethics Review ............................................................................................................... 82 
10.3 
Data Privacy .................................................................................................................. 82 
10.4 
Disclosure ..................................................................................................................... 83 
10.5 
Data Quality Assurance ................................................................................................ 83 
10.6 
Informed Consent.......................................................................................................... 83 
11 
OVERSIGHT ................................................................................................................... 85 
11.1 
Safety Review Committee ............................................................................................ 85 
11.2 
Quality Control and Assurance ..................................................................................... 85 
11.2.1 
Monitoring ................................................................................................................. 85 
11.2.2 
Audits ......................................................................................................................... 86 
11.2.3 
Records ...................................................................................................................... 86 
11.2.3.1 
Data Capture and Management ............................................................................... 86 
11.2.3.2 
Source Documentation ............................................................................................ 87 
11.2.3.3 
Records Retention ................................................................................................... 87 
11.3 
Study Termination or Study Site Closure ..................................................................... 87 
12 
PUBLICATION POLICY ............................................................................................... 89 
13 
FINANCING AND INSURANCE .................................................................................. 90 
14 
REFERENCES ................................................................................................................ 91 
15 
APPENDICES ............................................................................................................... 101 
 
LIST OF TABLES  
Table 1 
Schedule of Events for Study 2020-012-GLOB1 ................................................ 22 
Table 2 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments ......................................................................................................... 25 
Table 3 
Objectives and Corresponding Endpoints ............................................................ 39 
Table 4 
Dose Levels .......................................................................................................... 41 
Table 5 
Dose Expansion Cohorts ...................................................................................... 43 
Table 6 
Investigational Treatments Used in This Study ................................................... 60 
Table 7 
Dose Modification Sequence for Part 1 ............................................................... 62 
Table 8 
Dose Modification Sequence for Part 2 ............................................................... 62 
Table 9 
Dose Modification of Surufatinib for Hematologic and Nonhematologic 
Toxicity ................................................................................................................ 63 
Table 10 
Dose Modification of Surufatinib for Hepatic Disorders .................................... 63 


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Table 11 
Dose Modification of Surufatinib for Hypertension ............................................ 64 
Table 12 
Dose Modification of Surufatinib for Proteinuria ................................................ 65 
Table 13 
Dose Modification of Surufatinib for Hemorrhage ............................................. 66 
Table 14 
Estimated ORR and 2-Sided 95% Confidence Intervals ..................................... 77 
Table 15 
Time Point Response: Patients with Target Lesions (With or Without 
Non-Target Lesions) .......................................................................................... 109 
Table 16 
Time Point Response: Patients with Non-Target Lesions Only ........................ 109 
Table 17 
Best Overall Response When Confirmation of Complete Response and 
Partial Response Is Required ............................................................................. 110 
Table 18 
Medications That Are Substrates, Inhibitors, or Inducers of CYP3A or 
Substrates of P-gp and BCRP ............................................................................ 113 
Table 19 
Treatment Modifications for Symptoms of Infusion-Related or 
Hypersensitivity Reactions Associated with Study Drug(s) Administration ..... 124 
Table 20 
Recommended Diagnostic Tests in the Management of Possible 
Immune-Mediated Adverse Events .................................................................... 126 
Table 21 
Management of Immune-Mediated Adverse Events ......................................... 128 
 
LIST OF FIGURES  
Figure 1 
Study Design Schema .......................................................................................... 21 
Figure 2 
Severe or Hemorrhagic Events Management Flow Chart ................................. 118 
Figure 3 
Schema from American Heart Association/American College of 
Cardiology for Controlling Hypertension in Adults .......................................... 120 
 


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Amendment 5 
 
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Amendment 5 
 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ACE 
angiotensin converting enzyme 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASPS 
alveolar soft part sarcoma  
AST 
aspartate aminotransferase 
ATC 
anaplastic thyroid cancer 
BCRP 
breast cancer–resistant protein 
BID 
twice a day (bis in die) 
BP 
blood pressure 
BRAF  
B-Raf kinase  
BRAFV600E  
B-Raf kinase V600E mutations 
CxDx 
Cycle x, Day x 
CBR 
clinical benefit rate 
CD 
compact disc 
CL 
clearance 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase myocardial band 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form (paper or electronic) 
CRO 
clinical research organization 
CSF-1 
colony-stimulating factor-1  
CSF-1R 
colony-stimulating factor-1 receptor 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
cytochrome P450, family 3, subfamily A 
CYP3A4 
cytochrome P450, family 3, subfamily A4 
DCR 
disease control rate  
DLT 
dose-limiting toxicity 
DoR 
duration of response  


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Abbreviation 
Definition 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
epNET 
extrapancreatic neuroendocrine tumor 
ESMO 
European Society for Medical Oncology 
FDA  
Food and Drug Administration 
FcγR 
Fc-gamma-receptor immunoglobulin 
FGFR1 
fibroblast growth factor receptor 1 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEP 
gastroenteropancreatic 
HBV 
hepatitis b virus 
HCV 
hepatitis c virus 
HIV 
human immunodeficiency virus 
HPF 
high-power field 
HR 
hazard ratio 
IB 
Investigator’s Brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
imAE 
immune-mediated adverse event 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IP 
investigational product 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LVEF 
left ventricular ejection fraction 
mCRC 
metastatic colorectal cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events 
NET 
neuroendocrine tumor 
NR 
not reached 
ORR 
objective response rate  
OS 
overall survival 
PCR 
polymerase chain reaction 


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Abbreviation 
Definition 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s)  
pNET 
pancreatic neuroendocrine tumor 
PO 
oral(ly) 
PR 
partial response 
PT 
preferred term 
QxW 
every x weeks 
QD 
once daily  
QTcF 
QT interval corrected by the method of Fredericia 
RAS 
RAS oncoprotein 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RP2D 
recommended phase 2 dose  
SAE 
serious adverse event 
SANET-ep 
advanced epNET 
SANET-p 
advanced pNET 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SRC 
Safety Review Committee 
SSA 
somatostatin analog 
STS 
soft-tissue sarcoma 
TAM 
tumor-associated macrophage 
TBIL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TTR 
time to response 
ULN 
upper limit of normal 
UPS 
undifferentiated pleomorphic sarcoma 
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 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 1 8  
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 bel P hase I b /II St u d y of S ur ufati ni b i n C o m bi nati o n W it h 
Tisleliz u ma b i n S u bjects  W it h A d va nce d S oli d T u m ors 
S h ort Title  
S ur ufati ni b  i n C o m bi nati o n W it h Tisleliz u ma b i n A d va nce d S oli d T u m ors  
Acr o n y m  
N ot a p plica ble  
P h ase  
1 b/ 2  
St u d y St at us as of 
Pr ot oc ol A m e n d m e nt 5  
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 base d o n t he strate gic ree val uati o n of t he cli nical de vel o p me nt of 
s ur ufati ni b i n t he U nite d States a n d E ur o pe .  T his c ha 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 s ur ufati ni b a n d/ or tisleliz u ma b 
treat me nt.  
 
.  T he st u d y will be ter mi nate d eit her 9 0 da ys 
after t he last patie nt has rece i ve d tisleliz u ma b, or t he p oi nt at w hic h all 
i m m u ne-me diate d a d verse e ve nt  (i m A Es) ha ve res ol ve d or are n o l o n ger bei n g 
f oll o we d, w hiche ver occ urs  earlier .  
R ati o n ale  
S ur ufati ni b is a n o vel t yr osi ne ki nase i n hi bit or t hat i n hi bits vasc ular e n d ot helial 
gr o wt h fact or rece pt ors ( V E G F R) 1, 2 a n d 3, as well as fi br o blast gr o wt h fact or 
rece pt or ( F G F R) 1, w hic h res ults i n i n hi biti o n of a n gi o ge nesis.  I n a d diti o n, 
s ur ufati ni b i n hi bits si g nali n g via c ol o n y -sti m ulati n g fact or-1 rece pt or , w hic h is 
t h o u g ht t o d o w nre g ulate t u m or-ass ociate d macr o p ha ges , t h us pr o m oti n g a ntit u m or 
i m m u nit y.  
Tisleliz u ma b is a h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4)-varia nt a nti -cell deat h 
pr otei n 1 ( P D -1 ) m o n ocl o nal a nti b o d y s pecificall y e n gi neere d t o mi ni mize 
bi n di n g t o Fc -ga m ma -rece pt or i m m u n o gl o b uli n (Fcγ R ) o n macr o p ha ges.  I n 
precli nical st u dies, bi n di n g t o Fcγ R o n macr o p ha ges has bee n s h o w n t o 
c o m pr o mise t he a ntit u m or acti vit y of P D -1 a nti b o dies t hr o u g h acti vati o n of 
a nti b o d y-de p e n de nt macr o p ha ge -me diate d killi n g of T -effect or cells.  
C o m bi ni n g s ur ufati ni b wit h tisleliz u ma b ma y ha ve s y ner gistic effects, w here 
i n hi biti o n of a n gi o ge nesis al o n g wit h sti m ulati o n of a n i m m u ne res p o nse ma y 
e n ha n ce t he o verall a ntit u m or acti vit y c o m pare d t o t hat of eac h i n di vi d ual a ge nt 
al o ne. 
T ar g et P o p ul ati o n  
Male a n d fe male patie nts, ≥1 8 years of a ge, wit h e val ua ble or mea sura ble 
(acc or di n g t o Res p o nse E val uati 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 ]) a d va nce d or metastatic s oli d t u m ors (c ol orectal ca ncer, 
ne ur oe n d ocri ne t u m ors, s mall-cell l u n g ca ncer, gastric ca ncer,  s oft tiss ue sarc o ma, 
or a n a plastic t h yr oi d ca ncer ) a n d Easter n C o o perati ve O nc ol o g y Gr o u p 
perf or ma n ce  stat us of 0 or 1, w h o ha ve pr o gresse d o n or are i nt olera nt of sta n dar d 
t hera pies.  
I nter v e nti o n 
S ur ufati ni b ( H M P L -0 1 2) will be pr o vi de d as 5 0 -m g ca ps ules.  Tisleliz u ma b 
1 0  m g/ m L will be pr o vi de d as 1 0 0 m g/ m L  i n 1 0 m L sterile, n o n p yr o ge nic, a n d 
is ot o nic i njecta ble s ol uti o n f or i ntra ve n o us (I V) a d mi nistrati o n i n a b uffere d 
f or m ulati o n.   
T he s ur ufati ni b will be a d mi nistere d wit h 2 4 0 m L ( 8 o u nces) of water wit h i n 
1  h o ur after brea kfast . 
I n Part 1 ( d ose escalati o n ), s ur ufati ni b will be a d mi nistere d orall y ( P O) o nce dail y 
( Q D) at 2 5 0  m g or 3 0 0  m g wit h a 2 0 0 -m g tisleliz u ma b I V i nf usi o n e ver y 3 wee ks 
( Q 3 W). 
I n Part 2, t he i n dicati o n-s pecific e x pa nsi o n p orti o n of t he st u d y, patie nts will 
recei ve s ur ufati ni b at t he rec o m me n de d p hase 2 d ose (R P 2 D ) (3 0 0  m g Q D)  
selecte d i n Part 1  wit h 2 0 0  m g tisleliz u ma b I V , Q 3 W . 
C CI


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Amendment 5 
 
 
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Description of Sites 
Part 1 will have approximately 4 to 6 sites for patient recruitment in the United 
States.  Part 2 will include sites in the United States and Europe for patient 
recruitment.  
Objectives and Endpoints  
Objectives 
Part 1 Primary:  
• To evaluate the safety and tolerability of 
surufatinib, thereby determining the RP2D and/or 
the maximum tolerated dose (MTD) of surufatinib 
in combination with tislelizumab 
Part 2 Primary:  
• To evaluate the objective response rate (ORR) as 
assessed by the investigator in patients with 
advanced solid tumors when treated with 
surufatinib in combination with tislelizumab 
according to RECIST v1.1. 
Corresponding Endpoints 
Part 1 Primary:  
• Safety including dose-limiting toxicities 
(DLTs), treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs), adverse events (AEs) leading to 
discontinuation, ECGs, clinical laboratory 
abnormalities, and vital signs 
Part 2 Primary:  
• 
ORR at 12 weeks  
Part 1 Secondary:  
• To evaluate the antitumor activity in patients with 
advanced solid tumors when treated with 
surufatinib in combination with tislelizumab 
according to RECIST v1.1 
• To characterize the pharmacokinetics (PK) and 
immunogenicity of tislelizumab and surufatinib in 
combination 
Part 1 Secondary:  
• ORR, progression-free survival (PFS), 
disease control rate (DCR), clinical benefit 
rate (CBR), duration of response (DoR), 
time to response (TTR)   
• Concentrations of surufatinib in plasma 
and tislelizumab in serum 
• Incidence of antidrug antibodies (ADA) to 
tislelizumab 
Part 2 Secondary:  
• To evaluate further anticancer effects of surufatinib 
in combination with tislelizumab 
• To characterize the safety and tolerability of 
surufatinib in combination with tislelizumab 
• To characterize the PK and immunogenicity of 
tislelizumab and surufatinib in combination 
Part 2 Secondary:  
• PFS, DCR, CBR, DoR, TTR 
• Overall survival (OS); Cohorts A and F   
• Safety including TEAEs, SAEs, AEs 
leading to discontinuation, 
electrocardiograms (ECGs), clinical 
laboratory abnormalities, and study drug 
discontinuation due to AEs 
• Concentrations of surufatinib in plasma 
and tislelizumab in serum 
• Incidence of ADA to tislelizumab 
Brief Summary:  
The purpose of this study is to evaluate the safety, tolerability, PK, and efficacy of surufatinib in combination 
with tislelizumab in participants with advanced solid tumors.  Study details are outlined below. 
Condition/Disease 
Advanced or metastatic solid tumors (colorectal cancer, neuroendocrine tumors, 
small-cell lung cancer, gastric cancer, soft tissue sarcoma, and anaplastic thyroid 
cancer) 


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Study Duration 
Enrolled patients undergo a screening period of up to 28 days of the initial dose; 
patients may receive treatment for the treatment duration as described below.  All 
patients will undergo an End of Treatment Visit within 37 days after the last dose 
and may undergo efficacy and survival follow-up every 12 weeks. As of 
Amendment 5, after the End of Treatment Visit, patients will be contacted by the 
sites to follow-up on any resolving or new immune-mediated adverse events for 
up to 90 days.   
Treatment Duration 
Each patient will be treated until disease progression, unacceptable toxicity, 
withdrawal of consent, new anticancer therapy, lost to follow-up, or death. 
Health 
Measurement/Observation 
Safety, including DLTs, TEAEs, SAEs, AEs leading to discontinuation, ECGs, 
clinical laboratory abnormalities, vital signs, and MTD and/or RP2D 
Visit Frequency 
Cycle 1: every week (Day 8 ±1 day and Day 15 ±1 days) 
Cycle 2: every 2 weeks (±1 day) 
Cycle 3 and onward: every 3 weeks (±3 days) 
Treatment Completion: 30±7 days after completion 
Number of Participants 
The total number of patients enrolled will depend on the number of dose 
escalations.  The planned enrollment is approximately 122 patients. 
Part 1 – dose escalation: 6 to 12 patients 
Part 2 – dose expansion: 110 patients   
Intervention Groups and 
Duration 
Patients in both Part 1 and Part 2 will undergo screening period of up to 28 days 
and will receive treatment for the treatment duration as described above.  All 
patients will undergo an End of Treatment Visit within 30 days after the last dose 
and may undergo efficacy and survival follow-up every 12 weeks.  
Part 1 (all cohorts): patients will receive oral surufatinib at a dose based on cohort 
level and intravenous tislelizumab at a 200-mg dose 
Part 2 (all cohorts): patients will receive oral surufatinib at the RP2D (300 mg 
QD) selected in Part 1 and intravenous tislelizumab at a 200-mg dose 
Dose modification is allowed for surufatinib no more than twice by 50 mg daily.  
No dose reductions for tislelizumab are permitted.   
Data Monitoring/Other 
Committee 
Yes 
Safety monitoring and evaluation of the dose escalation part will be carried out by 
Safety Review Committee, which will consist 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.  


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1.1 
Study Schematic  
The study schematic is presented in Figure 1. 
Figure 1 
Study Design Schema  
 
ASPS=alveolar soft part sarcoma; ECOG PS=Eastern Cooperative Oncology Group performance status; 
GEP=gastroenteropancreatic; L=line of therapy (e.g., 4L=fourth line of therapy); NET=neuroendocrine tumor; 
Q3W=every 3 weeks; QD=once daily; SCLC=small-cell lung cancer; UPS=undifferentiated pleomorphic 
sarcoma. 
1.2 
Schedule of Events  
The schedule of events is presented in Table 1. 


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Table 1 
Schedule of Events for Study 2020-012-GLOB1  
Cycle/Period 
 
Cycle 1 
Cycle 2 
Cycle 3+ 
EOT20 
Efficacy 
Follow-up21 
Survival 
Follow-
up18 
Visit 
Screening 
Day 1 
Day 8 
Day 15 
Day 1 
Day 15 
Day 1 
Within 
30 Days 
After Last 
Dose 
Every 
12 Weeks 
From EOT 
Every 
12 Weeks 
From PD 
Visit window (days) 
-28 to -1 
 
±1 
±1 
±1 
±1 
±3 
±7 
±14 
±14 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
Tumor sample for PD-L1 testing2 
X 
 
 
 
 
 
 
 
 
 
Cohort F: Core needle biopsy19  
X 
 
 
 
X 
 
 
 
 
Medical history, disease history3 
X 
 
 
 
 
 
 
 
 
 
Demographics4 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
and concomitant procedures5 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Comprehensive physical exam6 
X 
 
 
 
 
 
 
X 
 
 
Limited physical exam7 
 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status8 
X 
X 
 
 
X 
 
X 
X 
 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory evaluations10 
 
 
 
 
 
 
 
 
 
 
Hematology 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistry 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
Blood amylase and lipase 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
Coagulation indicators 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
CK and CK-MB 
X 
X 
 
 
X 
 
X 
X 
 
 
Thyroid test  
(FT3, FT4, TSH)  
X11 
 
 
 
 
 
Every 3 cycles starting 
from C4D1 (ie, C4D1, 
C7D1, C10D1) 
X 
 
 
Serum pregnancy test 
X11 
 
 
 
 
 
 
X 
 
 


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Amendment 5 
 
 
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Table 1 
Schedule of Events for Study 2020-012-GLOB1  
Cycle/Period 
 
Cycle 1 
Cycle 2 
Cycle 3+ 
EOT20 
Efficacy 
Follow-up21 
Survival 
Follow-
up18 
Visit 
Screening 
Day 1 
Day 8 
Day 15 
Day 1 
Day 15 
Day 1 
Within 
30 Days 
After Last 
Dose 
Every 
12 Weeks 
From EOT 
Every 
12 Weeks 
From PD 
Visit window (days) 
-28 to -1 
 
±1 
±1 
±1 
±1 
±3 
±7 
±14 
±14 
Urine pregnancy test 
 
 
 
 
X 
 
X 
 
 
 
Urinalysis 
X11 
 
 
 
X 
 
X 
X 
 
 
Virological screening 
X 
 
 
 
 
 
 
 
 
 
PK and ADA assessments 
 
Refer to Table 2 
 
 
12-lead ECG12 
X11 
 
 
X 
X 
X 
X 
X 
 
 
ECHO/MUGA scan13 
X 
 
 
 
Every 12 weeks from C1D1 (±1 week) 
 
 
Tumor evaluation/imaging14 
X 
 
Q6W (±1 week) for the first 24 weeks from C1D1, then Q9W (±1 week) thereafter 
through EOT. 
X15 
 
Surufatinib administration 
 
QD, PO, based on dose escalation dose level in Part 1 and RP2D (300 mg) in 
Part 2 
 
 
 
Tislelizumab administration16 
 
X 
 
 
X 
 
X 
 
 
 
AEs/SAEs17 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Overall survival18 
 
 
 
 
 
 
 
 
 
X 
ADA=antidrug antibody; AE=adverse event; CK=creatine kinase; CK-MB=creatine kinase myocardial band; CxDx=Cycle x, Day x; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; FT3=serum free tri-iodothyronine; FT4=serum free thyroxine; 
ICF=informed consent form; imAE=immune-mediated adverse events; IV=intravenous; MUGA=multiple-gated acquisition; PD=progressive disease; PD-L1=programmed 
death-ligand 1; PO=orally; PK=pharmacokinetics; QD=once daily; QxW=every x weeks; RP2D=recommended phase 2 dose; SAE=serious adverse event; 
TSH=thyroid-stimulating hormone.  
 
1. A written informed consent form should be obtained prior to any protocol-specific procedure or test.  Procedural details for informed consent are available in 
Section 6.1.1. 
2. Submit formalin-fixed, paraffin-embedded tumor sample or a minimum of 10 unstained slides for PD-L1 analysis for all patients enrolled in Part 2 of the 
study.  Procedural details for archived tumor sample are available in Section 6.1.14. 
3. Procedural details for medical history are available in Section 6.1.2.  Tumor diagnosis and tumor treatment history are described in Section 6.1.3. 
4. Procedural details for patient demographics, including baseline characteristics, are available in Section 6.1.4. 
5. Procedural details for concomitant medications/treatments are available in Section 6.1.5. 
6. Procedural details for comprehensive physical examination are available in Section 6.1.6. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 2 4  
C O N FI D E N TI A L  
7.  Pr o ce d ural details f or li mite d p h ysical e x a mi nati o n are a vaila ble i n Secti o n  6. 1. 7 . 
8.  Pr o ce d ural details f or E C O G perf or ma n ce stat us are a vaila ble i n Secti o n  6. 1. 8 . 
9.  Pr o ce d ural details f or vital si g ns are a v aila ble i n Secti o n  6. 1. 9 . 
1 0.  Pr o ce d ural details f or la b orat or y e v al uati o ns are a vaila ble i n Secti o n  6. 1. 1 0 . 
1 1.  T hese tests s h o ul d be c o m plete d wit hi n 7 da ys bef ore t he start of treat me nt; if c o m plete d m ore t ha n 7 da ys bef ore first d ose,  t he y m ust b e re p eate d o n C 1 D 1 
pri or t o d osi n g.  
1 2.  E C G is t o be perf or me d pri or t o d osi n g of st u d y dr u gs a n d P K sa m ple c ollecti o n a n d E C H O assess me nts at eac h rele v a nt visit.  Ot her pr oce d ural details f or 
1 2 -lea d E C G are a vaila ble i n Secti o n 6. 1. 1 1 .  U nsc he d ule d E C G or ot her car diac e xa mi nati o ns ca n be perf or me d if cli nicall y i n dicate d. 
1 3.  Pr o ce d ural details f or E C H O assess me nts are a vaila ble i n Secti o n  6. 1. 1 2 .  M U G A sca ns are acce pta ble if E C H O ca n n ot be perf or me d. 
1 4.  Pr o ce d ural details f or t u m or e val uati o n a n d i ma gi n g are a vaila ble i n Secti o n  6. 1. 1 3 . 
1 5.  A n y patie nt w h o disc o nti n ues st u d y treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n s h o ul d be f oll o we d wit h t u m or e v al uati o n/i ma gi n g u ntil 
pr o gressi o n is d oc u me nte d or u ntil a ne w a ntica ncer treat me nt is i nitiate d.  
1 6.  Tisleliz u ma b will be d ose d o n da y 1 of e ver y c ycle starti n g at C 1 D 1 ( Q 3 W) as a n I V i nf usi o n.  
1 7.  A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil 3 0 da ys after t he last d ose or i nitiati o n of ne w a ntit u m or t hera p y, w hic he v er occ urs first.  T he rele va nt 
A Es will be f oll o we d u p u ntil t he y are rec o vere d t o t he baseli ne stat us, alrea d y i n a sta ble s tate as assesse d b y t he i n vesti gat or, or u ntil t he start of ne w 
a ntit u m or t hera p y, l oss t o f oll o w -u p, deat h, wit h dra wal of i nf or me d c o nse nt , or e n d of st u d y.  S A Es are c ollecte d fr o m t he si g ni n g of t he I C F u ntil 3 0  da ys 
after t he last d ose or i nitiati o n of ne w a ntit u m or t hera p y, a n d after t his peri o d, o nl y S A Es relate d t o t he i n vesti gati o nal d r u g are c ollecte d.  I n a d diti o n, 
tele p h o ne c o ntacts wit h patie nts s h o ul d be c o n d ucte d t o assess A Es a n d c o nc o mita nt me dicati ons (if a p pr o priate; ie, is ass ociate d wit h a n i m A E or is a ne w 
a ntica n cer t hera p y) at 6 0  da ys a n d 9 0 da ys ( ± 1 4 da ys) after t he last d ose of tisleliz u ma b, re gar dless of w het her or n ot p at ie nts starte d a ne w a ntica n cer 
t hera p y.  If patie nts re p ort a s us pecte d i m A E at a tele p h o ne f oll o w-u p c o ntact, t he i n vesti gat or s h o ul d arra n ge a n u nsc h e d ule d visit if f urt her assess me nt is 
i n dicate d. 
1 8.  All p atie nts i n d ose e x pa nsi o n c o h ort s A  a n d F ma y be f oll o we d f or s ur vi val stat us e ver y 1 2 wee ks u p t o 2 years fr o m last d ose, u ntil deat h, l ost t o 
f oll o w-u p, wit h dra wal of c o nse nt , or t he e n d of t he st u d y.  S ur vi val i nf or mati o n ca n be o btai ne d via p h o ne a n d/ or cli nical visits. 
1 9.  C o h ort F: Ma n dat or y c ore ne edle bi o psies at scree ni n g , a n d o n treat me nt ( bet wee n C 2 D 1 t o C 2 D 1 5).   Pr oce d ural details f or  c ore nee dle bi o ps y are a v ail able 
i n Secti o n 6. 1. 1 4. 1 . 
2 0.  All p atie nts o n acti ve treat me nt at t he 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.  Treat me nt wit h s ur ufati ni b a n d tisleliz u ma b s h o ul d be 
disc o nti n ue d o n Da y  2 8 of t he last c y cle 
 
  All E O T assess me nts d escri be d i n t he 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 nal c ollecti o n of patie nt dr u g diaries/fi nal dr u g acc o u nta bilit y 
re vie w.  After t he E O T  v isit, patie nts will be c o n tacte d b y t he sites t o f oll o w-u p o n a n y res ol vi n g or ne w i m m u ne -me diate d a d verse e ve nts f or u p t o 9 0 da ys .   
2 1.  All p atie nts o n acti ve treat me nt at t he ti me of A me n d me nt 5 will n ot be f oll o we d f or efficac y  after E O T . 
 
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Table 2 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments  
Visit 
Surufatinib1 
Tislelizumab 
Immunogenicity 
(Anti-Tislelizumab 
Antibodies) 
PK Sample Time Point2 
PK Sample Time Point2 
C1D1 
Predose3 
Preinfusion4 
Preinfusion4 
2 to 4 hours postdose 
EOI5 
C1D8 
Predose3 
Any time during visit 
- 
C1D15 
Predose3 
Any time during visit 
- 
2 to 4 hours postdose 
C2D1 
Predose3 
Preinfusion4 
Preinfusion4 
C5D1 
Predose3 
Preinfusion4 
Preinfusion4 
EOIe 
C9D1 
Predose3 
Preinfusion4 
Preinfusion4 
C17D1 
Predose3 
Preinfusion4 
Preinfusion4 
AE=adverse event; CxDx=Cycle X, Day X; hr=hours; EOI=end of infusion; EOT=end of treatment; 
PK=pharmacokinetic.  
Note: If at any time during an infusion day a patient should present with any ≥Grade 3 infusion-related AE, an 
additional blood PK sample may be taken to determine the serum concentration of tislelizumab.  The actual 
time of PK sample and the start time and end time of infusion must be recorded. 
1 
On days that both study drugs are administered, the surufatinib PK sample will be taken at the study site within 
15 minutes before the start of the tislelizumab infusion. 
2 
If dose delay occurs, then samples should be collected on the actual day of drug administration, not on the 
originally scheduled administration day.  Additional samples can be obtained to help assess safety issues. 
3 
The predose surufatinib PK sample should be taken within 15 minutes prior to dosing. 
4 
Pre-infusion PK and immunogenicity samples for tislelizumab should be collected within 60 minutes before 
starting tislelizumab infusion. 
5 
EOI sample should be taken within 30 minutes after completing tislelizumab infusion. 
6 
Upon implementation of Protocol Amendment 5, EOT samples for Tislelizumab and Immunogenicity will no 
longer be required.  
 
 


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2 
INTRODUCTION  
2.1 
Study Rationale  
Recent development of novel classes of targeted therapeutics include 2 main types of targeted 
therapies, immune checkpoint inhibitors and small-molecule inhibitors, both of which have led to 
further development of personalized therapeutics in oncology. 
One key immune checkpoint molecule is programmed cell death protein 1 (PD-1), which 
downregulate the magnitude of immune response and participate in peripheral tolerance.  
However, when upregulated, immune checkpoint signaling pathways such as PD‑1/programmed 
death-ligand 1 (PD-L1), protect cancer cells from immune surveillance.  Therefore, immune 
checkpoint molecules and their ligands are ideal anticancer treatment targets.  It is known that anti-
PD‑1 and anti-PD-L1 antibodies upregulates Ras-Raf-MEK-ERK and PI3K-AKT signaling 
pathways in immune cells by blocking PD-1/PD-L1.  As a result, anti-PD-1 or anti-PD-L1 
treatments can restore T cells from an exhausted state and thus enhance tumor-killing activity. 
Another important factor contributing to tumor growth is angiogenesis.  As tumor cells require 
large amounts of oxygen and nutrients, they secrete proangiogenic factors such as vascular 
endothelial growth factor (VEGF), fibroblast growth factor, and matrix metalloproteinase.  As a 
result, the balance of proangiogenic factors and antiangiogenic factors is disturbed and multiple 
angiogenic pathways are activated.  This abnormal angiogenesis leads to increased permeability 
of vessels, which allows tumor cells to leak into the circulation and leads to rapid tumor growth 
and metastasis.  
There is increasing evidence that suggests the tumor microenvironment is closely related to the 
development and progression of cancer.  Therefore, one effective strategy for inhibiting tumor 
growth is by targeting the tumor microenvironment via inhibition of angiogenesis while 
stimulating an immune response.  The process of angiogenesis is influenced by inflammatory 
mediators such as cytokines and immune cells, which can affect the immune microenvironment.  
Antiangiogenic agents can stimulate the immune system and act synergistically with immune 
checkpoint inhibitors to enhance antitumor response.  
Additionally, colony-stimulating factor-1 (CSF-1), a cell-surface tyrosine kinase inhibitor 
expressed by macrophages, promotes the infiltration and survival of immunosuppressive 
tumor-associated macrophages (TAMs) in the tumor microenvironment.  High levels of TAMs in 
tumors are associated with poor prognostic outcomes.  It has been proven that blocking CSF-1 
receptors (CSF-1R) or blocking its kinase activity may reduce tumor burden.  Consequently, by 
decreasing the immunosuppressive signals mediated by TAMs, some cells may upregulate PD‑L1.  
Recent evidence suggests that targeting the CSF-1R pathway in combination with immune 
checkpoint inhibitors may activate an antitumor immune response more effectively. 
Combining surufatinib with tislelizumab may have synergistic effects, where inhibition of 
angiogenesis along with stimulation of an immune response may enhance the overall antitumor 
activity compared to that of each individual agent alone.  


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 2 7  
C O N FI D E N TI A L  
2. 2  
B ac k gr o u n d   
2. 2. 1  
T ar get I n dic ati o n a n d P o p ul ati o n   
, e nr oll me nt t o st u d y 2 0 2 0-0 1 2 -G L O B 1 was halte d base d u p o n t he 
strate gic e val uati o n of s ur ufati ni b i n t he U nite d States a n d E ur o pe wit h H U T C H M E D as t he st u d y 
S p o ns or .  T his c ha n g e is n ot base d o n a n y c o n cer n f or p atie nt safet y or efficac y relati ve t o 
s ur ufati ni b treat me nt.  C urre ntl y e nr olle d patie nts w h o are deri vi n g cli nical be nefit fr o m treat me nt 
wit h s ur ufati ni b ma y c o nti n ue t o partici pat e i n t he st u d y  as p er t he 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 s ur ufati ni b t o cli nical trial sites wit h acti ve patie nts. 
2. 2. 1. 1  
C ol orectal Ca ncer   
C ol orectal ca ncer ( C R C) is a maj or gl o bal healt h iss ue, wit h a n esti mate d 1. 8 milli o n ne w cases 
a n d 8 81 0 0 0 deat hs i n 2 0 1 8 w orl d wi de ( Bra y  2 0 1 8 ).  At t he ti me of t he desi g n of t his st u d y, t he 
esta blis he d i nitial a n d sec o n d -li ne s yste mic t hera p y f or metastatic C R C  ( m C R C) c o nsiste d of 
fl u or o p yri mi di ne-, o xali plati n-, a n d iri n oteca n-b ase d c yt ot o x ic c he m ot h era p y (e g, F O L F O X: 
[ 5-Fl u or o uracil, le u c o v ori n, a n d o xali plati n] a n d F O L FI RI [ 5 -fl u or o uracil, le uc o v ori n, a n d 
iri n oteca n]).  I n a d diti o n, a bi ol o gic a nti-V E G F t hera p y was t y picall y gi ve n wit h c he m ot hera p y 
(e g, be vaciz u ma b), a n d if t he t u m or is R A S o nc o pr otei n ( R A S)  wil d t y pe, a n a nti -E G F R t hera p y 
(e g, cet u xi ma b) was a d mi nistere d.  I n t he s mall pr o p orti o n of p atie nts w h o  are defici e nt mis matc h 
re pair/ hi gh le vels of 
micr osatellite i nsta bilit y i n t he 
metastatic setti n g ( K o o p ma n  2 0 0 9 ), 
i m m u n ot hera p y 
wit h 
ni v ol u ma b 
or 
pe m br oliz u ma b 
ma y 
be 
use d (N C C N -C R C  2 0 2 0 , 
M orse  2 0 2 0 ). 
F or patie nts w h o ha d dis ease pr o gressi o n after t he first 2 li nes of c he m ot hera p y, t he esta blis he d 
o pti o ns were eit her:  
•  Trifl uri di ne/ti piracil ( L O N S U R F ® , T A S -1 0 2), a n oral c o m bi nati o n of trifl uri di ne, a 
n ucle osi de 
meta b olic i n hi bit or, a n d ti piracil, a t h y mi di ne p h os p h or ylase i n hi bit or 
(L O N S U R F  U S PI ) or 
•  Re g orafe ni b ( S TI V A R G A ® ), a m ulti ki nase i n hi bit or wit h n u mer o us i n vitr o tar gets t hat 
i ncl u de vasc ular e n d ot helial gr o wt h fact or rece pt ors  (V E G F R ) (S TI V A R G A  U S PI ) 
T here is a n u n met me dical nee d f or ne w me dicati o ns t hat are safe a n d effecti ve i n patie nts wit h 
refract or y m C R C w h o ha ve pr o gresse d o n, or ha d i nt olera ble t o xicit y fr o m, a vaila ble sta n dar d 
s yste mic t hera pies, a n d f or w h o m n o effecti ve t hera p y or sta n dar d o f care e xists.  A rece nt 
esti mati o n of t he me dia n o verall s ur vi val ( O S) f or patie nts wit h m C R C, base d o n dat a fr o m p hase 
3 cli nical trials, o bser vati o n st u dies, a n d re gistries, is 3 0 m o nt hs ( Gr ot he y  2 0 1 3 , Ma yer  2 0 1 5 ).  
D uri n g t his ti me, patie nts ma y recei ve s e veral li nes of t hera p y, wit h 1  or m ore “ brea ks. ”  B ot h 
T A S -1 0 2 a n d re g orafe ni b are a p pr o ve d i n t he t hir d or greater ( 3 + li ne) li ne of t hera p y after 
pr o gressi o n o n c he m ot hera p y, a n d t here are n o a p pr o ve d treat me nts f oll o wi n g pr o gressi o n o n t hese 
a ge nts.  I n t his setti n g, t he c urre nt o pti o ns f or patie nts wit h g o o d perf or ma nce stat us are t o e nter a 
cli nical trial or t o be rec halle n ge d wi t h pri or c he m ot hera p y (e g, 5-F U).  Patie nts wit h p o or 
perf or ma n ce stat us ge n erall y e nter h os pice care.   
2. 2. 1. 2  
Ne ur oe n d o cri ne T u m ors   
Ne ur oe n d o cri ne t u m ors ( N E Ts) are rare t u m ors t hat arise fr o m e m br y ol o gical ne ur oe n d o cri ne 
cells, a n d ma y pr o d uce p ol y pe pti de h or m o nes.  T hese t u m ors are br oa dl y cate g orize d i nt o 
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well-differentiated, moderately differentiated, or poorly differentiated tumors (Sackstein 2018).  
Well-differentiated NETs that arise from the pancreas, which comprise approximately 10-11% of 
all NETs (Man 2018), are referred to as pancreatic neuroendocrine tumors (pNETs), whereas those 
arising from nonpancreatic tissues are referred to as extrapancreatic (ep)NET. 
The prognosis of patients with NETs varies according to a number of different factors, such as 
location of primary and histological grade (Man 2018).  The 5-year survival rate is 26.1% for 
patients with tumors of low grade versus 8.7% for those with undifferentiated high-grade tumors 
at diagnosis (Man 2018).  The 5-year survival rate is 46.7% for patients with localized disease at 
diagnosis but 14.2% for those with distant metastasis (Man 2018). 
A substantial proportion of patients with NETs are found to have either distant metastatic (22.0%) 
or regionally advanced disease (17.2%) at the time of diagnosis (Man 2018).  This proportion is 
especially high for pNET patients (60.2%) (Halfdanarson 2008).  Therefore, the majority of 
patients with pNET are not eligible for surgical resection, which is currently the best option for 
long-term survival. 
Studies of the incidence of NETs based upon the National Cancer Institute’s (NCI) Surveillance 
Epidemiology and End Results database have consistently shown a marked increase in cases of 
NETs over the past 5 decades (Yao 2008, Dasari 2017, Sackstein 2018).  The increased incidence 
of NETs was observed for all primary tumor sites, tumor stages, and tumor grades.  Most of the 
growth is thought to be due to increased detection of early-stage tumors from improved techniques 
for detection (Hallet 2015). 
Given the increasing incidence of NETs, the trend toward more advanced stage at diagnosis, and 
the poor prognosis, there is great need for effective treatment options to help improve survival of 
patients with regionally advanced or metastatic NETs. 
Although approved therapies exist for the treatment of patients with locoregional advanced or 
metastatic NETs, they each have limitations.  Treatment options for managing locoregional and 
metastatic NETs consist primarily of cytoreductive surgery and systemic antitumor therapy, 
including somatostatin analogs (SSAs), everolimus, sunitinib (limited to pNET only), lutetium 
177-DOTATATE, interferon-alpha, and cytotoxic agents.  However, because of the lack of clear 
efficacy of these available treatments, there is currently no evidence-based consensus supporting 
a specific sequence of regional versus systemic treatment regimen and no standardized treatment 
course for locoregional advanced or metastatic NETs (Shah 2018, NCCN-NET 2020).  
Thus, there remains an unmet medical need for new medication that is safe and effective for 
patients with refractory NETs who have progressed through, or were intolerant of, the currently 
available systemic therapies.  
2.2.1.3 
Small-Cell Lung Cancer  
Neuroendocrine tumors account for approximately 20% of lung cancers; approximately 14% are 
small-cell lung cancer (SCLC) (NCCN-SCLC 2020).  In 2019, there were an estimated 29660 new 
cases in the United States (US) (Siegel 2019, NCCN-SCLC 2020).  SCLC is characterized by a 
rapid doubling time, high growth fraction, and early development of widespread metastases 
(NCCN-SCLC 2020).  Most patients with SCLC present with metastases.  SCLC is highly 
sensitive to initial chemotherapy; however, most patients will succumb to disease recurrence.  


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Systemic therapy alone can palliate symptoms and prolong survival; however, long-term survival 
is uncommon (NCCN-SCLC 2020).   
Platinum plus etoposide had been the standard treatment for patients with extensive stage SCLC; 
however, recently a randomized phase 3 trial demonstrated improved survival with the addition of 
atezolizumab (PD-L1 mAb) in combination with platinum and etoposide compared to 
chemotherapy alone.  Median OS was significantly longer with the addition of atezolizumab than 
without, 12.3 months and 10.3 months, respectively (95% confidence interval [CI], 10.8-15.9 and 
9.3-11.3, respectively) (Horn 2018).  Given the short life expectancy despite approved therapies 
for the treatment of SCLC, there remains an unmet medical need for additional effective therapies. 
2.2.1.4 
Gastric Adenocarcinoma  
Gastric cancer incidence and mortality have decreased in the US over the past several decades.  
However, gastric cancer ramines a major global health problem, with more than 1 million cases 
diagnoses in 2018, and causing more than 782000 deaths (NCCN-Gastric 2020).   
First-line systemic therapy for patients with locally advanced or metastatic gastric cancer provides 
symptom palliation and improved survival.  Preferred regimens included a fluoropyrimidine 
combined with a platinum agent (NCCN-Gastric 2020).  Patients with HER2 over-expressing 
tumors should have trastuzumab added to their treatment regimen (Bang 2010).  Second-line 
therapy should be tailored to patients’ prior therapy and performance status.  Options for 
second-line therapy include the biologic ramucirumab (VEGFR-2 mAb) alone or in combination 
with paclitaxel or additional cytotoxic chemotherapy (Fuchs 2014, Wilke 2014).  Immunotherapy 
options include pembrolizumab in patients with MSI-H/dMMR tumors as second-line therapy or 
as third-line therapy for tumor-expressing PD-L1 >1% (NCCN-Gastric 2020).  However, the 
landscape for immunotherapy in gastric adenocarcinoma treatment is evolving rapidly.  Emerging 
data from the Checkmate 649 trial has reported an overall survival advantage for patients treated 
with nivolumab in combination with cytotoxic chemotherapy versus chemotherapy alone in the 
first-line treatment of patients with metastatic gastric cancer, esophageal junction cancer, or 
esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score ≥5 
(BMS 2020).  
Despite multiple therapies options available to patients with gastric cancer, the vast majority will 
succumb to their disease.  Therefore, there remains an unmet need for additional effective 
therapies. 
2.2.1.5 
Soft Tissue Sarcoma  
Soft tissue sarcomas (STS) are malignant tumors that arise from mesenchymal tissue with 
heterogeneous differentiation.  International incidence rates range from 1.8 to 5 cases per 100000 
individuals per year (Wibmer 2010).  In the year 2019, there will be an estimated 12750 new cases 
and 5270 deaths from STS in the United States (American Cancer Society 2019).  Soft tissue 
sarcomas are heterogeneous, with more than 100 different subtypes identified by the World Health 
Organization and are classified according to tissue of origin (Bleloch 2017). 
For patients with incurable disease not amenable to locoregional therapies, first-line systemic 
treatment consists of cytotoxic chemotherapy.  Doxorubicin has been considered the standard 
systemic therapy in the management of metastatic sarcomas for several years (Bramwell 2003, 
Verma 2008).  Gemcitabine and docetaxel were found to have similar outcomes as doxorubicin 


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alone (Seddon 2017).  Other drugs that may have clinical activity as single agents are ifosfamide 
and paclitaxel (depending on histology) (Lorigan 2007, Nielsen 1998, Maki 2007, Okuno 2003).  
Since 2012, three drugs have been approved for the treatment of soft tissue sarcomas after failure 
of a first-line chemotherapy: pazopanib (VOTRIENT®) for all soft tissue sarcomas except 
adipocytic subtypes, eribulin for liposarcoma, and trabectedin for leiomyosarcoma and 
liposarcoma (van der Graaf 2012, Schoffski 2016, Patel 2019).  Despite new agents, treatments for 
advanced STS remain palliative only and remains an unmet medical need. 
Pazopanib is a multitargeted, oral, small molecule inhibitor of several tyrosine kinases including 
VEGFR 1, 2, and 3; platelet-derived growth factor receptor α and β; and fibroblast growth factor 
receptor-1 and -3 (VOTRIENT USPI).  Pazopanib was approved by the US Food and Drug 
Administration (FDA) in 2012 for the treatment of patients with soft tissue sarcomas, excluding 
adipocytic subtypes, who have received previous chemotherapy, based on results of the phase 3 
randomized, double-blind PALETTE study (NCT00753688) that compared pazopanib to placebo 
in 369 patients (van der Graaf 2012).  The median progression-free survival (PFS) was 4.6 months 
for patients who received pazopanib versus 1.6 months for patients who received placebo.  
However, the OS difference was not statistically significant.  
Recently, checkpoint inhibitors have been studied in STSs with limited success in select subtypes.  
The SARC028 trial demonstrated single-agent activity of the PD-1 mAb pembrolizumab in 
undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma, with an objective response 
rate of 40% and 20%, respectively (Tawbi 2017).  In Alliance trial A091401, limited efficacy of 
the single agent PD-1 mAb nivolumab was observed; however, the combination of nivolumab and 
ipilimumab (CTLA-4 mAb) demonstrated promising efficacy in sarcoma subtypes of 
undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma, and angiosarcoma 
(D’Angelo 2018).   
Based upon the premise that VEGF promotes an immunosuppressive microenvironment and 
contributes to immune checkpoint inhibitor resistance, a single-arm, phase 2 study of 
pembrolizumab in combination with the VEGFR kinase inhibitor axitinib reported encouraging 
activity in the subset of patients with alveolar soft part sarcoma (ASPS) with an overall response 
rate of 54.5% in 11 evaluable patients (Wilky 20199). 
2.2.1.6 
Anaplastic Thyroid Cancer  
Anaplastic thyroid cancer (ATC) is a highly aggressive cancer with a poor prognosis, having a 
median survival less than 6 months and 10-year survival rates less than 5% (Wendler 2016).  
Although ATC comprises less than 2% of thyroid cancers, it is estimated to be the cause of more 
than 50% of annual thyroid cancer-related mortality (Smallridge 2012). 
The current standard treatment of ATC includes surgical debulking, external beam radiation 
therapy, and chemotherapy.  However, due to its aggressive characteristics, surgery does not 
achieve satisfactory outcomes, and ATC acquires chemotherapy resistance easily.  Treatments for 
ATC remain palliative, with cytotoxic chemotherapies generally recommended despite no 
improvement in survival (Ferrari 2020).  
Recent studies have shown that 20% to 50% of ATCs harbor activating B-Raf kinase V600E 
mutations (BRAFV600E), which has shown to be a molecular driver associated with ATC 
tumorigenesis.  In a phase 2, open-label trial, 16 ATC patients with BRAFV600E mutations were 


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treated with a combination of a B-Raf kinase (BRAF) inhibitor (dabrafenib) and an MEK inhibitor 
(trametinib) (NCT02034110).  Patients achieved an overall response rate of 69% (95% CI: 
46.9, 86.6) and an estimated 12-month overall survival rate of 80% (Subbaiah 2018).  This trial 
demonstrated that the combination of dabrafenib + trametinib has robust clinical activity in 
BRAFV600E–mutant ATC; in 2018, the FDA approved the treatment combination for this patient 
population based on these results. 
Despite recent advancements in treatment for BRAFV600E-mutant patients, ATC remains a rare and 
aggressive disease.  There remains a high unmet medical need for effective therapies of patients 
with BRAF wild-type ATC and patients with BRAFV600E-mutant ATC following progression on 
dabrafenib + trametinib. 
Investigation of the combination of tislelizumab and surufatinib are desirable based upon the 
following facts: 
• PD-1 inhibitors combined with a VEGF tyrosine kinase inhibitor (lenvatinib) have 
demonstrated activity in ATC (Dierks 2021). 
• ATCs are highly vascular tumors. 
• ATCs are associated with enhanced levels of TAMs in the tumor microenvironment 
(Caillou 2011), which are thought to be a mechanism of resistance to immunotherapy 
alone. 
2.2.2 
Study Treatments  
Study drug is defined as a single therapeutic agent (eg, surufatinib or tislelizumab).  Study 
treatment is defined as a combination of therapeutic agents (eg, surufatinib in combination with 
tislelizumab). 
2.2.2.1 
Surufatinib  
Surufatinib (also known as HMPL-012) is a novel tyrosine kinase inhibitor developed by 
HUTCHMED Limited that inhibits VEGFR 1, 2, and 3, as well as fibroblast growth factor receptor 
(FGFR) 1, which results in inhibition of angiogenesis.  In addition, surufatinib inhibits signaling 
via CSF-1R, which is thought to down-regulate TAMs, thus promoting antitumor immunity.  
2.2.2.2 
Tislelizumab  
Tislelizumab is a humanized immunoglobulin G4 (IgG4)-variant anti–PD-1 monoclonal antibody, 
developed by BeiGene, specifically engineered to minimize binding to Fc-gamma-receptor 
immunoglobulin (FcγR).  In preclinical studies, binding to FcγR on macrophages has been shown 
to compromise the antitumor activity of PD-1 antibodies through activation of antibody-dependent 
macrophage-mediated killing of T-effector cells (Zhang 2018). 
2.2.2.3 
Justification of Dosing Strategy  
Surufatinib Dosing Strategy 
The optimal dose and dosing schedule for single agent surufatinib was determined in 2 phase 1 
studies: 1 conducted in China and the other conducted in the US.  A food effect study was also 
conducted to guide dosing in clinical trials. 


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In these early-phase studies, doses of 50 mg once daily (QD) to 350 mg QD as well as 125 mg 
twice a day (BID) and 150 mg BID were explored.  None of the dose cohorts studied reached the 
maximum tolerated dose (MTD).  However, drug exposure in the 350-mg QD group patients was 
no higher than that in the 300 mg QD group patients, therefore, increasing the dose was determined 
not likely to further increase the drug concentration in blood.  Based on the clinical safety, efficacy, 
and pharmacokinetic (PK) data, the recommended phase 2 dose (RP2D) of surufatinib was 
determined to be 300 mg QD. 
Surufatinib dosed at 300 mg QD has further demonstrated statistically significant and clinically 
meaningful efficacy in 2 completed phase 3 randomized, double-blind, placebo-controlled studies 
in patients with advanced epNET (SANET-ep) and patients with advanced pNET (SANET-p).  
Both studies were stopped early per Safety Review Committee (SRC) recommendation after 
meeting the primary endpoint at the interim analysis.  For more information, please refer to the 
surufatinib Investigator’s Brochure (IB). 
In an open-label, phase 1 dose-escalation and dose-expansion study of surufatinib and toripalimab, 
a monoclonal humanized IgG4 PD-1 antibody (NCT03879057), surufatinib doses of 200 mg QD, 
300 mg QD, and 250 mg QD were studied along with a fixed dose of toripalimab to determine the 
MTD and/or RP2D (Lu 2020). 
The RP2D was determined to be surufatinib 250 mg daily plus toripalimab.  One patient at 300 mg 
experienced dose-limiting toxicity of Grade 3 hyperthyroidism.  Four of 8 evaluable patients at 
RP2D achieved partial response (PR), and the objective response rate (ORR) and disease control 
rate (DCR) were 50% and 100%, respectively.  Additionally, there were no treatment-related fatal 
serious adverse events (SAEs).  
Preliminary PK analysis showed surufatinib exposure at steady state increased dose proportionally, 
and individual PK profiles were comparable to those of surufatinib or toripalimab from previous 
monotherapy trials.  
Surufatinib plus toripalimab was well tolerated with no unexpected safety signals observed, and 
showed encouraging antitumor activity in patients with advanced solid tumors (Lu 2020). 
Overall, the collective safety, efficacy, PK, and exploratory exposure-response results from 
single-agent and combination studies support a starting dose of 250 mg QD.  Alternate dose levels 
of 200 mg QD and 300 mg QD will allow for potential reduction or escalation based on safety and 
tolerability. 
Tislelizumab Dosing Strategy 
The clinical fixed dose of tislelizumab of 200 mg intravenously (IV), Q3W was selected based on 
comparable safety and efficacy profiles between 2 and 5 mg/kg in Study BGBA317_Study_001.  
Rates of treatment-related adverse events (AEs) and SAEs observed in patients receiving 2 mg/kg 
and 5 mg/kg Q2W and Q3W were comparable, suggesting no clear dose dependence across the 
regimens.  Additionally, PK data also show no relationship between exposure and 
treatment-emergent immune-mediated adverse events (imAEs). 
ORRs in patients treated with tislelizumab 2 mg/kg and 5 mg/kg Q2W ranged between 10% and 
15%, compared with a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg Q3W. 
Clearance of tislelizumab was not dependent of body weight, and the observed serum exposure of 
a 200-mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses.  Therefore, 


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clinical activity with a manageable and tolerable safety profile is expected to be maintained in 
patients receiving tislelizumab 200 mg Q3W. 
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.  These findings support a 200 mg Q3W dose 
regimen for pivotal studies.  Please refer to the tislelizumab IB for additional details. 
In conclusion, the observed clinical activity in patients with advanced tumors coupled with a 
manageable safety profile and supportive data support the tislelizumab dose of 200 mg IV, Q3W 
as the recommended dose for pivotal studies, and this dose will be used for combination dosing in 
this study. 
2.2.3 
Supportive Nonclinical Data  
Please refer to the surufatinib or tislelizumab IBs for additional details regarding nonclinical 
studies of surufatinib and tislelizumab, respectively. 
2.2.3.1 
Pharmacology  
Surufatinib 
Surufatinib mainly targets on VEGFR 1, 2, and 3, FGFR1, and CSF-1R.  By using a [32P-ATP] 
incorporation assay, the IC50 of surufatinib on VEGFR 1, 2, and 3 (also known as Flt1, KDR, and 
Flt4) were found to be 2 nM, 24 nM, and 1 nM, respectively.  The IC50 on the kinase activity of 
FGFR1, 2, and 3 was determined to be 15 nM, 236 nM and 181 nM, respectively.  The IC50 for 
CSF-1R (FMS) was 4 nM.  In vitro assays demonstrated that surufatinib inhibited VEGFR activity 
and suppressed phosphorylation of VEGFR with an IC50 of 2 nM and blocked cell proliferation of 
VEGF-dependent human umbilical vein endothelial cell (HUVEC) and VEGF-induced HUVEC 
tube formation.  In safety pharmacology studies, the results showed that surufatinib had a low risk 
on the cardiovascular, respiratory, and central nervous systems. 
Tislelizumab 
Tislelizumab (also known as BGBA317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against programmed cell death protein-1 (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 PD-L1 and 
programmed cell death protein ligand-2, thus inhibiting PD-1-mediated negative signaling in T 
cells.  Tislelizumab has demonstrated in vivo antitumor activity in several allogeneic xenograft 
models.  
2.2.3.2 
Toxicology  
Surufatinib 
In single-dose toxicology studies in rats and dogs, no mortality occurred up to the highest dose 
tested (2000 mg/kg), which indicated a good tolerability.  Repeat-dose toxicology studies in rats 
and dogs identified target organs that included the hepatobiliary system, kidney, immune system, 
hematopoietic system, skeletal system, pancreas, adrenal glands, uterus, and corpus luteum.  All 
effects were fully or partially reversible after a 4-week recovery period apart from effects on the 


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skeletal system (broken teeth).  In a fertility and early embryonic development study in rats, female 
fertility was affected.  In an embryo-fetal developmental study in rats, embryotoxic and teratogenic 
effects were observed, consisting of fetal external, visceral, and skeletal malformations.  In an 
embryo-fetal study in rabbits, effects on embryo formation were observed resulting in retarded 
embryonic development. Surufatinib was not genotoxic based on a standard battery of in vitro and 
in vivo studies and was also not phototoxic in vivo. 
Tislelizumab 
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 
no-observed-adverse-effect limit 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. 
2.2.4 
Supportive Clinical Data  
2.2.4.1 
Clinical Pharmacology and Pharmacokinetics  
Surufatinib 
In Chinese patients with cancer, surufatinib was absorbed rapidly, with the concentration reaching 
maximum level after 1.0 to 2.0 hours of dosing.  Mean plasma half-life ranging from 14.9 hours 
to 20.2 hours was observed.  Following multiple doses of surufatinib once daily (QD), the plasma 
surufatinib concentration reached steady state 14 days after dosing, with exposure accumulating 
1.2- to 2.4-fold at steady state compared to Day 1 (2009-012-00CH1 and 2014-012-00CH1).  
Preliminary PK results from the US patient population (2015-012-00US1 [ongoing]) showed 
surufatinib exposure, in general, increased proportionally with an increasing dose from 50 mg to 
400 mg QD.  There were no meaningful differences in surufatinib exposure between Chinese and 
US patients (Kauh 2020). 
A study for a single oral (PO) dose of surufatinib 250 mg under fasting or fed conditions indicated 
that the absorption extent of surufatinib was not affected by food intake, but the absorption rate 
was affected, as demonstrated by the significant difference in time to maximum concentration. 
Tislelizumab 
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 clearance mechanisms.  No time-varying clearance was observed in tislelizumab 
PK.  The typical estimates of clearance (CL), central volume (Vc), and peripheral volumes (V2, 
V3) were 0.164 L/day, 2.92 L, 0.928 L, and 1.39 L, respectively, with moderate interindividual 


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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 was 5.238 L and 
the terminal half-life was approximately 25.5 days (Deng 2012, Dirks 2010, Keizer 2010, 
Ryman 2017). 
Population PK analysis demonstrated that baseline age, race, alanine aminotransferase, aspartate 
aminotransferase, bilirubin, lactate dehydrogenase, estimated glomerular filtration rate, Eastern 
Cooperative Oncology Group (ECOG) performance status, immunogenicity, and sum of products 
of perpendicular diameters in classical Hodgkin lymphoma patients did not show a 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. 
2.2.4.2 
Clinical Safety  
Surufatinib 
As of 11 February 2021, the safety database includes 792 patients who received at least 1 dose of 
surufatinib as monotherapy in completed or ongoing studies.  
Of the 792 patients who received at least 1 dose of surufatinib as monotherapy, 781 patients 
(98.6%) experienced treatment-emergent adverse events (TEAEs) and 757 patients (95.6%) had 
at least 1 treatment-related TEAE.  The most commonly reported treatment-related TEAEs 
included 
proteinuria, 
hypertension, 
diarrhoea, 
blood 
bilirubin 
increased, 
aspartate 
aminotransferase increased, alanine aminotransferase increased, blood thyroid stimulating 
hormone increased, hypertriglyceridaemia, and occult blood positive.  A total of 568 patients 
(71.7%) reported TEAEs of Grade ≥3 and 509 patients (64.3%) had at least 1 treatment-related 
TEAE Grade ≥3.  Additionally, approximately one-third of patients experienced an SAE.  A total 
of 142 patients (17.9%) reported TEAEs leading to study drug discontinuation; 265 patients 
(33.5%) and 379 patients (47.9%) had TEAEs leading to dose reduction and dose interruption, 
respectively. 
Please refer to the surufatinib IB for the most up to date safety information, and additional details 
regarding adverse events reported in ongoing and completed studies of surufatinib. 
As of 11 February 2021, the safety database includes 163 patients who received surufatinib in 
combination with another therapeutic agent during completed or ongoing studies.  
Of 163 patients who received at least 1 dose of surufatinib in a combination regimen, 158 patients 
(96.9%) experienced TEAEs and 153 patients (93.9%) had at least 1 treatment-related TEAE.  A 
total of 76 patients (46.6%) reported TEAEs of Grade ≥3 and 58 patients (35.6%) had at least 1 
treatment--related TEAE of Grade ≥3.  A total of 64 patients (39.3%) reported TEAEs leading to 
dose interruption and 52 patients (31.9%) reported treatment-related TEAEs leading to dose 
interruption. 


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Tislelizumab 
As of 20 May 2020, a pooled analysis of 7 monotherapy studies was conducted to provide a 
comprehensive safety assessment separate from combination therapy.  There were 1181 patients 
treated with monotherapy in 5 solid tumor studies.  
Of the 1181 patients, 96.4% experienced at least 1 TEAE and 788 patients (66.7%) experienced at 
least 1 treatment-related TEAE.  TEAEs ≥Grade 3 were reported by 552 patients (46.7%).  One 
hundred sixty-seven patients (14.1%) experienced a ≥Grade 3 treatment-related TEAE.  Serious 
TEAEs were reported in 415 patients (35.1%), while 107 patients (9.1%) experienced a serious 
treatment-related TEAE.  Seventy-four patients (6.3%) died as a result of a TEAE. 
Infusion-related 
reactions, 
including 
high-grade 
hypersensitivity 
reactions, 
following 
administration of tislelizumab are common.  Of 1181 patients, 45 (3.8%) experienced at least 1 
infusion-related reaction of any grade.  Please refer to the tislelizumab IB for the most up to date, 
and additional details regarding clinical safety in ongoing and completed studies of tislelizumab. 
Immune-Mediated Adverse Events 
Anti-PD-1 therapies are known to cause imAEs in some patients and therefore have been defined 
as AEs of special interest (AESI) in tislelizumab clinical studies, and as such, are being reported 
expeditiously and monitored closely. 
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.  
imAEs 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. 
imAEs of hepatitis, pneumonitis, colitis, endocrinopathies, myocarditis, diabetes, and serious skin 
adverse reactions have been identified as risks for tislelizumab.  
Please refer to the tislelizumab IB for additional details regarding clinical safety in ongoing and 
completed studies of tislelizumab. 
2.2.4.3 
Clinical Efficacy  
Surufatinib 
Surufatinib has demonstrated statistically significant and clinically meaningful efficacy in 
2 completed phase 3 randomized, double-blind, placebo-controlled studies in China in patients 
with advanced epNET (SANET-ep) and patients with advanced pNET (SANET-p) and has shown 
promising antitumor activity in the US (Study 2015-012-00US1).  The SANET-ep study met its 
primary endpoint at the planned interim analysis, with significantly improved PFS in 
surufatinib--treated patients compared with placebo-treated patients (median PFS of 9.2 months in 
surufatinib--treated patients versus 3.8 months in placebo-treated patients; hazard ratio [HR] 
0.334; p<0.0001).  Similarly, surufatinib-treated patients in the SANET-p study showed a 
statistically significant improvement in PFS compared with placebo-treated patients (median PFS 
of 10.9 months in surufatinib-treated patients versus 3.7 months in placebo-treated patients; 
HR 0.491; p=0.0011).  In addition to the primary PFS endpoint, SANET-ep and SANET-p 
demonstrated meaningful improvements in other important efficacy measures such as ORR, DCR, 
duration of response (DoR), and time to response (TTR).  


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In Study 2015-012-00US1, patients with biliary tract cancer, epNET, pNET, and STS were 
enrolled.  Based on interim analysis for epNET and pNET cohorts, the PFS rate at 11 months for 
patients with epNETs (16 patients) was 51.1% (95% CI: 12.8, 80.3); and 57.4% (95% CI: 28.7, 
78.2) for patients with pNETs (16 patients).  The observed median PFS was 11.50 months (95% 
CI: 6.47, 11.50), and 15.18 months, (95% CI: 5.19, NR), for patients with epNETs and pNETs, 
respectively.  An ORR of 6.3% was observed for patients with epNETs, and 18.8% for patients 
with pNETs.  A disease control rate of 90.6% (95% CI: 75.0, 98.0) was observed for all NET 
patients (93.8% epNET; 87.5% pNET).  All patients had previously received everolimus and/or 
sunitinib (Paulson 2021).  Enrollment to the STS cohort is ongoing, and no analysis has been 
performed to date. 
Tislelizumab 
Efficacy data are available from 9 clinical studies, including 5 monotherapy and 4 combination 
studies.  Preliminary antitumor activity has been observed across multiple tumor subtypes.  Please 
refer to the tislelizumab IB for current details regarding efficacy of tislelizumab. 
2.2.5 
Benefit:Risk Assessment  
2.2.5.1 
Risk Assessment  
Appropriate exclusion criteria, monitoring, and dose modification guidance are included in the 
protocol to ensure the safety of patients enrolled in the clinical trial.  Patients are excluded if they 
have signs, symptoms, or history that may put them at risk in the context of the identified and 
potential risks of surufatinib.  Section 7.1.4 provides detailed guidance on dose modifications for 
AESI including liver function impairment, hypertension, proteinuria, and hemorrhage.  General 
dosing guidance to protect patients is included in Section 6.2.2.  Thus, the identified and potential 
risks of treatment with surufatinib and tislelizumab are appropriately mitigated by measures in the 
protocol. For the most up-to-date summary of potential risks and mitigation strategies, please refer 
the surufatinib and tislelizumab IBs, respectively.  
2.2.5.2 
Benefit Assessment  
Surufatinib 
Surufatinib has demonstrated statistically significant and clinically meaningful efficacy in 
2 completed phase 3 randomized, double-blind, placebo-controlled studies in patients with 
advanced epNET (SANET-ep) and patients with advanced pNET (SANET-p).  Additionally, data 
from the 2015-012-00US1 trial confirms that surufatinib also shows antitumor activity in a western 
patient population. 
Tislelizumab 
Preliminary data from ongoing phase 1 and phase 2 trials of single agent tislelizumab suggested 
that there is antitumor activity across a variety of tumor types.  Tislelizumab has also been shown 
to have antitumor 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, antitumor activity has been seen in, but not limited to, cholangiocarcinoma, 
gastric cancer, colorectal cancer, hepatocellular carcinoma, bladder cancer, and SCLC.  


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2.2.5.3 
Overall Benefit:Risk Conclusion  
There remains an unmet need for patients with advanced CRC, NETs, SCLC, gastric cancer, STS, 
and ATC.  Evidence to date suggests that both surufatinib and tislelizumab may potentially be 
efficacious in the treatment of various cancers, including those in this proposed trial.  
Safety data from the completed and ongoing studies showed that surufatinib and tislelizumab were 
both well tolerated, with most of the AEs reported as Grade 1 to 2 (see current IBs), and there have 
been no new or unexpected safety findings from the ongoing clinical trials to date.  
The potential drug-drug interaction between surufatinib, a small molecule drug product, and 
tislelizumab, a monoclonal antibody, is expected to be very low.  The tolerability of tyrosine kinase 
inhibitor and anti-PD-1 therapy combination has been demonstrated in other combination trials 
(eg, lenvatinib plus pembrolizumab in patients with advanced endometrial cancer [Makker 2020] 
and avelumab plus axitinib in patients with advanced hepatocellular carcinoma [Kudo 2019]).  The 
toxicity profile of each therapy appeared consistent with their monotherapy profiles; thus, no 
severe overlapping toxicity is expected with surufatinib in combination with tislelizumab. 
Combining surufatinib with tislelizumab may have synergistic effects, where inhibition of 
angiogenesis along with stimulation of an immune response may enhance the overall antitumor 
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 malignancies, the lack of effective alternative treatments, 
and the efficacy seen in previous and ongoing clinical trials, the overall benefit:risk assessment 
supports the continued administration of surufatinib 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 3. 
Table 3 
Objectives and Corresponding Endpoints  
Tier 
Objectives 
Endpoints 
Primary 
Part 1 
To evaluate the safety and tolerability of 
surufatinib, thereby determining the RP2D 
and/or the MTD of surufatinib in 
combination with tislelizumab 
Part 1 
Safety, including DLTs, TEAEs, SAEs, AEs 
leading to discontinuation, ECGs, clinical 
laboratory abnormalities, and vital signs 
Part 2 
To evaluate the ORR as assessed by the 
investigator in patients with advanced solid 
tumors when treated with surufatinib in 
combination with tislelizumab according to 
RECIST v1.1 
Part 2 
ORR at 12 weeks  
Secondary 
Part 1 
• 
To evaluate the antitumor activity in 
patients with advanced solid tumors 
when treated with surufatinib in 
combination with tislelizumab 
according to RECIST v1.1 
• 
To characterize the PK and 
immunogenicity of tislelizumab and 
surufatinib in combination 
Part 1 
• 
ORR, PFS, DCR, CBR, DoR, TTR   
• 
Concentrations of surufatinib in 
plasma and tislelizumab in serum 
• 
Incidence of ADA to tislelizumab  
Part 2 
• 
To evaluate further anticancer 
effects of surufatinib in combination 
with tislelizumab  
• 
To characterize the safety and 
tolerability of surufatinib in 
combination with tislelizumab 
• 
To characterize the PK and 
immunogenicity of tislelizumab and 
surufatinib in combination 
Part 2 
• 
PFS, DCR, CBR, DoR, TTR 
• 
OS: Cohorts A and F 
• 
Safety, including TEAEs, SAEs, 
AEs leading to discontinuation, 
ECGs, clinical laboratory 
abnormalities, and study drug 
discontinuation due to AEs 
• 
Concentrations of surufatinib in 
plasma and tislelizumab in serum 
• 
Incidence of ADA to tislelizumab  
Exploratory 
Part 2 
• 
To explore the distribution of PD-L1 
expression and potential association 
between PD-L1 expression and 
tislelizumab treatment effect 
• 
Cohort F: To explore the influence 
of gene abnormalities on safety, and 
efficacy 
Part 2 
• 
PD-L1 expression 
• 
Cohort F: Changes from baseline in 
tumor markers, correlation with drug 
exposure, and association with 
efficacy and safety parameters 
ADA=antidrug antibodies; AE=adverse event; CBR=clinical benefit rate; CRC=colorectal cancer; DCR=disease 
control 
rate; 
DLT=dose-limiting 
toxicity; 
DoR=duration 
of 
response; 
ECG=electrocardiogram; 
MTD=maximum tolerated dose; ORR=objective response rate; OS=overall survival; PD-L1=programmed 
death-ligand 1; PFS=progression-free survival; PK=pharmacokinetic(s); RECIST v1.1=Response Evaluation 
Criteria in Solid Tumors version 1.1; RP2D=recommended phase 2 dose; SAE=serious adverse event; 
TEAE=treatment-emergent adverse event; TTR=time to response.  


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4 
STUDY DESIGN  
The study design schema is presented in Figure 1. 
4.1 
Overall Design  
This open-label, phase 1b/2 study of surufatinib in combination with tislelizumab will evaluate the 
safety, tolerability, PK, and efficacy in patients with advanced solid tumors.  The study consists of 
2 parts: dose escalation (Part 1) and dose expansion (Part 2).  Part 1 will be conducted to determine 
the RP2D and/or the MTD of surufatinib in combination with tislelizumab in patients with 
advanced or metastatic solid tumors who have progressed on or are intolerant of standard therapies.  
Part 2 will be an open-label, multicohort design to evaluate the antitumor activity of surufatinib in 
combination with tislelizumab in patients with specific types of advanced or metastatic solid 
tumors.  Patients will receive the RP2D (300 mg surufatinib PO, QD + 200 mg tislelizumab, IV, 
Q3W) determined in Part 1 of this study. 
4.1.1 
Part 1 (Dose Escalation)  
Patients with advanced or metastatic solid tumors of any kind who have progressed on or are 
intolerant of standard therapies will be enrolled into a dose-escalation phase using a 3+3 design.  
A total of 6 to 12 patients will be enrolled into this portion of the study. 
2 dose levels will be evaluated during this phase of the study (Table 4).Dose level 1: 250 mg 
surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W 
• Dose level 2: 300 mg surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W 
A minimum of 3 patients will be enrolled at the starting dose (dose level 1). 
• If no patients experience a dose-limiting toxicity (DLT) (Section 4.1.2), then the dose will 
be escalated to dose level 2. 
• If one of the 3 patients at dose level 1 experiences a DLT, then 3 additional patients will be 
enrolled to dose level 1. 
− If one of 6 patients experience a DLT, then the dose will be escalated to dose level 2. 
− If two of 6 patients experience a DLT, then the dose will be deescalated to dose level -1, 
(200 mg surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W). 
• If >33% of patients at any dose level experience a DLT, then the dose escalation will be 
halted. 
Any patient who, in the opinion of the investigator, is deriving clinical benefit from the study 
treatment, may continue treatment beyond Cycle 1 until disease progression, unacceptable toxicity, 
withdrawal of consent, new anticancer therapy, lost to follow-up, or death. 


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Table 4 
Dose Levels  
Dose Level 
Dosage 
Surufatinib 
Tislelizumab 
-1 
200 mg PO, QD 
200 mg IV, Q3W 
1  
250 mg PO, QD 
200 mg IV, Q3W 
2 
300 mg PO, QD 
200 mg IV, Q3W 
IV=intravenous; PO=orally; Q3W=every 3 weeks; QD=once daily.  
4.1.2 
Assessment of Dose-limiting Toxicities  
If patients do not meet the below conditions, new patients will be enrolled as replacements to 
ensure there are at least 3 DLT-evaluable patients in each dose group. 
AEs will be assessed per the DLT criteria shown below during the 21-day DLT assessment 
window, which begins on the first day of the administration of the study treatment.  Patients will 
be considered evaluable for DLTs if they meet the following criteria: 
• Received ≥85% of scheduled surufatinib and ≥67% (approximately two-thirds) of 
scheduled tislelizumab administration during the DLT assessment window and/or 
• Experienced a DLT  
Patients will be considered not evaluable for DLTs if any of the following occur during the DLT 
assessment window: 
• They were withdrawn from the study. 
• They did not receive ≥85% of scheduled surufatinib and ≥67% (approximately two-thirds) 
of scheduled tislelizumab drug administration. 
• They received prophylactic supportive care that confounds the evaluation of DLTs (not 
including supportive care described as part of the DLT definition).  
• They have taken a strong inhibitor or inducer of enzyme cytochrome P450, family 3, 
subfamily A4 (CYP3A4) (Appendix 3) as the exposure to surufatinib may be impacted.  
Patients who are not DLT evaluable will be replaced.  
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. 
According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
evaluation criteria, the following AEs that occur within 21 days (DLT observation period) after 
the first drug administration of each cohort shall be defined as a DLT once they are determined by 
the investigator to be related to surufatinib and/or tislelizumab: 
1. Nonhematologic toxicities 
a. Grade 3 or higher nonhematologic toxicity will be considered DLTs, except for the 
following conditions: 
i. Grade 3 fatigue lasting <7 days. 
ii. Grade 3 rash that returns to baseline or ≤Grade 1 with appropriate supportive 
treatment within 7 days. 


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iii. Grade 3 hypertension downgraded to ≤Grade 1 within 7 days with appropriate 
supportive therapy. 
iv. Grade 3 endocrinopathy that is adequately controlled by hormonal replacement, 
does not require hospitalization, AND resolves to ≤Grade 1 within 7 days. 
v. Grade 3 or higher amylase or lipase elevation that is not associated with 
symptoms or clinical manifestations of pancreatitis. 
vi. Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care 
vii. Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not 
clinically complicated, and resolves spontaneously or responds to conventional 
medical interventions. 
1. Hematologic toxicities 
b. Grade 3 or higher febrile neutropenia (neutrophil count <1.0×109/L, accompanied 
with a single body temperature measurement of ≥38.3°C [101°F] or ≥38°C [100.4°F] 
persisting for 1 hour) 
c. Grade 4 neutropenia lasting >7 days 
d. Grade 4 thrombocytopenia lasting >7 days 
e. Grade 3 thrombocytopenia accompanied with severe bleeding 
f. Grade 4 anemia 
Any life-threatening complication or abnormality not covered in the NCI CTCAE v5.0. 
When counting abnormal laboratory results at the patient level, the most severe toxicity during 
study treatment will be chosen.  
4.1.2.1 
Recommended Phase 2 Dose and Maximum Tolerated Dose  
As of 02 September 2021, all patients enrolled in the Part 1 dose escalation phase of this study 
completed the DLT assessment period.  The SRC convened and determined the RP2D to be used 
for Part 2 dose expansion to be: 
300 mg surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W 
This determination was made based on review of the available cumulative safety data of all 
enrolled patients (n=12; dose level 1: 6, dose level 2: 6), and the observation of 2 DLTs (1 in 
each dose level).  In dose level 1, one patient experienced a DLT of Grade 3 fatigue.  In dose 
level 2, one patient experienced a DLT of Grade 3 dehydration. 
MTD was not reached. 
Overall treatment with the combination of surufatinib and tislelizumab was well tolerated across 
both dose levels.  
4.1.3 
Part 2 (Dose Expansion)  
The dose -expansion portion of this study will enroll approximately 110 patients with various types 
of advanced or metastatic solid tumors across 8 cohorts (Table 5) to evaluate the antitumor activity 
of surufatinib in combination with tislelizumab.  Patients will be enrolled to one of the cohorts 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 4 3  
C O N FI D E N TI A L  
de pe n di n g o n t heir t y pe of ca n cer .  Eac h p atie nt will be treate d u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, ne w a ntica ncer t hera p y, l ost t o f oll o w -u p , or deat h . 
A n y patie nt w h o, i n t he o pi ni o n of t he i n vesti gat or, is deri vi n g cli nical b e nefit fr o m t he st u d y 
treat me nt, ma y c o nti n ue treat me nt after disc ussi o n a n d a p pr o val fr o m t he s p o ns or.  
, e nr oll me nt t o st u d y 2 0 2 0 -0 1 2 -G L O B 1  was halte d base d u p o n t he 
strate gic e val uati o n of s ur ufati ni b i n t he U nite d States a n d E ur o pe wit h H U T C H M E D as t he st u d y 
S p o ns or .   
T he n u m ber of patie nts e nr olle d i n eac h c o h ort at t he ti me of Pr ot oc ol A me n d me nt 4  are s h o w n i n 
Ta ble 5 . 
A t t he ti me of  P r ot oc ol A me n d me nt 5, 
 
 T he st u d y will b e ter mi nate d eit her 9 0 d a ys after 
t he last patie nt has recei v e d tisleliz u ma b, or t he p oi nt at w hic h all i m A Es ha ve res ol ve d or are n o 
l o n ger bei n g f oll o we d, w hiche ver o cc urs  earlier. 
T a ble 5  
D ose E x p a nsi o n C o h orts   
Dise ase C o h ort  
Pl a n ne d N u m ber  of P atie nts  
Act u al N u m ber of P atie nts  as of 
A m e n d m e nt 4  
C o h ort A: C R C  
1 5  
1 5  
C o h ort B: N E T  
 
 
C o h ort B 1: T h oracic N E Ts  
1 0  
1 0  
C o h ort B 2: G E P N E Ts  
2 0  
2 0  
C o h ort C: S C L C  
1 5  
1 5  
C o h ort D:  G C  
1 5  
3  
C o h ort E: S T S  
 
 
C o h ort E 1: A S P S  
1 0  
0  
C o h ort E 2: U P S  
1 0  
9  
C o h ort F: A T C  
1 5  
3  
A S P S =al ve olar s oft part sarc o ma; A T C =a na plastic t h yr oi d ca ncer; C R C =c ol orectal ca ncer; G C = gastric ca ncer; 
G E P = gastr o e nter o pa n creatic; N E T = n e ur oe n d ocri ne t u m or; S C L C =s mall -cell l u n g ca ncer; S T S =s oft -tiss ue 
sarc o ma; U P S = u n differe ntiate d ple o m or p hic sarc o ma. 
P atie nts i n C o h ort  A  m ust ha ve l ocall y a d va n ce d or m C R C t hat is micr osatellite sta ble a n d was 
pre vi o usl y treate d wit h at least 3 pri or li nes of t hera p y.  
P atie nts i n C o h ort B,  wit h  t h oracic or gastr o e nter o pa ncreatic ( G E P ) N E T, m ust ha ve 
pr o gressi ve, l oc all y a d va nce d or metast ati c, l o w-t o-i nter me diate gra de ( Gra de 1 or G ra de 2), 
well -differe ntiate d N E Ts  t hat ha ve pr o gresse d o n at least 1 li ne of sta n dar d t hera p y. 
P atie nts i n C o h ort C  m ust ha ve l ocall y a d va n ce d or metastatic s mall-cell l u ng  ca ncer (S C L C ) 
t hat was pre vi o usl y pr o gresse d o n first-li ne c h e m ot hera p y. 
P atie nts i n C o h ort D  m ust ha ve  micr osatellite sta ble, P D -L 1 ≥5 %,  l ocall y a d va nce d or 
metastatic a de n o carci n o ma of t he st o mac h or gastr oes o p ha geal j u ncti o n , a n d pre vi o usl y bee n 
treate d wit h at least 2 li nes of sta n dar d t h era p y. 
C CI
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Patients in Cohort E, with ASPS or undifferentiated pleomorphic sarcoma (UPS), must have 
progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of standard 
therapy or be unsuitable for standard frontline cytotoxic chemotherapy. 
Patients in Cohort F must have locally advanced or metastatic ATC.  Patients who have a 
BRAFV600E mutation must have previously been treated with 1 line of systemic therapy (not 
including radiation therapy) with a BRAF-targeted therapy. 
4.2 
Design Rationale  
This open-label, dose-escalation, dose-expansion design was chosen to determine the RP2D and/or 
the MTD for the combination of surufatinib and tislelizumab in patients with solid tumors, and to 
explore the preliminary antitumor activity of the combination in various selected solid tumors. 
While both surufatinib and tislelizumab have been studied extensively as single agents in various 
tumor types, they have not been studied in combination previously.  It is hypothesized that the 
combination may improve response rates and duration of treatment, while maintaining a tolerable 
safety profile.  
The dose escalation and expansion design allows for management of known and potential risks, 
while investigating the possible benefits (ie, antitumor activity) of the combination in various solid 
tumors.  For further detail on the risk/benefit assessment, refer to Section 2.2.5.  


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 4 5  
C O N FI D E N TI A L  
5  
P O P U L A TI O N   
5. 1  
Recr uit me nt   
T o  e nr oll 6 – 1 2 patie nts i n Part 1, a p pr o xi matel y  4 -6  sites will be o pe ne d f or patie nt recr uit me nt.  
T o e nr oll a p pr o xi matel y 1 1 0  patie nts i nt o t he 8  i n dicati o n-s pecific c o h orts i n Part 2, sites i n t he 
U S a n d E ur o pe will be o pe ne d f or p atie nt recr uit me nt .  
, e nr oll me nt t o st u d y 2 0 2 0 -0 1 2 -G L O B 1  was halte d base d u p o n t he 
strate gic e val uati o n of  s ur ufati ni b i n t he U nite d States a n d E ur o pe wit h H U T C H M E D as t he st u d y 
S p o ns or .  T his c ha n ge was  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 
s ur ufati ni b treat me nt.  C urre ntl y e nr olle d patie nts w h o were  d eri vi n g cli nical be n efit fr o m 
treat me nt wit h s ur ufati ni b were a ble t o  c o nti n ue t o partici pate i n t he st u d y  as per t he pr ot o c ol .   
At t he ti me of P r ot oc ol A me n d me nt 5, 
 
 T he st u d y will b e ter mi nate d eit her 9 0 d a ys after 
t he last patie nt has recei v e d tisleliz u ma b, or t he p oi nt at w hic h all i m A Es ha ve res ol ve d or are n o 
l o n ger bei n g f oll o we d, w hic he ver o cc urs  earlier. 
5. 2  
Defi niti o ns   
Patie nt s officiall y e nter t he scree ni n g p eri o d f oll o wi n g pr o visi o n of i nf or me d c o nse nt eit her 
directl y or via a le gall y acce pta bl e  re prese ntati ve. 
Patie nt s w h o wit h dra w fr o m t he st u d y after si g ni n g t he i nf or m e d c o ns e nt f or m (I C F) a n d bef ore 
e nr oll me nt  will  be c o nsi d ere d scree n fail ures.   A scree n fail ure is a c o nse nte d patie nt  w h o has bee n 
dee me d i neli gi ble o n t he basis of 1 or m ore eli gi bilit y criteria or w h o has wit h dra w n c o nse nt pri or 
t o recei vi n g tr eat me nt.  Patie nt s w h o faile d t he ori gi nal scree ni n g ma y b e scree ne d a gai n usi n g 
t heir ori gi nal patie nt  i d e ntificati o n n u m ber as assi g ne d b y i nteracti ve we b res p o ns e s yste m 
(I W R S).  A patie nt  ma y o nl y b e rescree ne d o nce  a n d is n ot re q uire d t o si g n a n ot her I C F  if t he 
rescree ni n g oc c urs wit hi n 2 8 da ys fr om t he pre vi o us I C F si g nat ure d ate.  
A n e nr olle d patie nt  is o ne w h o has b ee n dee me d eli gi ble a n d has b ee n assi g ne d t o a treat me nt 
gr o u p.  
5. 3  
I ncl usi o n Criteri a  
T o be eli gi ble f or e nr oll me nt  i n t his st u d y, eac h i n di vi d ual m ust satisf y all of t he f oll o wi n g criteria: 
1.  Willi n g a n d a ble t o pr o vi de i nf or me d c o nse nt si g n e d b y st u d y patie nt or l e g all y acce pta ble 
re pres e ntati ve, as s pe cifi e d b y healt h a ut h orities a n d i nstit uti o nal g ui deli nes 
2.  ≥1 8 years of a ge  
3.  Part 1 : ha ve e val ua ble lesi o ns (acc or di n g t o Res p o nse E val uati 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 ]) 
4.  Part 2 : ha ve meas ur a ble l esi o ns (acc or di n g t o R E CI S T v 1. 1)  
5.  A bs ol ute ne utr o p hil c o u nt ( A N C) of ≥1. 5 × 1 0 9/ L, platelet c o u nt of ≥1 0 0 × 1 0 9/ L, a n d 
he m o gl o bi n ≥9  g/ d L  
6.  Ser u m t otal bilir u bi n ( T BI L) < 1. 5 ti mes t he u p per li mit of n or mal ( U L N)  
7.  Pr otei n uria < 2 + b y uri n al ysis; if p r otei n uria ≥2 +, pr otei n uria < 1  g b y 2 4 -h o ur uri nar y 
pr otei n test is re q uire d  
C CI
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8. Patients without liver metastases: must have alanine aminotransferase (ALT) and/or AST 
levels ≤2.5 times the ULN.  Patients with liver metastases: must have ALT and AST levels 
≤5 times the ULN 
9. Creatinine clearance ≥60 mL/min, as calculated by the Cockcroft-Gault formula  
10. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin 
time (aPTT) ≤1.5 × ULN, unless the patient is currently receiving anticoagulants for 
prophylactic purposes. 
11. Have a performance status of 0 or 1 on the ECOG scale 
12. Female patients of childbearing potential and male patients with partners of childbearing 
potential: agree to use a highly effective form(s) of contraception that results in a low 
failure rate when used consistently and correctly.  Additional details are described in 
Section 5.5.1.  
Dose Escalation: 
13. Histologically or cytologically documented, locally advanced or metastatic solid 
malignancy of any type that has progressed on or are intolerant of standard therapies and 
for which no curative therapy exists. 
Dose Expansion: 
14. Histologically or cytologically documented, locally advanced or metastatic 
g. Cohort A: adenocarcinoma of the colon or rectum that is microsatellite stable.  Patients 
must have progressed on or had discontinued due to intolerable toxicity to the following 
agents: fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF targeted therapy, and 
if RAS wild-type and anti-epidermal growth factor receptor antibody therapy.  
Treatment progression is defined as disease progression during or within 3 months after 
the last dose of standard therapy.  Prior therapy could have included adjuvant 
chemotherapy if a tumor had recurred within 6 months after the last administration of 
treatment. 
Note: Eligibility also requires knowledge of tumor RAS status (wild type or mutant) as 
reported by investigators. 
h. Cohort B: progressive, low, or intermediate grade (Grade 1 or Grade 2) NETs of 
thoracic (B1) or GEP (B2) origins.  Patients must have radiological documentation of 
progression of disease in the last 6 months prior to the initiation of study treatment and 
must have progressed on at least 1 line of standard therapy for metastatic disease. 
i. For NETs originating from the thorax, 
A. Grade 1 is defined as <2 mitoses/10 high-power field (HPF) and no necrosis. 
B. Grade 2 is defined as 2-10/10 HPF and/or foci of necrosis. 
ii. For NETs originating from GEP, 
A. Grade 1 is defined as <2 mitoses/10 HPF and/or <3% Ki-67 index. 
B. Grade 2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index  
iii. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade 
is used to assign classification. 
 


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Patients who have functioning NETs and have been on a stable dose of an SSA for a 
minimum of 2 months prior to the first dose of study treatment for control of their 
secretory symptoms will be eligible. 
 
Note: Prior therapy with a somatostatin analog is considered 1 line of therapy. 
 
i. Cohort C: SCLC that has progressed on standard first line chemotherapy treatment. 
j. Cohort D: Adenocarcinoma of the stomach or gastroesophageal junction and have 
progressed on at least 2 prior lines of therapy.  Must be microsatellite stable and have 
tumor stain for PD-L1 by combined positive score ≥5%. 
k. Cohort E: ASPS (E1) or UPS (E2).  Patients must have radiological documentation of 
disease progression in the last 3 months prior to the initiation of study treatment and 
have progressed on, or had discontinued due to intolerable toxicity to, at least 1 line of 
standard therapy or be unsuitable for standard frontline cytotoxic chemotherapy. 
l. Cohort F: Anaplastic thyroid cancer (a diagnosis that is noted to be consistent with 
anaplastic thyroid cancer is acceptable) that is considered not curable by resection.  
Patients with a BRAFV600E mutation must have previously been treated with 1 line of 
systemic therapy with a BRAF-targeted therapy.  Prior cytotoxic chemotherapy and 
radiation for local disease control is not considered a prior line of therapy. 
15. Patients in dose expansion: must be able to provide a minimum of 10 unstained slides for 
central confirmation of PD-L1 expression and microsatellite stability testing.  In the event 
archived tumor samples are not available for testing, patients may opt for a core needle 
biopsy prior to beginning protocol therapy if medically feasible.  Patients in Cohort F must 
also undergo core needle biopsy. 
5.4 
Exclusion Criteria  
An individual is ineligible for this study if he or she meets any of the following criteria: 
1. AEs due to previous antitumor therapy has not recovered to CTCAE ≤Grade 1, except 
alopecia and peripheral neurotoxicity with CTCAE ≤Grade 2 
2. Part 2 patients with CRC (Cohort A), NETs (Cohort B), ASPS (Cohort E1), and ATC 
(Cohort F): previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, anti-cytotoxic 
T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on 
T cell costimulatory or checkpoint pathway 
Note: Patients in the Part 1 and patients in Part 2 Cohorts C (SCLC), D (gastroesophageal 
junction or Gastric cancer), or E2 (UPS) may have received previous treatment with anti-
PD-1, anti-PD-L1/L2 antibodies, CTLA-4 antibody, or any other antibody acting on T cell 
costimulatory or checkpoint pathway; 
3. Previous treatment with surufatinib 
4. Uncontrollable hypertension, defined as systolic blood pressure (BP) ≥140 mmHg and/or 
diastolic BP ≥90 mmHg 
5. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, 
including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other 
digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal 
conditions that may cause bleeding or perforation by investigator's discretion 


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6. History or presence of a serious hemorrhage (>30 mL within 3 months), hemoptysis 
(>5 mL blood within 4 weeks), or life-threatening thromboembolic event within 6 months 
7. Clinically significant cardiovascular disease, including but not limited to, acute myocardial 
infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary 
artery bypass grafting, congestive heart failure according to the New York Heart 
Association classification ≥2, ventricular arrhythmias which need drug treatment, or left 
ventricular ejection fraction (LVEF) <50% 
8. QT interval corrected by the method of Fredericia (QTcF) ≥480 milliseconds 
9. Other malignant tumors within 5 years prior to screening (except cured basal-cell 
carcinoma or squamous carcinoma at skin and cervical carcinoma in situ) 
10. Antitumor therapy received within 2 weeks or 5 half-lives, whichever is shorter, prior to 
the initiation of the investigational treatment, including, but not limited to, chemotherapy, 
radical radiotherapy, targeted therapy, immunotherapy, hepatic embolization, cryoablation, 
and radiofrequency ablation 
11. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of 
the study treatment 
12. Strong inducers or inhibitors of Cytochrome P450, family 3, subfamily A (CYP3A) taken 
within 2 weeks (or 5x half-lives, whichever is greater) prior to the first study treatment 
13. Any clinically significant active infection, including, but not limited to, known human 
immunodeficiency virus (HIV) infection 
14. Known history of active viral hepatitis.  For patients with evidence of chronic hepatitis B 
virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if 
indicated.  Patients with hepatitis c virus (HCV) infection who are currently on treatment 
are eligible if they have an undetectable HCV viral load.  Patients with an unknown history 
of viral hepatitis must be screened for HBV with HBs antigen; HBc antibody and HBS 
antibody; and HBV-DNA, if indicated and for HCV with HCV antibody. 
a. Patients with detectable HBsAg or detectable HBV DNA should be managed per 
treatment guidelines.  Patients receiving antivirals at screening should have been 
treated for >2 weeks before the first dose of study treatment. 
b. Patients with a negative HCV antibody test at Screening or positive HCV antibody test 
followed by a negative HCV RNA test at Screening are eligible.  The HCV RNA test 
will be performed only for patients testing positive for HCV antibody. 
15. Brain metastases and/or leptomeningeal disease and/or spinal cord compression untreated 
with surgery and/or radiotherapy and without clinical imaging evidence of stable disease 
(SD) for 14 days or longer.  Patients requiring steroids within 4 weeks prior to start of study 
treatment will be excluded. 
16. Used corticosteroids (prednisone or other steroids with equivalent efficacy at a dose of 
>10 mg/day) or other immunosuppressants for systemic therapy within 2 weeks before the 
first drug administration.  Nasal spray, inhaled, or other topical steroids are allowed 
(ie, ≤10 mg/day of prednisone or other glucocorticoids at an equivalent dose) 
17. For patients with NETs: administration of SSAs in the absence of secretory symptoms 
discontinued at least 4 weeks before the first dose of study treatment;  
18. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 8) with the following exceptions: 
a. Controlled Type 1 diabetes 


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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) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
19. Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the 
duration of the study 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines and are not allowed. 
20. Major surgeries within 60 days prior to first dosing 
21. Uncontrollable malignant pleural effusion, ascites, or pericardial effusion (defined as 
ineffectively controlled by diuresis or puncture drainage judged by investigators) 
22. High risk of bleeding at screening due to tumor invasion into major vessels, such as 
pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by 
investigators 
23. Arterial thrombosis or thromboembolic events (including stroke and/or transient ischemic 
attack) within 12 months prior to first dosing 
24. Patients with a history of deep venous thrombosis within 6 months prior to first dose, unless 
they have been on a stable dose of anticoagulation for at least 4 weeks prior to first dosing 
or have completed a planned course of anticoagulation 
25. Tumor invasion of a large vascular structure (eg, pulmonary artery, the superior or inferior 
vena cava)  
26. Clinically significant abnormal electrolyte abnormality as judged by investigators 
27. Active severe infection or with an unexplained fever >38.3°C during screening or the first 
day of study treatment administration (at the discretion of the Investigator, patients with an 
infection that is controlled with appropriate therapy are eligible); refer to Appendix 10 for 
coronavirus disease 2019 (COVID-19) risk assessment  
28. Active pulmonary tuberculosis and receiving anti-tuberculosis treatment or with anti-
tuberculosis treatment within 1 year prior to first dosing 
29. History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation 
pneumonitis, drug-related pneumonia, severe impairment of the lung function, etc. that 
may interfere with the detection and treatment of suspected drug-related lung toxicity, 
except radiation pneumonitis in the radiation treatment area 
30. Female patients who are pregnant or breastfeeding 
31. History of allergies to any ingredient of surufatinib or its capsule shell, including tartrazine 
(E102), tislelizumab, or to any mono-antibody 
32. Any condition by which investigators judge patients not suitable to participate in this study. 
5.5 
Lifestyle Restrictions  
5.5.1 
Contraception  
Female patients of childbearing potential and male patients with partners of childbearing potential 
are required 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 


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methods include oral progestogen only hormonal contraception (combined oestrogen/progestogen 
should be avoided) or highly effective non-oral hormonal contraception (eg, Depo-Provera and 
Implanon) associated with inhibition of ovulation together with a barrier method (eg, diaphragm, 
always containing a spermicide), intrauterine device (IUD), intrauterine hormone-releasing system 
(IUS), bilateral tubal ligation, vasectomized partner, or sexual abstinence in line with the preferred 
and usual lifestyle of the patients.  Oral and non-oral hormonal contraception should always be 
combined with an additional contraceptive method (ie, barrier method) because of a potential 
interaction with the study drug.  Male patients must always use a condom.  
5.5.2 
Pregnancy and Lactation  
Women who are pregnant (ie, pregnancy test is positive before drug administration) or 
breastfeeding will be excluded from the study. 


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6 
STUDY CONDUCT  
6.1 
Study Procedures  
The following procedures will be performed according to the schedule in Table 1.  All assessments 
must occur within ±3 days (±1 day during Cycle 1 and Cycle 2) from the scheduled date, unless 
otherwise noted.  
6.1.1 
Informed Consent  
All patients must sign the ICF prior to any study-related examinations or protocol procedures.  
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. 
All patients who sign the ICF are to be entered into the IWRS.  The system will generate a patient 
identification number, which will be assigned to the patient and will be used throughout the study. 
6.1.2 
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. 
6.1.3 
Tumor Diagnosis and Treatment History  
Tumor diagnosis should include the date of primary diagnosis of disease, tumor type, disease stage, 
date of first metastasis, type of previous treatment, start and end date/s of previous treatment, best 
overall response, and date of progressive disease (PD) if applicable.  For patients in Part 2 with 
ATC, BRAFV600E mutation status should be recorded at screening if available. 
6.1.4 
Demographics  
Demographic characteristics, including year of birth, sex, and ethnic group/race, should be 
recorded at screening and in the applicable case report form (CRF) (as permitted by local 
regulations). 
6.1.5 
Concomitant Medication and Procedures  
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient.  All concomitant medications taken within 28 days before the first dose must be 
recorded in the CRF, including the generic name of the drug and daily dose, the reason/s for using 
the medication, as well as the start and stop date/s of the medication.  
6.1.6 
Comprehensive Physical Examination  
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. 


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6.1.7 
Limited Physical Examination  
Limited physical examination includes 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. 
6.1.8 
Eastern Cooperative Oncology Group Performance Status  
Patient performance status will be graded according to the ECOG performance status scale at study 
visits.  It is recommended that ECOG performance status scores be evaluated by the same 
investigator throughout the study.  Details on the ECOG grading scale are available in Appendix 1.  
6.1.9 
Vital Signs  
Vital signs include BP, heart rate, respiration rate, and temperature.  For patients with a baseline 
history of hypertension or with hypertension that develops during the study, BP should be 
monitored per institutional standard practice.  
For patients receiving antihypertensive medications who have either a baseline history of 
hypertension or new onset of hypertension during the study, blood pressure should be monitored 
per institutional standard practice. 
6.1.10 
Laboratory Evaluations  
6.1.10.1 
Hematology  
Hematology assessments include red blood cell count, hemoglobin, hematocrit, platelet count, and 
white blood count with differential (absolute counts). 
Note: If neutrophil count is ≤1.0×109/L or platelet count is ≤25×109/L, hematology assessments 
should be conducted per institutional standard practice.  
6.1.10.2 
Blood Chemistry  
The blood chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, magnesium, phosphorus, TBIL, ALT, AST, alkaline phosphatase 
(ALP), lactate dehydrogenase, uric acid, total protein, lipase, amylase, and albumin. 
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 (units, mL/min) should be calculated using the baseline serum creatinine 
(Scr) value according to the Cockcroft-Gault formula 
• For males: creatinine clearance = [(140 - age) × weight (kg)] / [72 × Scr (mg/dL) × ideal 
body weight] 
• For females: the same formula should be calculated and multiplied by 0.85. 


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6.1.10.3 
Coagulation Indicators  
Coagulation tests include prothrombin time, INR, and aPTT. 
6.1.10.4 
CK and CK-MB  
Creatine kinase (CK) and creatine kinase myocardial band (CK-MB) levels will be evaluated at 
specified time points and when clinically indicated.  If the CK-MB fractionation is not available, 
troponin I and/or troponin T should be tested instead.  If tislelizumab has been permanently 
discontinued, CK and CK-MB testing is no longer required.  Patients who continue to receive 
surufatinib monotherapy may receive CK and CK-MB testing if clinically indicated. 
6.1.10.5 
Thyroid Function  
Thyroid function tests include serum free tri-iodothyronine (FT3), serum free thyroxine (FT4), and 
thyroid stimulating hormone (TSH). 
6.1.10.6 
Pregnancy Test  
All female patients of childbearing potential must complete a serum pregnancy test at screening 
and within 30 days of the last dose (End of Treatment [EOT] Visit).  A urine pregnancy test must 
be done prior to dosing on Day 1 of every cycle starting at Cycle 2.  Serum pregnancy test should 
be repeated for women with suspected pregnancy.  This is not applicable for postmenopausal 
female patients (ie, no menses for 12 months without an alternative medical cause), and the date 
of menopause should be recorded instead.  Pregnancy testing and contraception are not required 
for women with documented permanent sterilization (eg, hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy, or tubal ligation). 
6.1.10.7 
Urinalysis  
Urinalysis parameters include urine pH, protein, glucose, and blood; microscopic for white and 
red blood cell count.  A 24-hour urine sample for quantitative protein must be collected from all 
patients with ≥2+ proteinuria during screening.  If urine protein is ≥2+ during the period of study 
treatment, a 24-hour urine sample for quantitative protein is to be collected within 1 week.  For 
conversions between quantitative and qualitative results, please see Appendix 7. 
6.1.10.8 
Virological Screening  
Virological screening includes HBV (HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb) and HCV 
(HCV antibody).  If HBsAg or HBcAb is positive, HBV DNA is also required to be assayed by 
polymerase chain reaction (PCR) method; HBV DNA-negative patients can be enrolled, and their 
HBV DNA is required to be monitored every cycle.  If HCV antibody is positive, HCV RNA is 
required to undergo PCR testing. 
6.1.11 
Electrocardiogram Monitoring  
Single 12-lead electrocardiograms (ECG) will be collected in all patients using standardized 
equipment.  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 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 5 4  
C O N FI D E N TI A L  
rest i n a s u pi ne p ositi o n f or at least 1 0 mi n utes bef ore a n d 5 mi n utes after t he sc he d ule d ti me p oi nt 
a n d s h o ul d refrai n fr o m tal ki n g or m o vi n g ar ms or le gs.  S ki n pre p arati o n s h o ul d be o pti mal t o 
o btai n hi g h -q ualit y E C Gs; if dee me d a p pr o priate, t he c hest s h o ul d be s ha ve d a n d pre pare d wit h 
li g ht a brasi o n. 
6. 1. 1 2  
Ec h oc ar di o gr a m   
A n ec h ocar di o gra m s h o ul d be d o ne at Scree ni n g a n d e ver y 1 2 wee ks t h ereafter t hr o u g h t h e E O T  
V isit.  Assess me nt para meters i ncl u de L V E F  a n d ge neral a ssess me nt of car diac f u ncti o n.  
M ulti ple -gate d ac q uisiti o n  sca ns are per mitte d if ec h ocar di o gra ms ca n n ot b e perf or me d.  
6. 1. 1 3  
T u m or E v al u ati o n/I m a gi n g   
T u m or e val uati o n of dis ease f or all patie nts will be d o ne d u rin g t he s cree ni n g peri o d a n d t he n 
re peat e d as i n dicate d i n Ta ble  1  u ntil disc o nti n uati o n criter ia are met.  
At scree ni n g , p atie nts will ha ve ra di ol o gical assess me nts b y cr oss -secti o nal i ma gi n g of t he c h est, 
a b d o me n, a n d pel vis ( c o m p ute d t o m o gra p h y [ C T ], ma g netic res o n a nce i ma gi n g [ M RI ], or a 
c o m bi nati o n of C T/ M RI) i n or der t o i de ntif y lesi o ns.  I n a d diti o n, ot her ra di o gra p hic pr oce d ures 
(s uc h as ra di o n ucli de b o n e sca ns), as dee me d a p pr o priate b y t he i n vesti gat or, will be perf or me d t o 
assess sites of n e o plastic i n v ol ve me nt.  Assess me nts t hr o u g h o ut t he st u d y s h o ul d be ma de usi n g 
t he sa me m o dalit y as t hat use d at scree ni n g.  T u m or res p o nse will be e val uate d l ocall y b y t he 
i n vesti gat or t o s u p p ort treat me nt decisi o ns as well as t he pri mar y e n d p oi nt of a ntit u m or acti vit y.  
T u m or res p o nse will be e val uate d per R E CI S T v 1. 1.  
I n v esti gat ors will assi g n tar get a n d n o n-t ar get lesio ns i n acc or da n ce wit h R E CI S T v 1. 1 g ui deli nes 
at scree ni n g.  T h ese l esi o ns will be f oll o we d l ocall y t hr o u g h o ut t he st u d y t o deter mi ne c o nti n uati o n 
of treat me nt.  
T u m or assess me nts c o m plete d as sta n d ar d of care pri or t o si g ni n g t he i nf or me d c o nse nt b ut wit hi n 
2 8 da ys of first d ose of st u d y treat me nt ma y be us e d as baseli ne s ca ns.  
 ce ntral ima gi n g c ollecti o n a n d st ora ge  f or all patie nt s will disc o nti n ue d . 
L ocal t u m or e val u ati o n m ust be perf or me d  acc or di n g t o Ta ble  1 .   
6. 1. 1 4  
Arc hi ve d T u m or S a m ple   
A f or mali n -fi xe d, p araffi n-e m be d de d t u m or sa m ple or a  mi ni m u m  of 1 0 u nstai ne d sli des will be 
re q ueste d f or all p atie nts e nrolle d i n Part 2 of t he st u d y.  T hese sa m ples will be use d f or ce ntr al 
c o nfir mati o n of P D -L 1 e x pressi o n a n d micr osatellite sta bilit y testi n g.   I n t he e ve nt arc hi ve d t u m or 
sa m ples are n ot a v aila ble f or testi n g, patie nt s ma y o pt f or a c ore nee dl e bi o ps y pri or t o be gi n ni n g 
pr ot oc ol t hera p y  if me di call y feasi ble. 
6. 1. 1 4. 1  
C ore Nee dl e Bi o ps y ( C o h ort F)   
Patie nts i n C o h ort F m ust s u b mit c ore nee dle t u m or bi o psies.  A mi ni m u m of 3 c ore s s h o ul d be 
c ollecte d b ot h pri or t o  starti n g treat me nt a n d o n treat me nt (bet wee n a n d i ncl u di n g C 2 D 1  t o 
C 2 D 1 5 ), if cli nicall y feasi ble.  T hese sa m ples will be us e d f or ce ntr al c o nfir mati o n of dia g n osis  
a n d e x plorat or y bi o mar ker a nal ys es.  Details re g ar di n g sa m ple pr ocessi n g ca n be f o u n d i n t he 
st u d y la borat or y  ma n ual.   
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6.1.15 
Patient Enrollment Process  
On Day -2 to Day 1, after verifying the patient’s eligibility, the site will log into the IWRS, and 
the patient will be assigned a serial number matching a bottle of investigational product (IP) in the 
site’s inventory.  The site will take the investigational product with the serial number assigned by 
IWRS from inventory and dispense it to the patient.  The first dose should be administered on 
Cycle 1 Day 1. 
6.1.16 
Pharmacokinetics Evaluations  
6.1.16.1 
Sample Collection and Handling  
Blood samples will be collected for analysis of surufatinib plasma concentration and tislelizumab 
serum concentration according to the PK schedule of events in Table 2.  Serum samples will be 
collected for analysis antibodies to tislelizumab for antidrug antibody (ADA) analysis according 
to Table 2.  The actual dates and times of PK and ADA sampling should be recorded in the 
appropriate CRF.  Samples collected for PK and immunogenicity analyses may be used to evaluate 
safety or efficacy aspects that address concerns arising during or after the treatment period. 
All reasonable measures must be taken to ensure accurate recording of information on study drug 
dosing in the CRF.  For surufatinib, the actual date and time of the dose administered 1 day prior 
to and during each PK sampling day must be recorded.  For tislelizumab, the actual start date and 
time of infusion, actual end date and time of infusion, infusion rate, infusion unit, as well as any 
action taken during the infusion (eg, interruption) for every infusion during each PK sampling day 
must be recorded. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided to the sites.  Collection, handling, storage, and shipment 
of samples must be under the specified and, where applicable, controlled temperature conditions 
as indicated in the laboratory manual. 
Upon implementation of Protocol Amendment 5, EOT PK samples for Tislelizumab and 
Immunogenicity will no longer be required (Table 2). 
6.1.16.2 
Analytical Procedures  
Plasma samples will be analyzed to determine concentrations of surufatinib using a validated, 
specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. 
Serum samples will be analyzed to determine concentrations of tislelizumab and ADA using a 
validated ELISA and ADA binding assay, respectively. 
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method.  If conducted, metabolite analysis will be reported 
outside of the clinical study report. 
6.1.17 
Screening Period  
There is a 28-day screening period.  Prior to any screening assessments, all patients must provide 
a signed ICF.  Prior to inclusion in the study, the patients must undergo all appropriate screening 
procedures to check for eligibility. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 5 6  
C O N FI D E N TI A L  
6. 1. 1 8  
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 (3 0 0  m g s ur ufati ni b P O, Q D + 2 0 0  m g tisleliz u ma b I V, Q 3 W)  i n P art 2.  All patie nts i n 
b ot h parts 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 .  
 
 
T here is n o pre d efi ne d d urati o n of tr eat me nt f or eac h patie nt.   Patie nts i n b ot h t he d ose es calati o n 
a n d e x pa nsi o n  parts  will be treate d 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 , wit h dra wal of c o nse nt , ne w a ntica ncer t h era p y, l ost t o f oll o w-u p , or deat h.  
  
 
 
6. 1. 1 9  
E n d of Tre at me nt Visit   
Patie nt s w h o ha ve c o m plete d t he st u d y or ha ve disc o nti n ue d st u d y treat me nt will be as ke d t o ret ur n 
t o t he i n vesti gati o nal site t o recei ve s afet y e x a mi nati o ns a n d assess me nts wit hi n 3 0  ( ±7)  da ys after 
t he last d ose of st u d y dr u g. 
6. 1. 2 0  
Effic ac y F oll o w -u p Peri o d   
If a p atie nt disc o nti n ues f or a n y reas o n ot her t ha n P D , t he y will c o nti n ue t o b e f oll o we d f or efficac y 
u ntil disease pr o gressi o n, wit h dra wal of c o nse nt, ne w a ntica ncer t hera p y , l ost t o f oll o w-u p , or 
deat h.  
As of P r ot oc ol A me n d m e nt 5, effic ac y f oll o w -u p after t he E O T will n ot be perf or me d.   
6. 1. 2 1  
S ur vi v al F oll o w -u p Peri o d   
All patie nt s i n e x pa nsi o n C o h ort s A  a n d F will be f oll o we d f or s ur vi val stat us e ver y 1 2 wee ks 
(± 1 4  da ys) f or a m a xi m u m of 2 years fr o m P D  u ntil deat h, l ost t o f oll o w -u p , wit h dra wal of c o nse nt , 
or e n d of st u d y .  S ur vi val i nf or mati o n ca n be o btai ne d via p h o ne, a n d i nf or mati o n will be 
d oc u me nte d i n t he s o urce d oc u me nts a n d rele va nt C R Fs.  
6. 1. 2 2  
E n d of St u d y   
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 he last patie nt  i n t he st u d y. 
6. 2  
Disc o nti n u ati o n or Wit h dr a w al   
6. 2. 1  
I n di vi d u al P atie nt s  
6. 2. 1. 1  
Per ma ne nt Disc o nti n uati o n of Treat me nt   
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 h e patie nt , reas o ns of n o nc o m plia nce (e g, misse d 
d oses, visits), or pre g na n c y.  
A n y patie nt  w h o disc o nti n ues treat me nt s h o ul d b e e n c o ura g e d t o ret ur n t o t he st u d y site f or a n 
E O T  Visit a n d  F oll o w -u p Visit s o utli ne d  i n Ta ble  1  as l o n g as t he reas o n f or p er ma n e nt 
disc o nti n uati o n is n ot wit h dra w al of c o nse nt .  T h e  pri mar y reas o n f or dis c o nti n uati o n m ust be 
rec or de d o n t he a p pr o pri ate C R F. 
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Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 5 7  
C O N FI D E N TI A L  
P atie nt s m a y be disc o nti n ue d fr o m tre at me nt f or a n y of t he f oll o wi n g re as o ns:  
1.  Disease pr o gressi o n (acc or di n g t o R E CI S T v 1. 1).  If t he patie nt is e x p erie nci n g a treat me nt 
be nefit i n t he o pi ni o n of t he i n vesti gat or, t he p atie nt ma y c o nti n ue st u d y treat me nt be y o n d 
ra di o gra p hic pr o gressio n u ntil cli nical pr o gressi o n.  Deter mi nati o n of cli nical pr o gressi o n 
is at t he dis creti o n of t he i n vesti gat or a n d m a y i ncl u de b ot h o bjecti ve a n d s u bjecti ve dat a.  
T he c o nti n uati o n d ecisi o n m ust  be ma de b y t he i n vesti gat or i n c o ns ult ati o n wit h t he 
s p o ns or. 
2.  Wit h dra wal of c o nse nt  
3.  I nt olera ble t o xicit y  
4.  P o or patie nt  c o m plia nce  
5.  Use of ot her a ntit u m or treat me nt d uri n g t he st u d y  
6.  Pre g na nc y  
7.  Patie nt  is l ost t o f oll o w-u p  
8.  T he i n vesti gat or or s p o ns or deter mi nes it is i n t he best i nterest of t he patie nt  
9.  St u d y is ter mi nate d b y t he s p o ns or  
1 0.  Deat h  
1 1.  E n d of t he st u d y 
Patie nts m ust be disc o nti n ue d if t he y e x peri e nce cert ai n hi g h -gra d e A Es , e x peri e nce rec urre nt 
A Es , or e x p erie n ce A Es  t hat warra nt disc o nti n u ati o n  of st u d y treat me nt as deter mi ne d b y t he 
pri nci pal i n vesti gat or, as o utli ne d i n Secti o n  7. 1. 3 . 
A n y patie nt w h o, i n t he o pi ni o n of t he i n vesti gat or, is deri vi n g cli nical b e nefit fr o m t he st u d y 
treat me nt f oll o wi n g dise ase pr o gressi o n, m a y c o nti n ue treat me nt after disc ussi o n a n d a p pr o val 
fr o m t he s p o ns or, if all of  t he f oll o wi n g criteria are met: A bse nce of cli nical s y m pt o ms a n d si g ns 
of disease pr o gressi o n (i ncl u di n g cli nicall y si g nifica nt w orse ni n g of la b orat or y val ues).  
2.  Sta ble E C O G p erf or ma n ce stat us. 
3.  A bse nce of ra pi d pr o gressi o n of disease or of pr o gressi ve t u m or at critical a nat o mical sites 
t hat re q uires ur g e nt alter nati ve me dical i nter v e nti o n.  
4.  I n v esti gat ors m ust i nf or m patie nt s t hat t his practice is n ot c o nsi dere d sta n dar d i n t he 
treat me nt of ca ncer. 
At t he ti me of P r ot oc ol A me n d me nt 5, t he S p o ns or has d eci de d t o ter mi n ate t his st u d y bas e d o n 
t he strate gic ree val uati o n of t he cli nical de vel o p me nt of s ur ufati ni b i n t he U nite d States a n d 
E ur o pe.   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 rel ati ve t o 
s ur ufati ni b a n d/ or tisleliz u ma b treat me nt.  
 
 T he st u d y will be ter mi nate d eit her 9 0 da ys 
after t he last patie nt has recei v e d tisleliz u ma b, or t he p oi nt at w hic h all i m A Es ha ve res ol ve d or 
are n o l o n ger bei n g f oll o we d , w hic he v er o cc ur s earlier. 
6. 2. 1. 2  
Wit h dra wal fr o m St u d y  
All patie nts  ha ve t h e ri g ht t o wit h dr a w fr o m t he st u d y at a n y ti me.  D uri n g t he treat me nt peri o d 
a n d f oll o w-u p peri o d, a p atie nt  w h o wit h dr a ws c o nse nt t o c o nti n ue partici p ati o n i n t he st u d y will 
n ot be f oll o we d f or a n y reas o n after c o n se nt has b ee n wit h dra w n.  E ver y eff ort s h o ul d be ma de t o 
o btai n i nf or mati o n o n patie nt s w h o disc o nti n ue st u d y treat me nt b ut w h o d o n ot wit h dra w c o ns e nt 
t o c o nti n ue partici pati o n i n t he st u d y.  If a p artici pa nt wit h dra ws c o nse nt f or discl os ure of f ut ure 
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Clinical Study Protocol 2020-012-GLOB1 
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information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
If a patient withdraws from the study, he or 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 Patients  
Patients who are not DLT evaluable (Section 4.1.2) in a dose-escalation cohort will be replaced to 
guarantee the protocol required number of DLT-evaluable patients for dose escalation evaluations.  
6.2.1.4 
Patients Lost to Follow-up  
A patient 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 patient is deemed lost to follow-up, the investigator or designee must make every effort 
to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a certified 
letter to the patient’s last known mailing address or local equivalent methods).  These contact 
attempts are to be documented in the patient’s medical record. 
Should the patient continue to be unreachable, he or she will be considered withdrawn from the 
study, and the withdrawal will be document in the patient’s medical record.  
6.2.2 
Stopping Rules  
6.2.2.1 
Individual Patients  
Dosing of individual patients will stop immediately in the event of the following: 
• A DLT or DLT equivalent (DLT that occurs outside the DLT assessment window) 
attributed to surufatinib that does not return to baseline or ≤Grade 1 within 21 days of onset 
• A DLT or DLT equivalent attributed to surufatinib in the setting of a dose reduction that 
does not return to baseline or ≤Grade 1 within 14 days of onset 
• An immune-related AE (non-DLT) attributed to tislelizumab that does not return to baseline 
or ≤Grade 1 within 12 weeks of onset 
6.2.2.2 
Part 1 (Dose Escalation)  
Dose escalation will be conducted in accordance with Section 4.1.1.  This study stage will end if 
any of the following conditions are met: 
• Excessive toxicity is present in dose level -1, defined as ≥2 patients experiencing a DLT 
• Dose escalation may be discontinued before MTD is reached if pharmacokinetic evidence 
suggests dose-exposure relationship is maximized 
Enrollment into Part 2 (indication-specific expansion cohorts) will begin once the MTD/RP2D has 
been determined in Part 1. 
6.2.2.3 
Part 2 (Dose Expansion)  
Dosing of additional patients within an expansion cohort will be halted until applicable data can 
be reviewed by the sponsor and investigators if one of the following events occur: 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 5 9  
C O N FI D E N TI A L  
•  T hree  o ut of t he first 6 patie nt s e x perie nce a D L T or D L T -e q ui vale nt a d v erse e ve nt ( wit hi n 
4 2  da ys of C ycle 1 , D a y 1) t hat d oes n ot ret ur n t o baseli ne or ≤Gra de 1 wit hi n 2 1 da ys of 
o nset   
•  T hree  o ut of t he first 6 patie nt s e x perie nce a D L T or D L T -e q ui vale nt a d v erse e ve nt ( wit hi n 
4 2  da ys of C ycle 1 , D a y 1) t hat d oes n ot ret ur n t o baseli ne or ≤Gra de 1 wit hi n 2 1 da ys of 
o nset i n t he setti n g of a pri or d ose re d u cti o n  
I n a d diti o n, safet 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 y ear , st u d y dat a will be re vie we d wit h i n vesti 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 b e s c he d ule d base d u p o n c o n cer ns of t he s p o ns or or 
i n vesti 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 h e st u d y pre mat urel y.  Reas o ns ma y i ncl u de efficac y, 
safet y, f utilit y, etc.  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.  
T his st u d y will be ter mi nate d b y t he S p o ns or.  
 
.  T his c ha n ge is n ot base d o n a n y c o ncer n f or patie nt 
safet y or effic ac y relati ve t o s ur ufati ni b a n d/ or tisleliz u ma b treat me nt.  
 
 a n d h a ve a n E O T 
visit, as descri be d i n 6. 1. 1 9 .  After t he E O T Visit, patie nts will be c o ntacte d b y t he sites t o 
f oll o w-u p o n a n y res ol vi n g or ne w i m A Es f or u p t o 9 0 da ys.  T he st u d y will be ter mi nate d eit her 
9 0 da ys after t he last patie nt has recei ve d tisleliz u ma b, or t he p oi nt at w hic h all i m A Es ha ve 
res ol ve d or are n o l o n ger bei n g f oll o we d, w hic he v er occ ur s earlier. 
T he st u d y will be st o p pe d if st o p pi n g r ules i n Part 1 or Part 2 are met . 
T he st u d y will be i m me diatel y s us pe n de d a n d n o a d diti o nal ne w patie nt s will be d ose d pe n di n g 
re vie w a n d dis c ussi o n of a p pr o priat e st u d y data b y t he s p o ns or a n d i n vesti gat ors if 1  or m ore 
patie nts at a n y d ose le vel e x perie nce deat h dee me d t o be relate d t o pr ot oc ol treat me nt b y t he 
in vesti gat or a n d/ or m e dic al m o nit or base d u p o n cl ose te m p oral rel ati o ns hi p or ot her fact ors . 
T he st u d y will n ot res u me e nr oll me nt u ntil all parties ha ve a gree d t o t he c o urse of acti o n a n d u ntil 
t he c o m pete nt a ut h orities a n d the I n de p e n de nt Et hics C o m mittee (I E C)/ I nstit uti o nal Re vie w B oar d 
(I R B) ha ve bee n n otifie d i n acc or da nce wit h l ocal re g ulati o ns.  
 
 
.  
C CI
C CI
C CI


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7 
STUDY INTERVENTIONS  
7.1 
Description of Products  
Table 6 
Investigational Treatments Used in This Study  
Product 
Section 
Dose 
Frequency 
Route 
Duration 
Surufatinib 
(HMP-012) 
7.1.1 
200 mg 
250 mg 
300 mg 
QD 
PO 
Until progressive disease, 
unacceptable toxicity, withdrawal 
of consent, new anticancer therapy, 
lost to follow-up, or death 
Tislelizumab 
7.1.2 
200 mg 
Q3W 
IV 
IV=intravenous; PO=orally; QD=once daily; Q3W=every 3 weeks.  
7.1.1 
Surufatinib (HMP-012)  
7.1.1.1 
Formulation, Storage, Preparation, and Handling  
Surufatinib comes as 50-mg capsules and should be stored and used according to the instructions 
on the label.  Surufatinib capsules should not be used beyond the expiration date provided by the 
manufacturer. 
7.1.1.2 
Dosing and Administration  
In Part 1, patients will receive surufatinib at a dose based on cohort level once daily by mouth.  
The dose is administered with 240 mL (8 ounces) of water within 1 hour after breakfast.  
In Part 2, the indication-specific expansion portion of the study, patients will enroll within 
8 disease cohorts to receive surufatinib at the RP2D (300 mg QD) dose selected in Part 1.  The 
dose will be administered with 240 mL (8 ounces) of water within 1 hour after breakfast. 
Patients should swallow the capsules whole and not chew them.  If vomiting occurs after dosing, 
the surufatinib dose should not be replaced.  If a dose is missed, a replacement dose can be taken 
if it is within 12 hours from the intended missed dose; otherwise, the patient should not make up 
the missed dose but resume schedule the following day.  The missed dose should be reported to 
investigators and recorded in the CRF. 
There is no predefined duration of treatment for each patient.  Patients in both the dose escalation 
and expansion parts will be treated until radiologically determined PD per RECIST v1.1, 
unacceptable toxicity, or withdrawal of consent, new anticancer therapy, lost to follow-up, or 
death.  
7.1.2 
Tislelizumab  
7.1.2.1 
Formulation, Storage, Preparation and Handling  
Tislelizumab (10 mg/mL) is presented as a sterile, nonpyrogenic, and isotonic injectable solution 
for IV administration in a buffered formulation.  Each vial contains a total of 100 mg of 
tislelizumab in 10 mL buffered isotonic solution.  The product should be stored in the carton box 
it came in at refrigerated conditions, and it is not to be frozen.  Tislelizumab will be administered 
by intravenous infusion through an intravenous line containing a sterile, nonpyrogenic, 


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low-protein-binding 0.2- or 0.22-micron in-line or add-on filter.  Refer to the pharmacy manual 
for mixing instructions for intravenous injection and use. 
7.1.2.2 
Dosing and Administration  
In Part 1, patients will receive tislelizumab 200 mg IV, and Q3W. 
In Part 2, patients will enroll within 8 disease cohorts to receive tislelizumab 200 mg IV, and Q3W. 
Tislelizumab is to be administered over 60 minutes in Cycle 1 and Cycle 2.  Patients must remain 
on site for 1 hour after the infusion is complete.  In Cycle 3 and beyond, tislelizumab can be 
administered over at least 30 minutes. 
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.  Refer to Appendix 9 for guidance regarding 
the management of adverse events associated with tislelizumab administration. 
There is no predefined duration of treatment for each patient.  Patients in both the dose escalation 
and expansion parts will be treated until radiologically determined PD per RECIST v1.1, 
unacceptable toxicity, or withdrawal of consent, new anticancer therapy, lost to follow-up or death.  
7.1.3 
Dose Modifications  
The dose modification sequence by starting dose is shown in Table 7 for Part 1 and Table 8 for 
Part 2.  If the patient is unable to tolerate surufatinib in either part, the dose will be reduced by 
50 mg daily.  A patient is allowed to have dose reductions of surufatinib no more than twice (ie, 
dose reductions of 50 mg from 300 mg QD to 250 mg QD and then to 200 mg QD). 
No dose reductions for tislelizumab are permitted; however, dosing may be interrupted for up to 
12 weeks if the patient is experiencing adverse reactions that, in the opinion of the investigator, 
are solely related to tislelizumab.  
If a patient discontinues surufatinib or tislelizumab due to toxicity, they may continue receiving 
the other study drug (tislelizumab or surufatinib) alone if the investigator, in consultation with the 
medical monitor, believes the patient can still benefit from treatment.  If 1 study drug is being held 
due to the toxicity, the patient may continue to receive the other study drug if, in the opinion of 
the investigator, the toxicity is solely related to only 1 of the study drugs. 
The severity of AEs will be graded according to the NCI CTCAE v5.0.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome will be documented in 
the patient’s chart and recorded on the CRF. 
• 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. 
• For toxicities that are considered by the investigator to be unlikely to develop into serious 
or life-threatening events, treatment will be continued at the same dose without reduction 


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or interruption.  In addition, no dose reductions or interruptions will be required for anemia 
(nonhemolytic) because it can be satisfactorily managed. 
• To recover from acute toxicity considered related to surufatinib, unless otherwise indicated, 
the treatment of surufatinib can be delayed for up to 21 days.  If a treatment delay longer 
than 21 days is required, the patient should be discontinued from the study drug.  
Continuation or resumption of surufatinib treatment after an interruption of more than 
21 days must be discussed with the medical monitor or designee. 
• Tislelizumab treatment may be temporarily suspended if the patient experiences a toxicity 
that is considered related to tislelizumab and requires a dose to be withheld.  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 the study drug 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 tislelizumab treatment should be discontinued. 
• Where several toxicities with different grades or severities occur at the same time, the dose 
modifications should be according to the highest grade observed. 
Table 7 
Dose Modification Sequence for Part 1  
Dose 
Surufatinib 
Tislelizumab 
Starting Dose 
Refer to dose level 
200 mg IV, Q3W 
-1 dose 
Reduce by 50 mg QD 
-2 dose 
Reduce by 50 mg QD 
IV=intravenous; Q3W=every 3 weeks; QD=once daily. 
 
Table 8 
Dose Modification Sequence for Part 2  
Dose 
Surufatinib 
Tislelizumab 
Starting Dose 
RP2D (300 mg QD) 
200 mg IV, Q3W 
-1 dose 
Reduce by 50 mg QD 
-2 dose 
Reduce by 50 mg QD 
IV=intravenous; Q3W=every 3 weeks; QD=once daily; RP2D=recommended phase 2 dose. 
Dose reduction guidelines for hematologic and nonhematologic toxicities other than hypertension, 
proteinuria, liver function impairment, and hemorrhage are shown in Table 9.  In principle, 
treatment of surufatinib should be held until the AE/toxicity resolves or improves to ≤Grade 1.  If 
a patient has a ≥Grade 3 toxicity that is expected to be manageable and reversible with a dose 
reduction, treatment should be held until toxicity resolves or improves to ≤Grade 1.  Patients with 
a ≥Grade 3 toxicity that does not resolve or improve to ≤Grade 1 within 21 days should 
permanently discontinue surufatinib.  


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Table 9 
Dose Modification of Surufatinib for Hematologic and Nonhematologic 
Toxicity  
NCI CTCAE Version 5.0 Toxicity Grading 
Action 
Grade 1 or Grade 2 
None 
Grade 3 or Grade 42 
 
Expected manageable/reversible with dose reduction 
Hold surufatinib1  
Toxicity remains ≥Grade 3 >14 days 
Discontinue surufatinib 
Toxicity lasts ≤14 days and resolves to ≤Grade 1 
Reduce 1 dose level 
Recurrence of Grade 3 toxicity 
Reduce 1 dose level or discontinue surufatinib1  
Recurrence of Grade 4 toxicity 
Discontinue surufatinib 
Not expected manageable/irreversible with dose reduction 
Discontinue surufatinib 
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute. 
Note: Patients who experience gastrointestinal perforation should permanently discontinue study drug.  
1 
Treatment should be withheld until toxicity resolves or improves to ≤Grade 1.  For patients who cannot 
recover to ≤Grade 1 within 21 days, the study drug should be discontinued permanently. 
2 
Patients with ≥Grade 3 heart failure or hemorrhage should permanently discontinue study drug.  
7.1.4 
Dose Modification of Surufatinib for Adverse Events of Special Interest  
Dose modifications for the AESIs for surufatinib are provided in Table 10 (hepatic disorders), 
Table 11 (hypertension), Table 12 (proteinuria), and Table 13 (hemorrhage).  AESIs of thyroid 
dysfunction and acute renal failure should also be monitored.  
Table 10 
Dose Modification of Surufatinib for Hepatic Disorders  
Grade and Definition 
Dose Adjustment 
Suggested Actions 
Grade 1: 
ALT >1 to 3×ULN or 
AST >1 to 3×ULN 
None 
Follow-up per planned schedule. 
Check total bilirubin.1 
Grade 2: 
ALT >3 to 5×ULN or 
AST >3 to5×ULN 
• 
If serum bilirubin >2×ULN, immediately 
hold surufatinib and tislelizumab and 
evaluate etiology1 
• 
If consistent with immune-mediated 
hepatitis, refer to Appendix 9  
• 
Continue treatment if NOT consistent with 
immune-mediated hepatitis and serum 
bilirubin <2×ULN.  
Provide supportive care and 
increase the frequency of liver 
function monitoring to 1 to 2 times 
a week, as clinically indicated. 


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Table 10 
Dose Modification of Surufatinib for Hepatic Disorders  
Grade and Definition 
Dose Adjustment 
Suggested Actions 
Grade 3: 
ALT >5×ULN or AST 
>5×ULN 
• 
If serum bilirubin >2×ULN, immediately 
hold surufatinib and tislelizumab and 
evaluate etiology1 
• 
If consistent with immune-mediated 
hepatitis, refer to Appendix 9 
• 
If NOT consistent with immune -mediated 
hepatitis and serum bilirubin <2×ULN, hold 
surufatinib and tislelizumab  
o 
If transaminase elevation improves to 
≤Grade 1 or baseline within 21 days, 
resume surufatinib treatment at one 
dose level lower and tislelizumab (no 
dose adjustment) once  
o 
If transaminase elevation does not 
improve to ≤Grade 1 or baseline within 
21 days, discontinue surufatinib and 
tislelizumab 
Provide supportive care and 
increase the frequency of liver 
function monitoring to twice a 
week, as clinically indicated; 
consult hepatic expert, if 
necessary.  
Grade 4: 
ALT >20×ULN or  
AST >20×ULN 
Discontinue surufatinib and tislelizumab. 
Urgent medical intervention 
indicated. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. 
1 
If ALT or AST escalates to 3 times baseline level with bilirubin >2×ULN or the biochemical criteria for Hy’s 
Law have been met, surufatinib should be discontinued immediately, and the event should be reported to the 
sponsor within 24 hours.  See Appendix 4 for important additional information. 
 
Table 11 
Dose Modification of Surufatinib for Hypertension  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1: 
Prehypertension (systolic BP 
120 mmHg to 139 mmHg or 
diastolic BP 80 mmHg to 
89 mmHg) 
None 
None 


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Table 11 
Dose Modification of Surufatinib for Hypertension  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 2: 
Stage 1 hypertension (systolic BP 
140 mmHg to 159 mmHg or 
diastolic BP 90 mmHg to 
99 mmHg), medical intervention 
indicated, recurrent or persistent 
(≥24 hours), symptomatic increase 
by >20 mmHg (diastolic) or to 
>140/90 mmHg if previously within 
normal range, or monotherapy 
indicated 
None 
Treatment target: control blood 
pressure to below 140/90 mmHg.  
If patient has already received 
antihypertensive treatment at 
baseline, the dose should be 
increased or treatment changed.  
If patient did not receive treatment 
at baseline, monotherapy should 
be administered. 
Refer to relevant antihypertensive 
treatment guidelines for dose 
administration and modification 
and consult cardiologist if 
necessary. 
Grade 3: 
Stage 2 hypertension (systolic 
pressure ≥160 mmHg or diastolic 
pressure ≥100 mmHg), medical 
intervention indicated, >1 drug or 
more intensive therapy than 
previously used indicated 
If BP 160/100 mmHg lasts for 
>3 days after initiation of 
antihypertensive treatment or 
modification of current 
antihypertensive treatment, 
surufatinib treatment should be 
held.  If hypertension resolves or 
improves to ≤Grade 1 within 
21 days, surufatinib treatment can 
be restarted at a lower dose level. 
Treatment target: control blood 
pressure below 140/90 mmHg. 
Initiate antihypertensive treatment, 
increase dose of current treatment, 
or add other treatments.  
For use and adjustment of 
antihypertensive treatment, refer to 
relevant treatment guidelines or 
consult cardiologist if necessary. 
Grade 4: 
Life-threatening consequences 
(eg, malignant hypertension, 
transient or permanent neurologic 
deficit, hypertensive crisis) or 
urgent intervention indicated 
Discontinue surufatinib treatment. 
Emergent medical intervention. 
BP=blood pressure. 
 
Table 12 
Dose Modification of Surufatinib for Proteinuria  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1: 
1+ proteinuria or urinary protein 
<1.0 g/24 hours 
None. 
Follow-up per planned schedule. 
Grade 2: 
2+ or 3+ proteinuria or urinary protein 
1.0 g to 2.0 g /24 hours 
None. 
Provide supportive treatment and 
increase the frequency of urine 
monitor to once a week; consult 
nephrologist if necessary. 
Grade 2: 
Proteinuria 2+ or 3+ or urinary protein 
2.0 g to <3.5 g /24 hours 
Hold surufatinib treatment and 
resume treatment at the same 
dose level if proteinuria resolves 
to ≤Grade 1 within 21 days. 
Provide supportive treatment and 
increase the frequency of urine 
monitor to once a week; consult 
nephrologist if necessary. 


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Table 12 
Dose Modification of Surufatinib for Proteinuria  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 3: 
Urinary protein ≥3.5 g/24 hours 
Hold surufatinib.  If test results 
resolve to ≤Grade 1 within 
21 days, resume at a lower dose. 
Provide supportive treatment and 
increase the frequency of urine 
monitor to once or twice a week; 
consult nephrologist if necessary. 
AE=adverse event; CTCAE= Common Terminology Criteria for Adverse Events; QD=once daily 
Note: If urine dipstick reveals proteinuria 2+, 24-hour urine collection should be performed for determination of 
total protein within 1 week.  The CTCAE grade recorded for proteinuria should be determined by the 24-hour 
urine collection; however, the start date of the AE will be recorded as the first instant of proteinuria (ie, urine 
dipstick).  If surufatinib dose has been reduced to 200 mg QD and a further dose reduction is required for 
recurrent proteinuria, keep the same daily dose of 200 mg QD of surufatinib for 3 consecutive weeks followed 
by a 1-week drug holiday, and repeat for each treatment cycle, (ie, 3 weeks on and 1 week off; every 4 weeks 
constitutes a treatment cycle).  If proteinuria cannot resolve to ≤Grade 1 after a dose interruption of 21 days, 
continuation or resumption of surufatinib treatment should be discussed with the medical monitor.  Surufatinib 
treatment should be discontinued if a patient develops nephrotic syndrome. 
 
Table 13 
Dose Modification of Surufatinib for Hemorrhage  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1 
None 
Follow-up per planned schedule. 
Grade 2 
Hold surufatinib treatment; resume 
at a lower dose if resolves to 
≤Grade 1 within 21 days. 
Active management. 
≥Grade 3 
Discontinue surufatinib. 
Immediate medical intervention to 
identify and treat the source of 
bleeding. 
Recommendations for managing imAEs are detailed in Appendix 9. 
7.2 
Treatment Assignment and Bias Minimization  
7.2.1 
Treatment Allocation  
In Part 1, patients with locally advanced or metastatic solid tumors of any kind who have 
progressed on or are intolerant of standard therapies for which no curative therapy exists will be 
enrolled into a dose-escalation phase using a 3+3 design.  A total of 6 to 12 patients will be enrolled 
into this portion of the study. 
In Part 2, the dose-expansion portion of this study will enroll approximately 110 patients with 
various types of advanced or metastatic solid tumors across 8 cohorts (Table 5) to evaluate the 
antitumor activity of surufatinib in combination with tislelizumab as outlined in Section 4.1.3.  
7.3 
Assessment and Verification of Compliance  
Site personnel will conduct capsule counts for surufatinib to estimate compliance and document 
on the CRF. 
Doses of tislelizumab will be administered intravenously every 3 weeks during a patient visit; site 
personnel will document dose administration and document on the CRF. 


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7.4 
Prior and Concomitant Therapies  
7.4.1 
Prohibited Therapies  
Any therapy intended for the treatment of cancer (with the exceptions as noted in Section 7.4.2), 
whether currently marketed or experimental, is prohibited.  This includes, but is not limited to, the 
following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, or herbal therapy. 
Prophylactic 
antiemetics, 
granulocyte 
colony-stimulating 
factors, 
granulocyte 
macrophage -colony stimulating factors, platelet simulating factors, or erythropoietin are not 
allowed during the DLT observation period in the dose-escalation phase. 
The use of gastroduodenal mucosal protective agents, such as sucralfate, are allowed, but they 
must be taken at least 2 hours after the administration of surufatinib. 
For patients with nonfunctioning NETs, concomitant use of SSAs is not permitted and must have 
been discontinued at least 4 weeks before administration of the first dose of study drug. 
Concomitant use of medications that are known to cause QT prolongation and/ or Torsades des 
Pointes is not permitted.  Consult the current list at http://www.qtdrugs.org/, which is updated 
continuously, for the most complete information. 
Palliative radiation for symptom control is allowed provided it does not compromise tumor 
assessments of target lesions.  However, surufatinib treatment should be suspended during the 
radiation period and resumed at least 7 days after radiation only after meeting the following 
criteria: 
• Radiation related toxicities resolves to ≤Grade 2. 
• No disease progression is observed. 
Live vaccines and immune-stimulant herbal medications are prohibited during treatment and for 
60 days after last dose.  
Systemic corticosteroids >10 mg daily (prednisone or equivalent) are prohibited except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic treatment. 
7.4.2 
Permitted Therapies  
Patients who use hormonal therapy with gonadotropin releasing hormone agonists for prostate 
cancer, oral contraceptives, hormone-replacement therapy, or other allowed maintenance therapy 
should continue their use. 
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 low-dose anticoagulation agents at study entry, 
the following guidance should be followed: 
• Patients who are receiving warfarin or Coumadin-like products should have their INR 
monitored and maintained at the lower end of the therapeutic range (ie, close to 2.0 if the 
therapeutic range is 2.0 to 3.0). 
• Patients who require low-molecular-weight heparin should receive the prophylactic dose 
and monitoring as specified by the appropriate product information label. 


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Patients who develop arterial thromboembolic events should discontinue the study treatment.  If a 
patient suffers a venous thromboembolic event while still receiving study treatment, it may still be 
possible for him or her to receive study treatment under adequate monitoring and dose 
modification.  The continuation decision must be made by the investigator in consultation with the 
sponsor. 
Patients who have functioning NETs and who have been on a stable dose of an SSA for a minimum 
of 2 months prior to the first dose of study drug for control of their secretory symptoms will be 
permitted to enroll in the -dose expansion phase. 
All supportive measures consistent with optimal patient care will be given throughout the study. 
7.4.3 
Drug-Drug Interactions  
In vitro metabolism data indicate that CYP3A plays an important role in the metabolism of 
surufatinib.  The potential effects of medications that can affect the PK of surufatinib via the 
CYP3A pathway have not been tested in the clinic.  Therefore, medications that are strong 
inhibitors or inducers of CYP3A are prohibited and should not be administered concomitantly with 
surufatinib during the course of the study.  Examples of these medications are listed in Appendix 3. 
In vitro, surufatinib is shown to have the potential to inhibit CYP3A, P-glycoprotein (P-gp), and 
breast cancer–resistant protein (BCRP) (refer to the IB).  Patients should avoid concomitant use of 
medications that are sensitive substrates of CYP3A, P-gp, or BCRP where possible.  If used 
together, patients should be monitored more frequently for adverse reactions, and a dose reduction 
should be considered of the CYP3A, P-gp, or BCRP substrate medication.  Examples of the 
medications that are sensitive substrates of CYP3A, P-gp, and BCRP are listed in Appendix 3. 
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 surufatinib, 
is very low given tislelizumab is a therapeutic monoclonal antibody. 


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8 
SAFETY MONITORING  
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). 
These safety evaluations will be performed from the time of ICF signature, throughout the 
treatment phase, and up to 90 days after the last study treatment administration.  AEs and SAEs 
ongoing at the EOT will be followed until resolution.  Any new SAE possibly related to study 
treatment and occurring any time after the EOT should be reported.  The NCI CTCAE v5.0 will 
be used to classify the severity of all AEs and laboratory abnormalities. 
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 in humans, 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), including 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, invasive screening procedures such as biopsies) 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication.  Asymptomatic overdose will not be reported as an AE/SAE unless 
it is an intentional overdose taken with possible suicidal or self-harming intent.  Such 
overdoses should be reported regardless of outcome. 
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 it 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 
normal life functions 
• A congenital anomaly/birth defect 


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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. 
8.1.3 
Adverse Events of Special Interest  
An adverse event of special interest (serious or nonserious) is one of scientific and medical concern 
specific to the sponsor’s product or program for which ongoing monitoring and rapid 
communication by the investigator to the sponsor may be appropriate.  Such an event might 
warrant further investigation in order to characterize and understand it. 
AESIs for surufatinib include hepatic disorder, proteinuria, hypertension, thyroid dysfunction, 
hemorrhage, and acute renal failure. 
AESIs for tislelizumab include imAEs of hepatitis, pneumonitis, colitis, endocrinopathies, 
myocarditis, diabetes, and serious skin adverse reactions.  
8.2 
Adverse Event Reporting  
8.2.1 
Timeframe for Collection of Adverse Events  
After signing the informed consent, all AEs and 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.  Immune-mediated AEs and SAEs should be collected until 90 days after the last dose 
of tislelizumab regardless of whether or not the patient starts a new anticancer therapy.  Any SAEs 
that are considered to be related to either study drug by the investigator should be collected without 
regard to time elapsed since the last dose. 
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 study.  The investigator must report such events (both 
initial and follow-up) to the sponsor 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 the investigator’s causality assessment:  
• SAEs 
• Abnormal liver function laboratory results 
− Serum AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, regardless of 
seriousness 
− Hy’s Law: Increase in serum AST or ALT ≥3 × ULN together with total bilirubin ≥2 × 
ULN and when 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 


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(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 
Appendix 4 for additional information regarding Hy’s Law 
− For management of hepatic function abnormal events, refer to Table 10.   
• Hemorrhagic events 
− CTCAE ≥Grade 3 hemorrhagic event, regardless of seriousness. 
− For management for hemorrhagic events, refer to Table 13 
− The management of severe or serious hemorrhagic events will be conducted according 
to Appendix 5.  
• Pregnancy 
8.3 
Eliciting Adverse Events  
A consistent methodology of nondirective questioning for eliciting AEs at all patient evaluation 
time points should be adopted.  Examples of nondirective questions include 
• “How have you felt since your last clinic visit?” 
• “Have you had any new or changed health problems since you were last here?” 
8.4 
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 CRF, 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.  The following guideline should be used 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, 
and/or intervention not indicated 
• Grade 2: “moderate;” minimal, local or noninvasive intervention indicated; and/or limiting 
age-appropriate instrumental activities of daily living (ADL).  Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
• Grade 3: severe or medically significant but not immediately life--threatening; 
hospitalization or prolongation of hospitalization indicated, disabling, and/or limiting self-
care ADL.  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not being bedridden. 
• Grade 4: life-threatening consequences and/or urgent intervention indicated 
• Grade 5: Death related to AE 
8.5 
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 


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considered to be related to the study drug.  To ensure consistency of causality assessments, 
investigators should apply the general guidelines provided below: 
• Related: An adverse event will be considered as “related” to the use of the IP if 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 rechallenge, 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: An adverse event will be considered as “not related” to the use of the IP if 
there is not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to the 
lack of reasonable temporal relationship between administration of the drug and the event, 
the presence of a biologically implausible relationship between the product and the adverse 
event, or the presence of a more likely alternative explanation for the adverse event.  
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  A causal relationship 
in cases where the disease under study has deteriorated due to lack of effect should be 
classified as no reasonable possibility. 
8.6 
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 CRF, 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 designee within 24 hours of knowledge of the 
event. 
Only 1 medical concept should be recorded in the event field on the CRF. 
8.6.1 
Diagnosis Versus Symptoms and Signs  
If known, a diagnosis should be recorded on the CRF 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 CRF.  If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
8.6.2 
Adverse Event 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 CRF if the dehydration is mild. 


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However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF.  For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. 
8.6.3 
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 CRF unless the severity changes.  If 
a persistent AE becomes more or less severe, it should be recorded again in a new CRF 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 CRF separately. 
8.6.4 
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 for 
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 CRF. 
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 CRF.  If the laboratory 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 CRF unless their severity, seriousness, or 
etiology changes. 
8.6.5 
Preexisting Medical Condition  
A preexisting medical condition is one that is present at screening.  Such conditions should be 
recorded on the CRF 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 


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the CRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 
8.6.6 
Pregnancy  
A female patient must be instructed to stop taking the study treatment 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 treatment).  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 treatment 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 treatment.  If such 
an event occurs, it should be reported as described above. 
Pregnancy loss of any kind should always be classified as serious AE (as the sponsor considers 
these medically significant), recorded on the CRF, and expeditiously reported to the 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. 
8.6.7 
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. 
8.6.8 
Death  
All deaths that occur during the 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.  If the primary cause of death is unknown and 
cannot be ascertained at the time of reporting, please record “Unknown cause death” on the CRF, 
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. 
8.6.9 
Overdose  
For this study, any dose of surufatinib >300 mg daily dose or tislelizumab ≥600 mg in a 24-hour 
period will be considered an overdose.  No specific information is available on the treatment of 
overdose of surufatinib or tislelizumab.  In the event of overdose, further surufatinib or 
tislelizumab administration should be withheld 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 sponsor study representatives immediately, or no later than 24 hours after becoming aware 
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• An overdose associated with AEs/SAEs should be recorded as the AE diagnosis/symptoms 
secondary to overdose on the relevant AE/SAE modules in the CRF and on the study drug 
CRF module. 
• An intentional overdose should be reported as an AE, regardless of any associated signs or 
symptoms. 
• An overdose with no associated signs or symptoms should only be reported on the study 
drug CRF module. 
8.7 
Duration of Safety Follow-up for Adverse Events  
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 within 30 days (±7 days) after the last 
dose of study drugs or before the initiation of new anticancer therapy, whichever occurs first.  In 
addition, telephone contacts with patients should be conducted to assess imAEs and concomitant 
medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 and 
90 days (±14 days) after the last dose of tislelizumab, regardless of whether or not patients have 
started 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. 
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 CRF 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 CRF. 
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. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -G L O B 1  
S ur uf ati ni b  
A m e n d m e nt 5  
 
 
H U T C H M E D Li mite d  
Pa ge 7 6  
C O N FI D E N TI A L  
9  
A N A L Y SI S   
All statistical a nal ysis will be perf or me d u n der t he directi o n of t he s p o ns or’s pers o n nel.  Details 
of t he statistical a nal ysis a n d data re p orti n g will be pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P), 
w hic h will be fi nalize d pri or t o t he data bas e l oc k.  
T he ti mi n g of a nal ysis f or eac h c o h ort m a y be differe nt d e pe n di n g o n t he c o m pleti o n of eac h 
c o h ort, a n d t he fi nal a nal ysis of t he st u d y will be c o n d ucte d at t he ti me of a nal ysis of t he last 
c o h ort.  H o we ver, t h e accr ue d data fr o m a n y c o h ort ma y be a n al yze d  f or i nt er nal decisi o n-ma ki n g 
p ur p oses (f or e xa m ple, t o pr o vi de i nf or mati o n f or a p ote ntial p hase 3 st u d y desi g n ). 
Data will b e s u m marize d usi n g descri pti ve statistics (c o nti n u o us d ata) a n d/ or c o nti n ge nc y ta bles 
(cate g orical d ata) f or d e m o gra p hic a n d baseli ne c haracteristics, efficac y meas ure me nts, s afet y 
meas ure me nts, a n d P K meas ure me nts.  Ti me t o e ve nt varia bl es will be s u m marize d des cri pti vel y 
usi n g Ka pla n -Mei er me di a ns a n d q u artiles.  A nal yses will be perf or me d usi n g S A S ® ( Versi o n  9. 1 
or hi g her).   U nless ot her wise state d, data will be s u m marize d b y d ose le vel f or Part 1 a n d b y 
disease c o h orts f or Part 2 of t he st u d y . 
9. 1  
H y p ot hesis   
N o f or mal h y p ot hesis testi n g is pla n ne d f or t his st u d y.   F or efficac y e n d p oi nts  O R R , D C R, a n d 
C B R , t he st u d y will pr o vi de t he esti mates a n d t he c orres p o n di n g 2 -si de d Cl o p per-Pears o n 9 5 % CI 
f or precisi o n. 
9. 2  
P o p ul ati o n   
9. 2. 1  
S a m ple Size R ati o n ale   
T he t otal n u m ber of patie nts e nr olle d will d e pe n d o n t he n u m ber of d ose es calati o ns a n d  t he nee d 
t o c haracterize i n di vi d ual c o h orts i n t he e x pa nsi o n p hase  f urt her.  T h e pla n ne d e nr oll me nt f or t his 
st u d y is a p pr o xi matel y 1 2 2  patie nts, i ncl u di n g 6  t o 1 2 patie nts i n Part  1 , a n d a p pr o xi matel y 
1 1 0  patie nts i n Part 2.  
, f urt her e nr oll me nt t o t his st u d y was st o p pe d a n d t he pla n ne d n u m ber of 
patie nts i n t he i m pacte d c o h orts i n Part 2 of t he st u d y were u p date d t o reflect c urre nt e nr oll me nt 
n u m bers at t he ti me e nr oll me nt was st o p pe d ( Ta bl e 5 ). 
9. 2. 1. 1  
Part 1   
T o deter mi ne t he rec o m me n de d p has e 2 d ose ( R P 2 D) a n d/ or t h e 
M T D of s ur ufati ni b i n 
c o m bi nati o n wit h tisleliz u ma b, a t otal of 6  t o 1 2 patie nts will be e nr olle d i nt o t his p orti o n of t he 
st u d y.  T he e xact n u m ber will be deter mi ne d b y t he n u m ber of D L Ts  acr oss t he 3 p ote ntial d ose 
le vels of sur ufati ni b .  
9. 2. 1. 2  
Part 2   
T he sa m ple size selecte d f or eac h c o h ort i n Part 2 of t he st u d y ca n pr o vi de a de q uate precisi o n f or 
t he esti mate d i nci de nce rate of e n d p oi nt  O R R.  
Ta ble 1 4  s h o ws t he ra n ge of o bser ve d O R R  a n d t he c orres p o n di n g 2 -si de d 9 5%  c o nfi d e nce 
i nter vals f or c o h orts of size 1 0, 1 5, a n d 2 0. 
C CI


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Table 14 
Estimated ORR and 2-Sided 95% Confidence Intervals  
Number of 
Patients 
Number of Cases 
Estimated Rate 
95% CI Lower 
Limit 
95% CI Upper 
Limit 
10 
0 
0.00 
0.00 
0.31 
2 
0.20 
0.03 
0.56 
4 
0.40 
0.12 
0.74 
6 
0.60 
0.26 
0.88 
8 
0.80 
0.44 
0.97 
10 
1.00 
0.69 
1.00 
15 
0 
0.00 
0.00 
0.22 
3 
0.20 
0.04 
0.48 
6 
0.40 
0.16 
0.68 
9 
0.60 
0.32 
0.84 
12 
0.80 
0.52 
0.96 
15 
1.00 
0.78 
1.00 
20 
0 
0.00 
0.00 
0.17 
5 
0.25 
0.09 
0.49 
10 
0.50 
0.27 
0.73 
15 
0.75 
0.51 
0.91 
20 
1.00 
0.83 
1.00 
CI=confidence interval; ORR=objective response rate. 
Note: 95% Clopper-Pearson Interval for binomial distribution 
9.2.2 
Analysis Populations  
The following analysis populations have been defined for the study: 
• Safety analysis set: All enrolled patients who received at least 1 dose of surufatinib 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 Part 1 of the study who are evaluable 
for DLT assessment.  A patient is DLT evaluable if he/she meets the following criteria:  
− received ≥85% of scheduled surufatinib and ≥67% (approximately two-thirds) of 
scheduled tislelizumab administration during the DLT assessment window and/or 
− experienced a DLT.   
Patients will be considered not evaluable for DLTs if during the DLT assessment window 
they  
− were withdrawn from the study,  
− did not receive ≥85% of scheduled surufatinib and ≥67% (approximately two-thirds) 
of scheduled tislelizumab drug administration,  
− received prophylactic supportive care that confounds the evaluation of DLTs (not 
including supportive care described as part of the DLT definition), OR  


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− have taken a strong inhibitor or inducer of enzyme CYP3A4 (Appendix 3).  
• Response evaluable analysis set: All patients who receive study treatment and have a 
baseline tumor assessment and at least 1 post-baseline assessment, unless any clinical PD 
or death occurred before the first post-baseline assessment, will be considered evaluable for 
antitumor efficacy endpoints. 
• Antidrug antibody (ADA) analysis set: All patients who received at least 1 dose of study 
treatment and have a baseline and at least 1 post-baseline ADA result. 
• Pharmacokinetic analysis set: All patients with at least 1 quantifiable plasma concentrations 
of surufatinib combined with tislelizumab will be included in the pharmacokinetic analysis 
population. 
9.3 
Statistical Analysis  
9.3.1 
Patient Disposition  
The number and percentage of patients that were enrolled in the study, treated, and discontinued 
from study drug(s) will be presented for all enrolled patients.  The primary reason for treatment 
discontinuation will be summarized according to the categories in the CRF.  Patient disposition 
will be summarized by dose level for Part 1 and by tumor types for Part 2. 
Important protocol deviations will be summarized and listed by category. 
9.3.2 
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. 
9.3.3 
Prior and Concomitant Medications  
Prior medications will be defined as medications that were stopped before the day of the first dose 
of study drug(s).  Concomitant medications will be defined as medications that 1) started before 
the first dose of study drug(s) and were continuing at the time of the first dose of study drug(s) or 
2) started on or after the date of the first dose of study drug(s) up to 30 days after the patient’s last 
dose.  Any steroid use will 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 summarized overall and by tumor types.  A listing 
of prior and concomitant medications will be provided. 
9.3.4 
Safety Analysis  
The summary of the exposure to study drug(s), AEs, AEs leading to drug modification or 
discontinuation including DLTs, changes in laboratory results, and changes in vital signs, etc., will 


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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 Medical Dictionary for Regulatory Activities (MedDRA).  
TEAEs are defined as AEs that started or worsened in severity on or after the first dose of study 
drug and no later than 30 days after the date of last study drug 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 (dose-escalation phase)  
• Summary of DLT-equivalent (DLTs which 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 
• 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 drug. 
Drug exposure, including number of cycles received, total duration of exposure, cumulative dose 
received (mg), dose intensity, and relative dose intensity of surufatinib 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.  
The reasons for dose modifications will also be summarized. 
For laboratory tests that are graded by NCI CTCAE v5.0 or higher, results will be summarized by 
grade for each visit during the treatment period.  Treatment-emergent changes will be summarized 
by the maximum post-baseline grade.  A shift-table summarizing shifts from baseline to maximum 
post-baseline 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. 
9.3.5 
Efficacy Analysis  
No formal hypothesis testing is planned for this study.   
9.3.5.1 
Primary Efficacy Analysis  
9.3.5.1.1 
Objective Response Rate (ORR)  
The ORR is defined as the proportion of patients with a confirmed best overall response (BOR) 
complete response (CR) or PR as determined by the investigator using RECIST v1.1.  To be 


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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 v1.1 progression or the start date of new anticancer therapy, whichever 
comes first.  
The ORR and the corresponding 2-sided Clopper-Pearson 95% CI will be presented.  Both 
confirmed and unconfirmed ORR will be summarized. 
ORR will be summarized by dose level for Part 1 and by tumor types for Part 2.   
As a sensitivity analysis, ORR will be presented for the response evaluable analysis set.   
9.3.5.2 
Secondary Efficacy Analysis  
9.3.5.2.1 
Progression-free Survival (PFS)  
Progression-free survival is defined as the time (months) from the start of study treatment until the 
first radiographic documentation of objective progression as assessed by the investigator using 
RECIST v1.1 (Appendix 2), or death from any cause.  Patients who have not objectively 
progressed or died by the date of the analysis cut-off or received any further antitumor therapy will 
be censored at the date of the last evaluable objective tumor assessment before the cut-off date or 
the antitumor therapy start date. 
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) and 95% CI will also 
be reported.  Detailed censoring rules will be included in the SAP. 
PFS will be summarized by dose level for Part 1 and by tumor types for Part 2.  Additional 
summaries may be based on all dose levels overall and by tumor types, if necessary. 
9.3.5.2.2 
Disease Control Rate (DCR)  
Disease control rate is defined as the proportion of patients with a BOR of CR, PR, or SD lasting 
for at least 7 weeks as determined by the investigator using RECIST v1.1.  The DCR and the 
corresponding 2--sided Clopper-Pearson 95% CI will be presented. 
9.3.5.2.3 
Clinical Benefit Rate (CBR)  
Clinical benefit rate 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.  Durable SD is SD for at least 6 months.  
The CBR and the corresponding 2-sided Clopper-Pearson 95% CI will be presented. 
9.3.5.2.4 
Duration of Response (DoR)  
Duration of response 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.  Censoring rules for DoR will be aligned with PFS. 


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9.3.5.2.5 
Time to Response (TTR)  
Time to response is defined as the time (months) from start of study treatment until the date of first 
occurrence of PR or CR.  TTR will be summarized only for responders using KM methodology. 
9.3.5.2.6 
Overall Survival (OS)  
Overall survival is defined as the time (months) from the 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) with 95% CI will also be reported.  OS will be 
assessed in patients enrolled to the expansion Cohorts A (CRC) and F (ATC). 
9.3.6 
Pharmacokinetic Analysis  
Evaluation on PK will be performed on the PK analysis set.  Concentration data of surufatinib in 
plasma and tislelizumab in serum will be tabulated and summarized using descriptive statistics 
(number of patients [n]; arithmetic mean with standard deviation; coefficient of variation [CV%]; 
and geometric mean, median, minimum, and maximum) as appropriate. 
9.3.7 
Immunogenicity Analysis  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs to tislelizumab.  The incidences of positive 
ADAs and neutralizing ADAs to tislelizumab will be reported for evaluable patients.  The effect 
of immunogenicity on PK, efficacy, and safety may be evaluated if data allow. 
9.3.8 
Other Exploratory Analyses  
Distribution of PD-L1 expression will be examined in all patients.  Potential association between 
PD-L1 expression and tislelizumab treatment effect will be explored.  Other potential predictive 
markers will be assessed. 
Methodology for exploratory analyses will be described in the SAP.  


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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be conducted in accordance with the protocol, consensus and ethical principles 
derived from international guidelines, including the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences International Ethical Guidelines, applicable ICH 
GCP guidelines, and applicable regulations and guidelines governing clinical study conduct. 
10.2 
Ethics Review  
The IEC/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 or 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 IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IEC/IRB 
• Notifying the IEC/IRB of SAEs or other significant safety findings as required by 
IEC/IRB procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IEC/IRB, 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 
Data Privacy  
All information about surufatinib and tislelizumab (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.  HUTCHMED Limited 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.  CRFs and other documents submitted to the sponsor should 
not contain the patient’s name.  


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• Patients will be assigned a unique identifier by the sponsor.  Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information that would make the patient identifiable will not be transferred. 
• Patients are identified only by 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 patient must be informed that his or 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 patient, who will be required to give consent for their data to be 
used as described in the ICF.  
• The patient must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IEC/IRB members, and by inspectors from regulatory authorities. 
10.4 
Disclosure  
Final study results will be published on a public clinical study website according to applicable 
local guidelines and regulations. 
10.5 
Data Quality Assurance  
• To ensure the safety of patients 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 patient data relating to the study will be recorded on CRFs 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 physically or electronically 
signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, and responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
will be 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]). 
10.6 
Informed Consent  
• Investigators or designees must obtain the signed ICF from patients prior to conducting 
any study-related procedures.  
• The investigator or designee will explain the nature of the study to the patient or their 
legally acceptable representative and answer all questions regarding the study. 


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• Patients must be informed that their participation is voluntary.  Patients or their legally 
acceptable 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 (HIPAA) requirements, where applicable, and the 
IEC/IRB 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 CRF.  
• If the benefit:risk assessment changes after the safety analysis, the ICF needs to be 
reviewed and updated, and all updated information should be provided to patients or their 
legally acceptable representative (including patients who have already received the study 
drug). 
• A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 


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11 
OVERSIGHT  
11.1 
Safety Review Committee  
Safety monitoring and evaluation of the dose escalation part will be carried out by the SRC, which 
will consist of the sponsor’s study team members (including, but not limited to, the medical 
monitor, safety monitor, and PK scientist [as applicable]) and the site principal investigators.  
Safety data will be evaluated to determine whether it is safe to continue the assigned dosing 
combination for dose escalation, stay at the currently assigned dose level, or whether the dose 
should be de-escalated to the lower dose level.  Pharmacokinetic data may also be reviewed if 
available.  The SRC will be charged with determining the RP2D and/or MTD.The MTD will be 
defined as the maximum dose at which <33% of patients at a single dose level experience a DLT 
in the first cycle (Cycle 1, Days 1–21). The decision regarding the RP2D will take the following 
into consideration:The MTD, if reached 
• Pharmacokinetic data may also be reviewed with or without associated safety and 
preliminary efficacy findings 
These criteria constitute the basis for RP2D determination, and the SRC must collectively 
determine the RP2D. 
The SRC may also review safety data during Part 2 of the study. 
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 CRFs 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 CRFs, the adherence of the protocol to GCP, 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 CRF entries.  The sponsor’s monitoring standards require full verification of 
the informed consent form, 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 CRFs are performed 
according to the study-specific monitoring plan. 
11.2.2 
Audits  
Authorized representatives of HUTCHMED Limited, a regulatory/competent authority, and/or an 
IEC/IRB representative may visit the site to perform audits or inspections, including source data 
verification.  Should this occur, the investigator is responsible for 
• 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 subject to audit or inspection include but are not limited to all source 
documents, CRFs, medical records, correspondence, ICFs, IEC/IRB 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 CRF refers to 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 CRFs is complete, accurate, and that entry and updates are performed in a timely 
manner.  Blood samples for PK and tumor samples for biomarker assessments will be collected by 
study sites and sent to the designated central laboratory for processing.  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 
holding. 
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 
or 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 


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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. 
11.2.3.2 
Source Documentation  
• The investigator/institution should maintain adequate and accurate source documents and 
study records for all patients that support the information entered in the CRF.   
• 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 CRFs 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 are enrolled earlier than expected  


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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 
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 staff or 
consultants from HUTCHMED Limited) will be listed in the publication.  HUTCHMED Limited 
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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surufatinib in U.S. patients with neuroendocrine tumors (NETs). Journal of Clinical Oncology. 
2021; 39. 4114-4114. 
 
Ryman 2017  
Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacometrics Syst 
Pharmacol 2017;6(9):576-88. 
 
Sackstein 2018  
Sackstein PE, O'Neil DS, Neugut AI, Chabot J, Fojo T. Epidemiologic trends in neuroendocrine 
tumors: An examination of incidence rates and survival of specific patient subgroups over the past 
20 years. Semin Oncol 2018;45(4):249-58. 
 
Schoffski 2016  
Schoffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus 
dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a 
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Surufatinib 
Amendment 5 
 
 
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Seddon 2017  
Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, et al: Gemcitabine and docetaxel 
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metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol 
2017;18(10):1397-410.  
 
Siegel 2019  
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin 2019;69(1):7-34. 
 
Soar 2008  
Soar J, Pumphrey R, Cant A, et al. Emergency treatment of anaphylactic reactions--guidelines for 
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STIVARGA USPI  
STIVARGA® (regorafenib) US Prescribing Information. Bayer HealthCare Pharmaceuticals, Inc, 
Whippany, NJ. Revised April 2017. 
 
Shah 2018  
Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. NCCN 
guidelines insights: neuroendocrine and adrenal tumors, Version 2.2018. J Natl Compr Canc Netw 
2018;16(6):693-702. 
 
Smallridge 2012  
Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, et al. American Thyroid 
Association Anaplastic Thyroid Cancer Guidelines Taskforce. American Thyroid Association 
guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012 
Nov;22(11):1104-39. 
 
Subbaiah 2018  
Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and 
Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant 
Anaplastic Thyroid Cancer. J Clin Oncol. 2018 Jan 1;36(1):7-13. 
 


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Surufatinib 
Amendment 5 
 
 
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Tawbi 2017  
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Wendler J, Kroiss M, Gast K, Kreissl MC, Allelein S, Lichtenauer U, et al. Clinical presentation, 
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SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
An Open-Label Phase Ib/II Study of Surufatinib in Combination with Tislelizumab in 
Subjects With Advanced Solid Tumors 
 
 
 
Protocol Number: 
2020-012-GLOB1 
 
 
 
Name of Test Drug: 
Surufatinib (HMPL-012) 
Tislelizumab (BGB-A317) 
 
 
Phase: 
1b/2 
 
 
 
Sponsor Name: 
HUTCHMED Limited 
 
No.4, Lane 720, Cailun Road,  
 
Zhangjiang Hi-tech Park, Shanghai, China 
 
Post Code: 201203 
 
Analysis Plan Version 
Version 2.0 
 
 
Effective Date 
19 September 2024 
 
 
 
 
Compliance: The study described in this report was performed according to the principle of Good Clinical Practice 
(GCP).  
Confidentiality Statement 
The information contained in this Statistical Analysis Plan (SAP) is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Hutchmed Limited, Ltd or its 
subsidiaries. 
 






 
 
 
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TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
INTRODUCTION ......................................................................................................12 
2. 
STUDY DETAILS .....................................................................................................13 
2.1. 
Study Objectives .........................................................................................................13 
2.2. 
Study Design ...............................................................................................................14 
2.3. 
Determination of Sample Size ....................................................................................17 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1. 
Definition of Analysis Sets .........................................................................................19 
3.1.1. 
Enrolled Set ................................................................................................................19 
3.1.2. 
Safety Analysis Set .....................................................................................................19 
3.1.3. 
DLT-Evaluable Analysis Set ......................................................................................19 
3.1.4. 
Response Evaluable Analysis Set ...............................................................................19 
3.1.5. 
Pharmacokinetics (PK) Analysis Set ..........................................................................20 
3.1.6. 
Antidrug Antibody (ADA) Analysis Set ....................................................................20 
3.2. 
Protocol Deviations ....................................................................................................20 
4. 
ENDPOINTS ..............................................................................................................21 
4.1. 
General Principles for Derived and Transformed Data ..............................................21 
4.1.1. 
Reference Start Date and End Date and Study Day ...................................................21 
4.1.2. 
Baseline and Change from Baseline ...........................................................................21 
4.1.3. 
Treatment Period ........................................................................................................21 
4.2. 
Exposure Endpoints ....................................................................................................22 
4.3. 
Safety Endpoints .........................................................................................................24 
4.3.1. 
Dose Limiting Toxicities (DLTs) ...............................................................................24 
4.3.2. 
Adverse Events (AEs) .................................................................................................25 
4.3.3. 
Laboratory ...................................................................................................................26 


 
 
 
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4.3.4. 
ECG ............................................................................................................................27 
4.3.5. 
Vital Signs ..................................................................................................................29 
4.3.6. 
Performance Status .....................................................................................................29 
4.3.7. 
Echocardiogram ..........................................................................................................29 
4.3.8. 
Physical Examination .................................................................................................30 
4.4. 
Efficacy Endpoints ......................................................................................................30 
4.4.1. 
Primary Endpoint ........................................................................................................30 
4.4.2. 
Secondary Endpoints ..................................................................................................32 
4.4.2.1. 
Progression-free Survival (PFS) .................................................................................32 
4.4.2.2. 
Disease Control Rate (DCR) ......................................................................................33 
4.4.2.3. 
Clinical Benefit Rate (CBR) .......................................................................................34 
4.4.2.4. 
Duration of Response .................................................................................................34 
4.4.2.5. 
Time to Response (TTR) ............................................................................................34 
4.4.2.6. 
Overall Survival (OS) .................................................................................................34 
4.5. 
Other Endpoints ..........................................................................................................35 
4.5.1. 
Pharmacokinetic Endpoint ..........................................................................................35 
4.5.2. 
Immunogenicity ..........................................................................................................36 
4.5.3. 
Other Exploratory Analyses .......................................................................................36 
5. 
ANALYSIS METHODS ............................................................................................37 
5.1. 
General Principles .......................................................................................................37 
5.1.1. 
General Methodology .................................................................................................37 
5.1.2. 
Handling Missing Data ...............................................................................................38 
5.1.2.1. 
Adverse Events Start/End Date ..................................................................................38 
5.1.2.2. 
Concomitant Medication/Procedure/Surgery Start/End Date .....................................39 
5.1.2.3. 
Subsequent Anti-cancer Therapy Date .......................................................................39 
5.1.2.4. 
Primary Diagnosis Date and Metastatic Disease Diagnosis Date ..............................40 
5.1.3. 
Visit Windowing .........................................................................................................40 
5.1.4. 
Adjustment of Covariates ...........................................................................................42 
5.2. 
Analysis Methods .......................................................................................................42 


 
 
 
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5.2.1. 
Patient Disposition ......................................................................................................42 
5.2.2. 
Protocol Deviations ....................................................................................................42 
5.2.3. 
Demographic and Other Baseline Characteristics ......................................................43 
5.2.4. 
Disease Characteristics ...............................................................................................43 
5.2.5. 
Medical History ..........................................................................................................44 
5.2.6. 
Prior and Subsequent Anti-cancer Therapy ................................................................44 
5.2.6.1. 
Prior and Subsequent Anti-cancer Medication ...........................................................45 
5.2.6.2. 
Prior and Subsequent Anti-cancer Radiotherapy ........................................................45 
5.2.6.3. 
Prior and Subsequent Anti-cancer Procedure or Surgery ...........................................45 
5.2.7. 
Prior and Concomitant Medications ...........................................................................46 
5.2.8. 
Concomitant Procedure ..............................................................................................46 
5.2.9. 
Exposure of Study Treatment .....................................................................................46 
5.2.10. 
Safety Analyses ..........................................................................................................47 
5.2.10.1. 
Dose-Limiting Toxicity (DLT) ...................................................................................47 
5.2.10.2. 
Adverse Events ...........................................................................................................48 
5.2.10.3. 
Death ...........................................................................................................................51 
5.2.10.4. 
Laboratory Evaluations ...............................................................................................51 
5.2.10.5. 
ECG ............................................................................................................................51 
5.2.10.6. 
Vital Signs ..................................................................................................................52 
5.2.10.7. 
Performance Status .....................................................................................................52 
5.2.10.8. 
Echocardiogram ..........................................................................................................52 
5.2.10.9. 
Physical Examination .................................................................................................52 
5.2.11. 
Efficacy Analyses .......................................................................................................53 
5.2.11.1. 
Primary Efficacy Analyses .........................................................................................53 
5.2.11.2. 
Sensitivity Analysis for Efficacy Endpoint ................................................................53 
5.2.11.3. 
Multiplicity Control ....................................................................................................53 
5.2.11.4. 
Secondary Efficacy Analyses .....................................................................................53 
5.3. 
Other Analyses ............................................................................................................55 
5.3.1. 
Pharmacokinetic Analysis ..........................................................................................55 


 
 
 
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5.3.1.1. 
Handling of Missing Concentration Data ...................................................................56 
5.3.1.2. 
Handling of Dose Reduction or Interruption ..............................................................56 
5.3.1.3. 
Handling of below the lower limit of quantification (BLQ) Data ..............................56 
5.3.1.4. 
Handling of the Difference between the Scheduled (nominal time) and the 
Actual Sampling Times (actual time) .........................................................................56 
5.3.2. 
Immunogenicity Analysis ...........................................................................................57 
5.3.3. 
Other Exploratory Analyses .......................................................................................58 
6. 
PLANNED ANALYSIS .............................................................................................59 
6.1. 
Independent Data Monitoring Committee ..................................................................59 
6.2. 
Interim Analysis ..........................................................................................................59 
6.3. 
Final Analysis .............................................................................................................59 
7. 
CHANGE FROM THE PROTOCOL ........................................................................60 
REFERENCE .................................................................................................................................61 
APPENDIX 1: STUDY SCHEDULE OF EVENTS .....................................................................62 
APPENDIX 2: NCI CTCAE CRITERIA V5.0 FOR LABORATORY PARAMETERS .............66 
APPENDIX 3: AESI CATEGORIES AND PREFERRED TERM ..............................................69 
APPENDIX 4: IMAE FOR TISLELIZUMAB (PREFERRED TERM) .......................................70 
 
 
 


 
 
 
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List of Tables 
Table 1 
Dose Expansion Cohorts .............................................................................................16 
Table 2 
Estimated ORR and 2-Sided 95% Confidence Intervals ............................................18 
Table 3 
Algorithms for Calculating Parameters Relevant to the Dose Exposure and 
Intensity ......................................................................................................................22 
Table 4  
Laboratory Assessment ...............................................................................................26 
Table 5 
Potentially Clinically Significant Criteria for ECG ....................................................28 
Table 6  
Potentially Clinically Significant Criteria for Vital Signs ..........................................29 
Table 7 
Best Overall Response When Confirmation of CR and PR are Required ..................31 
Table 8 
Censoring Rules for PFS ............................................................................................33 
Table 9 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments ................................................................................................................35 
Table 10  
Treatment/Cohort Display in TLFs ............................................................................37 
Table 11  
Visit Windowing .........................................................................................................41 
 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ASPS 
alveolar soft part sarcoma 
ATC 
anatomic therapeutic classification (WHO Drug Dictionnary) 
ATC 
anaplastic thyroid cancer  
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
BRAF 
B-Raf kinase 
BRAFV600E 
B-Raf kinase V600E mutations 
CBR 
clinical benefit rate 
CFB 
change from baseline 
CI 
confidence interval 
CR 
complete response 
CRC 
colorectal cancer 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4  
cytochrome P450, family 3, subfamily A4 
DBL 
database lock 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOI 
end of infusion 
EOT 
end of treatment 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEP 
gastroenteropancreatic 
ICF 
inform consent form 
ICH 
International Council on Harmonization 
imAE 
immune-mediated AE 


 
 
 
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Abbreviation 
Term 
IV 
intravenous(ly) 
LVEF 
left ventricular ejection fraction 
LLQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
MTD 
maximum tolerated dose 
NET 
neuroendocrine tumor 
OC 
observed case 
ORR 
objective response rate 
OS 
Overall survival 
PD 
progressive disease 
PD-L1 
programmed death-Ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
oral(ly) 
PR 
partial response 
PT 
preferred term 
QD 
once daily 
QxW 
every x weeks 
QTcF 
QT interval corrected by the method of Fredericia 
RAS 
rat sarcoma 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RP2D 
recommended Phase 2 dose  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SMQs 
standardized MedDRA queries 
SOC 
system organ class 
SRC 
Safety Review Committee 
STS 
soft-tissue sarcoma 
TEAE 
treatment-emergent adverse event 
TLF 
table, listing, figure 


 
 
 
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Abbreviation 
Term 
TPR 
timepoint response 
TTR 
time to response 
UPS 
undifferentiated pleomorphic sarcoma 
WHO-DD 
World Health Organization Drug Dictionary 


 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses and data 
presentations for study 2020-012-GLOB1. The SAP is based on Protocol amendment 5, dated 29 
November 2023. Study measurements and assessments, planned statistical methods, and derived 
variables are summarized in this plan. Planned tables, figures, and listings are specified. All 
decisions regarding final analyses, as defined in this SAP document, have been made prior to 
locking the database. Any deviations from these guidelines will be documented in the clinical 
study report (CSR). 
The analyses related to PK endpoints will be described in a separate analysis plan. 
 


 
 
 
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2. STUDY DETAILS 
2.1. Study Objectives 
Objectives 
Part 1 Primary:  
x 
To evaluate the safety and tolerability of 
surufatinib, thereby determining the recommended 
Phase 2 dose (RP2D) and/or the maximum tolerated 
dose (MTD) of surufatinib in combination with 
tislelizumab 
Part 2 Primary:  
x 
To evaluate the objective response rate (ORR) as 
assessed by the investigator in patients with advanced 
solid tumors when treated with surufatinib in 
combination with tislelizumab according to 
RECIST v1.1 
Corresponding Endpoints 
Part 1 Primary:  
x 
Safety including dose-limiting toxicities 
(DLTs), treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), 
adverse events (AEs) leading to 
discontinuation, electrocardiograms (ECGs), 
clinical laboratory abnormalities, and vital 
signs 
Part 2 Primary:  
x 
ORR at 12 weeks  
Part 1 Secondary:  
x 
To evaluate the antitumor activity in patients with 
advanced solid tumors when treated with surufatinib in 
combination with tislelizumab according to RECIST 
v1.1 
x 
To characterize the pharmacokinetics (PK) and 
immunogenicity of tislelizumab and surufatinib in 
combination 
Part 1 Secondary:  
x 
ORR, progression-free survival (PFS), 
disease control rate (DCR), clinical benefit 
rate (CBR), duration of response (DoR), time 
to response (TTR)   
x 
Concentrations of surufatinib in plasma 
and tislelizumab in serum 
x 
Incidence of antidrug antibodies (ADA) 
to tislelizumab 
Part 2 Secondary:  
x 
To evaluate further anticancer effects of 
surufatinib in combination with tislelizumab 
x 
To characterize the safety and tolerability of 
surufatinib in combination with tislelizumab 
x 
To characterize the PK and immunogenicity of 
tislelizumab and surufatinib in combination 
 
 
 
 
Part 2 Exploratory: 
x 
To explore the distribution of PD-L1 expression 
and potential association between PD-L1 
expression and tislelizumab treatment effect 
Part 2 Secondary:  
x 
PFS, DCR, CBR, DoR, TTR   
x 
Overall Survival (OS): Cohorts A 
(colorectal cancer) and F (anaplastic thyroid 
cancer) 
x 
Safety including TEAEs, SAEs, AEs 
leading to discontinuation, electrocardiograms 
(ECGs), clinical laboratory abnormalities, and 
study drug discontinuation due to AEs 
x 
Concentrations of surufatinib in plasma 
and tislelizumab in serum 
x 
Incidence of ADA to tislelizumab 
Part 2 Exploratory: 
x 
PD-L1 expression 
x 
Cohort F: Changes from baseline in tumor 
markers, correlation with drug exposure, and 


 
 
 
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2.2. Study Design 
This open-label, Phase 1b/2 study of surufatinib in combination with tislelizumab will evaluate 
the safety, tolerability, PK, and efficacy in patients with advanced solid tumors.   
 
The study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2).   
 
Part 1 will be conducted to determine the RP2D and/or the MTD of surufatinib in combination 
with tislelizumab in patients with advanced or metastatic solid tumors who have progressed on or 
are intolerant of standard therapies.   
 
Part 2 will be an open-label, multicohort design to evaluate the antitumor activity of surufatinib 
in combination with tislelizumab in patients with specific types of advanced or metastatic solid 
tumors.  Patients will receive the RP2D determined in Part 1 of this study. 
 
Part 1 (Dose Escalation) 
Patients with advanced or metastatic solid tumors of any kind who have progressed on or are 
intolerant of standard therapies will be enrolled into a dose-escalation phase using a 3+3 design.  
A total of 6 to 12 patients will be enrolled into this portion of the study.  
 
2 dose levels will be evaluated during this phase of the study. 
x Dose level 1: 250 mg surufatinib, oral (PO), once daily (QD) + 200 mg tislelizumab, 
intravenous (IV) every 3 weeks (Q3W) 
x Dose level 2: 300 mg surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W 
A minimum of 3 patients will be enrolled at the starting dose (dose level 1). 
x If no patients experience a DLT, then the dose will be escalated to dose level 2. 
x If one of the 3 patients at dose level 1 experience a DLT, then 3 additional patients will 
be enrolled to dose level 1. 
 
 If one of 6 patients experience a DLT, then the dose will be escalated to dose 
level 2. 
x 
 Cohort F: To explore the influence of gene 
abnormalities on safety, and efficacy 
association with efficacy and safety 
parameters 


 
 
 
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 If two of 6 patients experience a DLT, then the dose will be deescalated to 
dose level -1, (200 mg surufatinib, PO, QD + 200 mg tislelizumab, IV, Q3W). 
 
x >33% of patients at any dose level experience a DLT, then the dose escalation will be 
halted. 
 
 




 
 
 
H U T C H M E D Li mite d 
St u d y Pr ot oc ol: 2 0 2 0- 0 1 2- G L O B 1 
 
S A P Versi o n 2. 0 
 
C O N FI D E N TI A L 
Pa ge 1 7 of 7 3 
Date: 1 9 Se pte m ber 2 0 2 4 
 
 
 
 
 
 
 
( Gra d e 1 or Gr a de 2), well differe ntiate d N E Ts t hat ha ve pr o gresse d o n at least o ne li ne of 
sta n dar d t her a p y. 
Patie nts i n C o h ort C m ust  ha ve l ocall y a d v a nce d or metastatic s mall-cell l u n g ca ncer ( S C L C) 
t hat was pre vi o usl y pr o gr esse d o n first-li ne c h e m ot hera p y. Patie nts i n C o h ort C m ust ha ve 
l ocall y a d va nce d or metastatic s mall-cell l u n g ca n cer ( S C L C) t hat was pre vi o usl y pr o gresse d o n 
first-li ne c he m ot her a p y. 
Patie nts i n C o h ort D m ust ha ve micr osatellite  sta ble, P D-
a de n ocarci n o ma of t he st o mac h or gastr o es o p ha geal j u ncti o n, a n d pre v i o usl y bee n treate d wit h at 
least 2 li nes of sta n dar d t hera p y. 
Patie nts i n C o h ort E, wit h al ve olar s oft part  sarc o ma ( A S P S) or u n differe ntiate d ple o m or p hic 
sarc o ma ( U P S), m ust ha ve pr o gress e d o n at least 1 li ne of sta n dar d t hera p y or ref us e d sta n dar d 
fr o ntli ne c yt ot o xic c he m ot hera p y. 
Patie nts i n C o h ort F  m ust ha ve l ocall y a d va nce d or metastatic a na pl astic t h yr oi d ca ncer ( A T C). 
Patie nts w h o ha ve a B R A F V 6 0 0 E m utati o n m ust ha ve pre vi o usl y bee n treate d wit h 1 li ne of s yste mic 
t hera p y ( n ot i ncl u di n g ra diati o n t hera p y) wit h a B R A F-tar gete d t hera p y. 
 
T he ti mi n g of a nal ysis f or eac h c o h ort ma y b e differe nt de p e n di n g o n t he c o m pleti o n of eac h 
c o h ort, a n d t he fi n al a nal ysis of t he st u d y will be  c o n d ucte d at t he ti me of a nal ysis of t he last 
c o h ort.  H o we v er, t he accr ue d dat a fr o m a n y c o h ort ma y be a nal y ze d f or i nter nal decisi o n-
ma ki n g p ur p oses (f or e xa m ple, t o pr o vi de i nf o r mati o n f or a p ote ntial P hase 3 st u d y desi g n). 
 
2. 3.  Deter mi n ati o n of S a m ple Size 
T he t otal n u m ber of patie nts e nr olle d will de pe n d o n t he n u m ber of d ose es calati o ns a n d t he nee d 
t o c haracterize i n di vi d ual c o h orts i n t he e x pa nsi o n p hase f urt her.  T he pla n ne d e nr oll me nt f or 
t his st u d y is a p pr o xi matel y 1 2 2 patie nts, i ncl u di n g 6 t o 1 2 patie nts i n Part 1, a n d a p pr o xi matel y 
1 1 0 patie nts i n Part 2.  
, f urt her e nr oll me nt t o t his st u d y was st o p pe d a n d t he pla n ne d n u m ber 
of patie nts i n t he i m pacte d c o h orts i n Part 2 of t he st u d y were u p dat e d t o reflect c urre nt 
e nr oll me nt n u m bers at t h e ti me e nr oll me nt was st o p pe d (Ta ble 2 ). 
Part 1 
T o deter mi ne t he R P 2 D a n d/ or t he M T D of s ur ufati ni b i n c o m bi nati o n wit h tisleliz u ma b, a t otal 
of 6 t o 1 2 patie nts will be e nr o lle d i nt o t his p orti o n of t he st u d y.  T he e xact n u m ber will be 
deter mi ne d b y t he n u m ber of D L Ts.  
Part 2 
T he sa m ple size selecte d f or eac h c o h ort i n Part 2 of t he st u d y ca n  pr o vi de a de q uate precisi o n f or 
t he esti mate d i nci de nce r ate of e n d p oi nt O R R. 
C CI


 
 
 
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Table 2 shows the range of observed ORR and the corresponding 2-sided 95% confidence intervals 
for cohorts of size 10, 15, and 20. 
Table 2 
Estimated ORR and 2-Sided 95% Confidence Intervals 
Number of 
Patients 
Number of Cases 
Estimated Rate 
95% CI Lower 
Limit 
95% CI Upper 
Limit 
10 
0 
0.00 
0.00 
0.31 
2 
0.20 
0.03 
0.56 
4 
0.40 
0.12 
0.74 
6 
0.60 
0.26 
0.88 
8 
0.80 
0.44 
0.97 
10 
1.00 
0.69 
1.00 
15 
0 
0.00 
0.00 
0.22 
3 
0.20 
0.04 
0.48 
6 
0.40 
0.16 
0.68 
9 
0.60 
0.32 
0.84 
12 
0.80 
0.52 
0.96 
15 
1.00 
0.78 
1.00 
20 
0 
0.00 
0.00 
0.17 
5 
0.25 
0.09 
0.49 
10 
0.50 
0.27 
0.73 
15 
0.75 
0.51 
0.91 
20 
1.00 
0.83 
1.00 
CI=Confidence Interval; ORR=Objective Response Rate. 
Note: 95% Clopper-Pearson Interval for binomial distribution 


 
 
 
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3. ANALYSIS SETS 
3.1. Definition of Analysis Sets  
3.1.1. 
Enrolled Set 
The enrolled set includes all patients who signed ICF (inform consent form). 
 
3.1.2. 
Safety Analysis Set 
The safety analysis set includes all enrolled patients who received at least 1 dose of surufatinib or 
tislelizumab.  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. 
 
3.1.3. 
DLT-Evaluable Analysis Set  
All patients enrolled in Part 1 (dose escalation) of the study who are evaluable for DLT 
assessment.   
 
A patient is DLT evaluable if he/she meets the following criteria:  
- 
UHFHLYHG  RI VFKHGXOHG VXUXIDWLQLE DQG  DSSUR[LPDWHO\ WZR-thirds) of 
scheduled tislelizumab administration during the DLT assessment window and/or 
- 
experienced a DLT.   
 
Patients will be considered not evaluable for DLTs if during the DLT assessment window they  
- 
were withdrawn from the study,  
- 
GLG QRW UHFHLYH  RI VFKHGXOHG VXUXIDWLQLE DQG  DSSUR[LPDWHO\ WZR-thirds) of 
scheduled tislelizumab drug administration,  
- 
received prophylactic supportive care that confounds the evaluation of DLTs (not 
including supportive care described as part of the DLT definition), or 
- 
have taken a strong inhibitor or inducer of enzyme CYP3A4  
 
3.1.4. 
Response Evaluable Analysis Set 
The response evaluable analysis set will include all patients who receive study treatment and 
have a baseline tumor assessment and at least one post-baseline assessment, unless any clinical 
progressive disease (PD) or death occurred before the first post-baseline assessment.  Sensitivity 
analysis for efficacy endpoints ORR, DCR, CBR, DoR, and TTR will be conducted using this 
analysis set. 
 


 
 
 
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3.1.5. 
Pharmacokinetics (PK) Analysis Set 
The pharmacokinetic analysis set include all patients with at least one quantifiable concentration 
of surufatinib or tislelizumab. 
 
3.1.6. 
Antidrug Antibody (ADA) Analysis Set  
The antidrug antibody analysis set include all patients who received at least one dose of 
tislelizumab and have a baseline and at least one post-baseline ADA result. 
 
3.2. Protocol Deviations  
Protocol deviations are recorded in the clinical trial management system as outlined in the latest 
version of the Protocol Deviation and Non-compliance Management Plan.  Protocol deviations are 
categorized as major/minor before database lock. 
 
Protocol deviations including deviations that are related to COVID-19 are recorded in the 
Clinical trial management system as outlined within the Protocol Deviation and Non-Compliance 
Plan. 


 
 
 
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4. ENDPOINTS 
4.1. General Principles for Derived and Transformed Data 
4.1.1. 
Reference Start Date and End Date and Study Day 
Reference start date is defined as the first date when a non-zero dose of any study drug 
(surufatinib or tislelizumab, whichever occurs first) was administrated (first administration/dose 
date). Day 1 is the day of the first dose of study treatment in Cycle 1.  
Study day will be calculated from the reference start date, and it will be used to show start/stop 
day of assessments and events relative to the first administration of study treatment. 
 If the date of the event is on or after the reference start date, study day = (date of event – 
reference start date) + 1. 
 If the date of the event is prior to the reference start date, study day = (date of event – 
reference start date). 
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings. 
Reference end date is defined as the last date when a non-zero dose of any study drug was 
administered. 
4.1.2. 
Baseline and Change from Baseline 
Baseline is defined as the last non-missing assessment prior to the first administration of any 
study drug (whichever occurs first), including scheduled and unscheduled visits, unless 
otherwise specified. For quantitative measurements,  
 change from baseline (CFB) will be calculated as: CFB = assessment value at visit X – 
baseline value;  
 percentage CFB (% CFB) will be calculated as % CFB = (assessment value at each visit X – 
baseline value)/baseline value × 100. 
4.1.3. 
Treatment Period 
Unless otherwise specified, the treatment period is defined as the period from first administration 
date of treatment to [30 days + 7 days protocol defined window] after last administration date on 
treatment. For safety data, only the assessments/events collected during the treatment period will 
be evaluated (except for related SAE and immune-mediated AE [imAE]). 
The worst post-baseline is defined as the worst assessments/events during the treatment period 
including both scheduled and non-scheduled visit. The end of treatment (EOT) measurement is 
defined as the latest non-missing measurement taken during the treatment period. 
 




 
 
 
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Dose Interruptions, Dose Reductions, and Dose Withdrawal  
 Dose interruptions, dose reductions, and dose withdrawal are all based on the dose 
administration data, the associated reasons for each of them include categories: (1) AE, and 
(2) Other. Dose reduction is not allowed for Tislelizumab. 
 Dose modifications of study drug include dose interruption and dose reduction. 
 
The following endpoints to reflect study drug adjustment will be derived.  
 
 
Dosing modifications (including both dosing interruption and dose reduction): number of 
patients with any dosing modification, and categorized frequency of dosing modification (0, 1, 2, 
3, 4, 5, 6, >6). This will be derived only for surufatinib.  
 
Dosing interruption: number of patients with any dosing interruption and reasons for dosing 
interruption, and categorized frequency of dosing interruptions (0, 1, 2).  
 
Dose reduction: number of patients with any dose reduction and reasons for dose reduction, and 
categorized frequency of dose reduction (0, 1, 2). This will be derived only for surufatinib.  
 
 
 


 
 
 
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4.3. Safety Endpoints  
The primary endpoint for Part 1 dose escalation is safety.  
The safety analysis set is used to evaluate the safety variables including AEs, clinical laboratory 
data, vital signs, single 12-lead ECG parameters, echocardiogram (ECHO)/ multiple-gated 
acquisition (MUGA) scan parameters, physical examinations, Eastern Cooperative Oncology 
Group (ECOG) performance status, and death.  The safety data during the treatment period will 
be evaluated, and the treatment period is defined as the duration from the date of the first study 
drug administration until [30 days + 7 days protocol defined window] after the last dose.   
4.3.1. 
Dose Limiting Toxicities (DLTs) 
AEs will be assessed per the DLT criteria shown below during the 21-day DLT assessment 
window, which begins on the first day of the administration of the study drug. 
Patients will be considered evaluable for DLTs if they meet the criteria (see criteria in section 
3.1.3). 
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. 
According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 evaluation criteria, the following AEs that occur within 21 days (DLT 
observation period) after the first drug administration of each cohort shall be defined as a DLT 
once they are determined by the investigator to be related to surufatinib and/or tislelizumab: 
1. Nonhematologic toxicities 
a. Grade 3 or higher nonhematologic toxicity will be considered DLTs, except for 
the following conditions: 
i. 
Grade 3 fatigue lasting <7 days. 
ii. 
Grade 3 rash that returns to baseline or Grade 1 with appropriate supportive  
treatment within 7 days. 
iii. 
Grade 3 hypertension downgraded WR Grade 1 within 7 days with appropriate 
supportive therapy. 
iv. 
Grade 3 endocrinopathy that is adequately controlled by hormonal 
replacement, does not require hospitalization, AND resolves to Grade 1 within 7 
days. 
v. 
Grade 3 or higher amylase or lipase elevation that is not associated 
with symptoms or clinical manifestations of pancreatitis. 
vi. 
Grade 3 nausea/vomiting or diarrhea for less than 72 hours with 
adequate antiemetic and other supportive care 
vii. 
Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not 
clinically complicated, and resolves spontaneously or responds to conventional 
medical interventions. 


 
 
 
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2. Hematologic toxicities 
a. Grade 3 or higher febrile neutropenia (neutrophil count <1.0×109/L, accompanied 
with a single body temperature measurement of 38.3°C [101°F] or 38°C [100.4°F] 
persisting for 1 hour) 
b. Grade 4 neutropenia lasting >7 days 
c. Grade 4 thrombocytopenia lasting >7 days 
d. Grade 3 thrombocytopenia accompanied with severe bleeding 
e. Grade 4 anemia 
Any life-threatening complication or abnormality not covered in the NCI CTCAE v5.0. 
When counting abnormal laboratory results at the patient level, the most severe toxicity during 
study treatment will be chosen. 
4.3.2. 
Adverse Events (AEs) 
All AEs will be coded from verbatim text to preferred term (PTs) and grouped by system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version 27.0. 
AEs will be collected from the time of signature of informed consent throughout the treatment 
period. AEs will be graded by investigator according to NCI CTCAE v5.0.  
An AE is considered a TEAEs : 
 
1)  If the onset date is on after the start of study treatment (surufatinib or tislelizumab) or if 
the onset date is missing or 
2)  If the AE has an onset date before the start of study treatment but worsened in severity  
after the study drug administration until [30 days + 7 days protocol defined window] after 
the last dose of study treatment. After this period, treatment-related SAEs will also be 
considered as TEAEs.  
3) The TEAEs 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.   
 
Other AE variables include drug-related AEs, AEs leading to study drug modifications (i.e. dose 
interruption, dose reduction, or study drug withdrawal), AEs leading to death, and SAEs.  
An AE is considered treatment-related in the summaries if it is assessed as related to any study 
drug by the investigator (surufatinib or tislelizumab) or if the assessment of relationship to study 
treatment is missing. 
 
Severity of AEs is graded from Grade 1 to Grade 5 according to the NCI CTCAE v5.0. Missing 
severity grade is imputed as Grade 3.   
 




 
 
 
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Change from baseline in laboratory test results to each assessment will be calculated.  
The non-protocol specified tests (if any reported) will not be summarized; they will only be 
included in listings.  
Data recorded by the laboratory will be converted to the International System of Units (SI) and 
all presentations will use SI units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (LLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. 
as “< X” or “> X” in the listings. 
Clinical laboratory results will be graded according to CTCAE criteria, CTCAE v5.0 criteria (see  
Appendix 2).  Any graded abnormality that occurs following the initiation of study drug and 
represents at least a 1-grade increase from the baseline assessment is defined as treatment 
emergent. Any assessment for which CTCAE toxicity grades are not available, will not be 
included in any analyses for which toxicity grades are required. 
 
Analysis of Abnormal Hepatic Laboratory Values 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments.  
x Alanine aminotransferase (ALT) or/and aspartate aminotransferase (AST) >5 x ULN 
x AST or/and ALT > 3× XSSHU OLPLW RI QRUPDO 8/1 DQG  ×ULN 
x Total bilirubin > 2×ULN 
x Potential Drug-Induced Liver Injury (DILI): AST and/or ALT > 3×ULN and total 
bilirubin > 2×ULN 
x Hy's Law criteria: AST and/or ALT > 3×ULN and total bilirubin > 2×ULN and ALP 
 
< 2× ULN. 
Additionally, the minimum and maximum values for each patient over the entire treatment 
period for each hematology and chemistry laboratory parameter will also be derived. The change 
from baseline will be calculated using these minimum and maximum values. 
 
4.3.4. 
ECG 
Electrocardiogram (ECG) parameters include heart rate, PR interval, RR interval, QT, QTcF and 
QRS intervals. Change from baseline to each post-baseline visit will be calculated and 
summarized by visit.  




 
 
 
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4.3.5. 
Vital Signs 
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory 
rate, heat rate, body temperature, weight, and height. Body Mass Index (BMI) will be computed 
as weight (kg)/[height (m)]2.   
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated.  
The potentially clinically significant findings of vital signs will also be defined based on criteria 
defined in Table 6.  
Additionally, the minimum and maximum values for each patient over the entire treatment 
period for each vital sign parameter will also be derived. The change from baseline will be 
calculated using these minimum and maximum values. 
Table 6  
Potentially Clinically Significant Criteria for Vital Signs  
Vital Sign Parameter 
Criterion Value   
SBP (mmHg), DBP 
(mmHg), Heart rate (bpm) 
Respiratory rate 
(breaths/min) 
Increase from baseline of 
ޓ 0 -    
ޓ 20 -    
ޓ 40  
Decrease from baseline of 
ޓ 0 -    
ޓ 20 -    
ޓ 40 (except for respiratory rate) 
Weight (kg) 
Percentage decrease from baseline of 
ޒ 5%  
  – < 10%  
  - < 20%  
  
Percentage increase from baseline of 
ޒ 5%  
  – < 10%  
  - < 20%  
  
 
4.3.6. 
Performance Status 
ECOG performance status is collected at screening and during the treatment period (i.e., Day 1 
of each Cycle).  
4.3.7. 
Echocardiogram 
ECHOs will be done at Screening and every 12 weeks from C1D1 thereafter through the end of 
treatment visit.  Assessment parameters include left ventricular ejection fraction (LVEF) and 


 
 
 
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overall interpretation of cardiac function.  Multiple-gated acquisition scans (MUGAs) are 
permitted if ECHOs cannot be performed. 
4.3.8. 
Physical Examination 
A comprehensive physical examination (PE) at Screening and end of treatment visit, it includes 
general appearance, eyes, ears, nose and throat, head and neck, respiratory, cardiovascular, 
abdomen (gastrointestinal), skin, genitourinary system, lymph nodes, musculoskeletal, 
neurological assessments. 
Limited physical examination at scheduled visits is a subset the comprehensive physical 
examination as deemed appropriate by the investigator. 
Abnormal clinically significant findings in PE were to be reported as AEs (post-baseline) or 
MHs (screening). 
 
These data will only be available in listings.  
 
4.4. Efficacy Endpoints 
 
4.4.1. 
Primary Endpoint 
The primary endpoint of Part 2 is the ORR defined as the proportion of patients with a confirmed 
best overall response (BOR) of complete response (CR) or Partial Response (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 v1.1 progression or the start date of new anticancer therapy, whichever 
comes first (see Table 7 for definition) 
 
 




 
 
 
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For patients in the Safety Analysis set, who do not have any post-baseline tumor assessment 
(patients who died or progressed clinically prior to the first scheduled tumor assessment), the 
response category “NA” will be assigned for BOR of the patient. 
ORR will be calculated using two different ways: 
 Scenario #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. 
Objective response will be derived as no/yes variable. Patients with a BOR of confirmed CR 
or PR will be assigned ‘Yes’. Patients not having a BOR of confirmed CR or PR will be 
assigned ‘No’. Hence, ORR is defined as the proportion of patients with objective response 
being “Yes”.  
 Scenario #2: ORRUNCONFIRMED will be calculated using all responses regardless of 
confirmation. Objective response will be derived as no/yes variable.  Patients with a BOR of 
confirmed CR, confirmed PR, unconfirmed CR or unconfirmed PR will be assigned “Yes”.  
All patients with other BOR values will be assigned “No”. Hence, ORRUNCONFIRMED is 
defined as the proportion of patients with objective response being “Yes”. 
Both ways (confirmed and unconfirmed) of assigning BOR will be implemented.  
 
4.4.2. 
Secondary Endpoints 
4.4.2.1. 
Progression-free Survival (PFS) 
Progression-free survival is defined as the time (months) from the 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.   
More specifically, PFS will be determined using all the assessment data up until the last evaluable 
visit prior to or on the date of  
(i) disease progression as defined by RECIST Version 1.1 or death;  or 
(ii) withdrawal of consent; or 
(iii) receiving subsequent anti-cancer therapy (not including radiotherapy and procedures), 
whichever is earlier. 
Patients without report of PD or death from any cause at the time of analysis are censored as 
described in Table 8 below. 
 
The PFS time will always be derived based on scan dates not tumor assessment dates. If PD is 
documented between scheduled visits, the actual date of documented progression will be used as 
an uncensored value in the analysis of PFS. RECIST assessments/scans contributing towards a 
particular visit may be performed on different dates. The following rules are applied: 


 
 
 
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 Date of progression is determined based on the earliest of the dates of the component that 
triggered the progression. 
 When censoring a patient for PFS, the patient is censored at the latest of the dates 
contributing to a particular overall visit assessment. 
 
Table 8 
Censoring Rules for PFS 
Rule  Situation 
Date of Progression or Censoring 
Outcome 
1 
PD documented between schedule 
radiological assessment visits 
Date of documented disease progression 
Event 
2 
Death between scheduled radiological 
assessment visits 
 
Death before first documented PD 
 
Death after one missing radiological 
assessment visit 
Date of death 
Event 
3 
Documented PD directly following a 
missing radiological assessment visit, 
if having not had disease progression 
observed previously 
Date of documented disease progression 
Event 
4 
No baseline or post-baseline 
radiological assessments available 
Date of start of study treatment  
Censored 
5 
No death or PD by the time of data 
cut-off for final analysis (Alive 
without progressive disease, Lost to 
follow-up, withdrawal of consent) 
Date of last adequate radiological assessment 
Censored 
6 
Lost to follow-up or withdrawal of 
consent before PD or death 
Date of last adequate radiological assessment 
Censored 
7 
New anti-tumor therapy started prior 
to PD 
Date of last adequate radiological assessment prior 
to or on date of initiation of new therapy visit 
Censored 
8 
Death or PD occurred after two or 
more consecutive missed radiological 
assessment visits 
Date of last adequate radiological assessment prior 
to missed visits 
Censored 
Note: An adequate radiologic assessment is defined as an assessment where the Investigator determined radiological response is 
CR, PR, SD, or PD. If PD and new anti-cancer therapy occur on the same day, will assume that the progression was 
documented first, e.g. outcome is progression and the date is the date of the assessment of progression 
Note: Two consecutive scheduled tumor assessments is equal to 98 days (=2* [6 weeks *7+ 7 days]) since previous evaluable  
RECIST 1.1 or baseline assessment if there is no post baseline tumor assessment until 24 weeks and  140 days (=2* [9 
weeks *7+ 7 days]) after. 
4.4.2.2. 
Disease Control Rate (DCR) 
Disease control rate is defined as the proportion of patients with a BOR of CR, PR, or SD lasting 
for at least 7 weeks as determined by the investigator using RECIST v1.1.   


 
 
 
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4.4.2.3. 
Clinical Benefit Rate (CBR) 
Clinical benefit rate 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.   
Durable SD is SD for at least 6 months.  
 
4.4.2.4. 
Duration of Response 
Duration of response (DoR) is defined as the time from the first occurrence of PR or CR by 
RECIST v1.1, until disease progression or death, whichever comes first.  
Only those patients with objective responses of CR or PR will be included in this analysis.  
Both the unconfirmed DoR based on the patients with unconfirmed CR/PR and the patients with 
confirmed DoR based on the confirmed CR/PR will be derived. For the confirmed DoR, the first 
date to observe the CR/PR will be as the response date for confirmed responder. 
Censoring will follow the rules outlined for PFS in Table 8 of Section 4.4.2.1.  
For those patients who do not have censored DoR, it is calculated as (date of death or PD or last 
assessment – date of first occurrence of CR or PR + 1)/30.4375. 
 
4.4.2.5. 
Time to Response (TTR) 
Time to response is defined as the time (months) from start of study treatment until the date of 
first documented objective response, either CR or PR (whichever status is recorded first), 
according to RECIST v1.1.  It will be calculated for patients whose BOR is either CR or PR. 
 
TTR is calculated as (date of first occurrence of CR or PR – date of start of study treatment + 
1)/30.4375. 
 
Date of CR/PR should use the latest tumor assessment date at the CR/PR visit.  
Time to response will be based on tumor assessments up to PD, death or initiation of a further 
anti-tumor therapy, whichever occurs earlier.   
 
Both the unconfirmed TTR based on the patients with unconfirmed CR/PR and the patients with 
confirmed TTR based on the confirmed CR/PR will be derived.  For the confirmed TTR, the first 
date to observe the CR/PR will be used as the response date for confirmed responder. 
 
4.4.2.6. 
Overall Survival (OS) 
Overall survival will be performed for part 2 (Dose Expansion) on Cohort A (CRC) and Cohort F 
(ATC) only. 


 
 
 
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OS is defined as the time (months) from the start of study treatment until the date of death due to 
any cause.  
That is, OS is calculated as (date of death or last known alive – date of start of study treatment + 
1)/30.4375.   
In the rare case, if year and month of death date are known but the day is unknown, day will be 
imputed as 15 if there are no visits or assessments after the 15th of the moth. For example, if a 
patient is reported to die on Dec2017, the death date will be imputed as 15 Dec2017 if there are 
no visits or assessments after 15Dec2017. 
Patients with no event during the study will be censored at the date last known to be alive. OS 
will not be censored if a patient receives subsequent anticancer treatments after discontinuation 
of the study drugs. 
Moreover, the last known alive date will be derived for patients not known to have died at the 
analysis cut-off date using the latest date (including complete date and partial date with Month 
and Year information) among the following data: 
 
All assessment dates (e.g. laboratory, vital signs assessments, ECG, ECOG, performance 
status assessment, tumor assessment dates etc.). 
 
Medication dates including study medication, concomitant medications, anticancer therapies 
administered after study treatment discontinuation. 
 
Adverse events start and end date. 
 
Date latest known alive collected during the survival follow-up. 
 
4.5. Other Endpoints  
4.5.1. 
Pharmacokinetic Endpoint 
Blood samples will be collected for analysis of surufatinib plasma concentration and tislelizumab 
serum concentration according to the PK schedule of events in Table 9.   
Table 9 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments 
Visit 
Surufatinib1 
Tislelizumab 
Immunogenicity 
(Anti-Tislelizumab 
Antibodies) 
PK Sample Time Point2 
PK Sample Time Point2 
C1D1 
Predose3 
Preinfusion4 
Preinfusion4 
2 to 4 hours post-dose 
EOI5 
C1D8 
Predose3 
Any time during visit 
- 
C1D15 
Predose3 
Any time during visit 
- 


 
 
 
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Table 9 
Time and Events Schedule for Pharmacokinetics and Immunogenicity 
Assessments 
Visit 
Surufatinib1 
Tislelizumab 
Immunogenicity 
(Anti-Tislelizumab 
Antibodies) 
PK Sample Time Point2 
PK Sample Time Point2 
2 to 4 hours post-dose 
C2D1 
Predose3 
Preinfusion4 
Preinfusion4 
C5D1 
Predose3 
Preinfusion4 
Preinfusion4 
EOIe 
C9D1 
Predose3 
Preinfusion4 
Preinfusion4 
C17D1 
Predose3 
Preinfusion4 
Preinfusion4 
EOT 
- 
Any time during visit 
Any time during visit 
CxDx=Cycle X, Day X; hr=hours; EOI=end of infusion; EOT=end of treatment; PK=pharmacokinetic.  
Note: If at any time during an infusion day a patient should present with any Grade 3 infusion-related AE, an 
additional blood PK sample may be taken to determine the serum concentration of tislelizumab.  The actual 
time of PK sample and the start time and end time of infusion must be recorded. 
1 
On days that both study drugs are administered, the surufatinib PK sample will be taken at the study site within 
15 minutes before the start of the tislelizumab infusion. 
2 
If dose delay occurs, then samples should be collected on the actual day of drug administration, not on the 
originally scheduled administration day.  Additional samples can be obtained to help assess safety issues. 
3 
The predose surufatinib PK sample should be taken within 15 minutes prior to dosing. 
4 
Pre-infusion PK and immunogenicity samples for tislelizumab should be collected within 60 minutes before 
starting tislelizumab infusion. 
5 
EOI sample should be taken within 30 minutes after completing tislelizumab infusion. 
 
4.5.2. 
Immunogenicity  
Serum samples will be collected for analysis antibodies to tislelizumab for antidrug antibody 
(ADA) analysis according to table above. 
 
4.5.3. 
Other Exploratory Analyses 
Exploratory analyses will be performed only for part 2 (Dose Expansion).  
 
Distribution of PD-L1 expression 
PD-L1 expression will be available at screening for all patients enrolled in Part 2. A summary 
table of PD-L1 expression on tumor cells at screening will be presented by cohort on the safety 
analysis set using following cut offs: 
x %,  
x 5%  
x 0%.  


 
 
 
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5. ANALYSIS METHODS  
5.1. General Principles  
5.1.1. 
General Methodology 
In general, all efficacy and safety will be summarized using descriptive statistics and graphs as 
appropriate. Continuous variables will be summarized by descriptive statistics (sample size [n], 
mean, standard deviation, minimum, 25% percentile [Q1], median, 75% percentile [Q3], and 
maximum). Categorical variables will be summarized in frequency tables (frequencies and 
percentages).  
Time to event variable will be analyzed using the Kaplan-Meier method and summarized with 
median, 25% and 75% percentiles with their corresponding 95% confidence intervals (CI) which 
are calculated from a log-log transformation based on the method of Brookmeyer and Crowley 
(1982). Individual data will be presented in patient listings.   
Analyses will be implemented using SAS® 9.4 or higher (SAS Institute, Cary, North Carolina, 
USA). The International Conference on Harmonization (ICH) numbering convention, i.e. ICH-
E3, will be used for all tables and listings.  
All summary tables, listings, and figures (TLFs) will be presented by treatment groups as defined 
in Table 10.  
Table 10  
Treatment/Cohort Display in TLFs 
Part of the study 
Treatment Group 
Treatment Description in Data Display  
Part 1 - Dose 
Escalation 
-1  
Surufatinib 200 mg + Tislelizumab 
1 
Surufatinib 250 mg + Tislelizumab 
2 
Surufatinib 300 mg + Tislelizumab 
Part of the study 
Cohort group 
Cohort Description in Data Display  
Part 2 - Dose 
Expansion 
1 
Cohort A CRC 
2 
Cohort B1 Thoracic NETs 
3 
Cohort B2 GEP NETs 
4 
Cohort C SCLC 
5 
Cohort D GC 
6 
Cohort E1 ASPS 
7 
Cohort E2 UPS 
8 
Cohort F ATC 
For continuous data, unless otherwise specified, the mean, median, Q1, and Q3 will be presented 
with one more significant digits than the original values, and standard deviation will be reported 
with 2 more significant digits than the original values.  The minimum and maximum should 
report the same significant digits as the original values. The derived variables will be presented 
with one decimal place. Percentages will be reported with one decimal point; if the count is 0, no 


 
 
 
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percentage will be presented. Value of percentage less than 1% will be presented as “<1%.” 
Value of percentage OHVV WKDQ  EXW   ZLOO EH SUHVHQWHG DV ³!´ $Q\ URXQGLQJ
will be done after all calculations are made.  
 
5.1.2. 
Handling Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing — no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only.  
However, imputation of missing AE and concomitant medication onset and stop dates will be 
used to determine the status of each AE and the prior/concomitant status of each medication. The 
specific imputation rules are provided below, refer to Section 5.1.2.1 for the method of 
imputation of missing AE onset and stop date and Section 5.1.2.2 for the method of imputation 
of missing concomitant onset and stop dates. However, the imputed dates should not be shown in 
listings. 
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Unless otherwise specified, patients with missing data will be excluded 
only from analyses for which data are not available. 
5.1.2.1. 
Adverse Events Start/End Date 
AEs with onset/end dates that are partially/completely missing will be imputed as follows.  
(i) AE start date: 
 
If the AE onset date is completely missing, the AE start date will be imputed as the reference 
start date (ie date of first treatment); 
 
If the AE onset date is partial missing, then  
 If both the year and the month are available and the year and the month are the 
corresponding year and month of the reference start date, then the AE start date will be 
imputed as the reference start date;  
 If both the year and the month are available and the year and the month are not equal to 
the corresponding year and month of the reference start date, then the AE start date will 
be imputed as the 1st day of the month; 
 If only the year is available and the available year is the corresponding year of the 
reference start date, then the AE start date will be imputed as the reference start date; 
 If only the year is available, and the available year is not equal to the corresponding year 
of the reference start date, then the AE start date will be imputed as the January 1st of the 
year 


 
 
 
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(ii) AE end date will be imputed as below for the partial date only, the imputation rules only 
apply when the AE is not ongoing: 
 
If both the year and the month are available, AE end date will be imputed as the last day of 
the month; 
 
If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date for patients known to be dead at end of study 
or cut off date, the date of the death will be used for AE end date. If the imputed AE end date is 
after the last known alive date for patients alive at the end of study or cut off date, the date of last 
known alive date will be used for AE end date.  
For AE continuing at the cut-off date, the end date will not be imputed and instead will be 
reported as “ongoing”. 
5.1.2.2. 
Concomitant Medication/Procedure/Surgery Start/End Date 
Concomitant Medication/Procedure/Surgery with onset/end dates that are partially/completely 
missing will be imputed as follows. 
(i) start date: 
 
1st day of the month will be used to impute the start date if only the day is missing 
 
January 1st will be used to impute the start date if both the day and month are missing 
 
If the date is completely missing, then the day before the reference start date will be imputed 
as the start date. 
(ii) end date: 
 
Last day of the month will be used to impute the end date if only the day is missing 
 
December 31st of the year will be used to impute the end date if both the day and month are 
missing 
 
If the date is completely missing, assign ‘continuing’ status to the end date 
If the imputed end date is after the death date or last known alive date, the date of the death or 
last known alive date will be imputed as the Concomitant medication/procedure/surgery end 
date. 
5.1.2.3. 
Subsequent Anti-cancer Therapy Date 
When a partial new anti-tumor therapy start date is reported, every effort will be made to identify 
the precedence relationship of starting date of new anti-tumor therapy relative to the reference 
end date. Below rules will be used: 
 
If the date is completely missing, new anti-tumor therapy date will be imputed as reference 
end date + 1; 
 
If only the day is missing, 15th day will be imputed as the new anti-tumor therapy date; 


 
 
 
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 
If both the day and the month are missing, then July 1st will be imputed as the new anti-tumor 
therapy; 
If the imputed date is earlier than reference end date, then it will be replaced with reference end 
date + 1, if the imputed date is later than the date of death or last known alive date, it will be 
replaced with the date of death or last known alive date. 
 
5.1.2.4. 
Primary Diagnosis Date and Metastatic Disease Diagnosis Date 
When a partial date of primary diagnosis or a partial date of first metastatic disease diagnosis is 
reported, the below imputation rules will be used: 
 
If the date is completely missing, no imputation will be conducted; 
 
If only the day is missing, 15th day will be assigned; 
 
If both the day and the month are missing, then July 1st will be assigned. 
Check that the imputed date is not after or equal to the informed consent date. 
 
5.1.3. 
Visit Windowing 
It is expected that there will be a variation between patients in the actual number of study days 
from the start of administration of study drug within each cycle defined as Day 1, to the dates 
that the scheduled visits occur. To handle this, for tables and figures where data are grouped by 
visit, assessments will be categorized using visit windows based on study days (relative to the 
Day 1 of each cycle). The visit-window mapping is described in Table 11. Visit-based 
summaries will be based on the windowed visits. All data, whether or not within the visit 
windows, will be presented in patient’s listings.  
For windowed visits during the treatment cycles, if more than one visit occurs during a visit 
window, the visit closest to the scheduled day will be assigned to the windowed visit. If two 
visits are equidistant from the scheduled day, the later visit will be assigned to the windowed 
visit. If there are multiple assessments on the same day, the worst case will be used.  
For the EOT, the last assessment in the window will be included in the summary.  
For a patient who prematurely discontinues the study, the premature visit will be slotted 
accordingly. The window for EOT will be "last dose date of last cycle to last dose date of last 
cycle + [30 days + 7 days protocol defined window]”. 
 
Note that due to the database design all surufatinib cycles after cycle 25 will be stored as UNS. 
Thus for cycles 26+ the tislelizumab dosing information will be used. Additionally, if from cycle 
26+ tislelizumab is not taken then the unscheduled visits will be sorted by date if surufatinib 
dosing and the cycle will be assigned sequentially. 




 
 
 
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5.1.4. 
Adjustment of Covariates 
Not applicable  
5.2. Analysis Methods  
5.2.1. 
Patient Disposition 
Summary of study disposition will be provided by dose level for Part 1 and by cohort for Part 2 
for the following: 
 Number of patients who signed the informed consent  
 Number of screen failures 
 Reason for screen failure 
 Number of patients who did not receive study treatment 
 Number of patients who received study treatment 
 Patients still on study treatment  
 Reason for study drug discontinuation for each study drug (adverse event, radiological 
disease progression, consent withdrawn and does not agree to future follow-up, patient 
decision and agrees to future follow-up, investigator decision, lost to follow-up, death, 
other) 
 Number of patients going into efficacy follow-up  
 Number and percentage of patients who discontinue the efficacy follow-up 
 Reasons for discontinuation of the efficacy follow-up (death, lost to follow-up, withdrawal 
of consent, progressive disease, other, reasons are based on the reasons efficacy follow-up 
not conducted) 
For Cohorts A and F (patients with PD) only: 
 Number of patients going into survival follow-up 
 Number and percentage of patients who discontinue the study 
 Reason for discontinuation of the study (death, lost to follow-up and withdrawal of consent,  
reasons are based on the survival status) 
A separate table will be presented to show the patients included in each analysis set and summary 
reasons for exclusion from an analysis set.  
Patient’s discontinuation status and inclusion in analysis sets will be also listed. 
 
5.2.2. 
Protocol Deviations 
Protocol deviations will be summarized descriptively for patients with at least one major protocol 
deviation by dose level and overall for Part 1 as well as by cohort and overall for Part 2.   
 
A patient can have multiple important deviations and will be counted once per major/minor 
deviation. 
 


 
 
 
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COVID-19-related protocol deviations will be summarized descriptively by dose level and overall 
for Part 1 as well as by cohort and overall for Part 2.   
In addition, all protocol deviations including deviations that are related to COVID-19 will be 
provided in a by-patient listing. 
5.2.3. 
Demographic and Other Baseline Characteristics 
The following demographic and other baseline characteristics will be summarized by dose level 
and overall for Part 1 as well as by cohort and overall for Part 2 on the safety analysis set:  
x Age (years) at screening, age groups (18-65, >65-75, >75 years and <65,  65 years ),  
x Gender, childbearing potential (female only) 
x Race  
x Ethnicity  
x Region (United States, Europe)  
x Country  
x Baseline height (cm)  
x Baseline weight (kg)  
x Baseline BMI (kg/m2) calculated as baseline weight (kg)/ [baseline height (m)]2, BMI 
FDWHJRU\   DQG   NJP2) 
x Baseline ECOG status. 
5.2.4. 
Disease Characteristics  
Oncology history will be summarized descriptively by dose level and overall for Part 1 as well as 
by cohort and overall for Part 2 for the safety analysis set for the following: 
x Primary Diagnosis 
o Colorectal Cancer 
o Thoracic Neuroendocrine tumors  
o Gastroenteropancreatic Neuroendocrine tumors  
o Small-cell lung cancer  
o Gastric cancer  
o Soft tissue sarcoma (alveolar soft part sarcoma)  
o Soft tissue sarcoma (undifferentiated pleomorphic sarcoma)  


 
 
 
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o Other  
x RAS Status (wild type, mutant, not applicable, unknown) 
x BRAF Status (wild type, V600 E mutation, other) 
x NET Functional Status (functional, non functional, not applicable, unknown) 
x Time since first diagnosis of disease (months)  
x Anatomical location of primary tumor  
x Time since diagnosis of locally advanced/metastatic disease (months)  
x Prior oncology treatments (prior anti-cancer medication, prior anti-cancer radiotherapy, 
prior anti-cancer procedures) 
Time since first diagnosis of disease (months) = (date of first study treatment administration – date 
of first diagnosis of disease + 1)/30.4375 
Time since metastatic disease (months) = (date of first study treatment administration – date of 
diagnosis of metastasis disease + 1)/30.4375 
Prior oncology treatments including prior anti-cancer mediation, prior anti-cancer radiotherapy, 
prior anti-cancer procedure or surgery are summarized descriptively by dose level and overall for 
Part 1 as well as by cohort and overall for Part 2 for the safety analysis set.   
 
5.2.5. 
Medical History  
The conditions/diseases from medical history are those conditions/diseases that stopped prior to 
the study entry. Medical history will be coded to SOC and PT using MedDRA version 27.0 
The number and percentage of patients with any past medical/surgical history within each SOC 
and PT will be provided by dose level/cohort on the safety analysis set.  
A patient will only be counted once within a particular SOC (PT) even if he/she has multiple 
conditions/diseases in the same SOC (PT).   
Each summary will be ordered by descending order of incidence of SOC according to total 
column and PT within each SOC. If the frequencies tie, an alphabetic order will be applied.  
5.2.6. 
Prior and Subsequent Anti-cancer Therapy 
Prior and subsequent anti-cancer therapy, including mediation, radiotherapy, and procedure or 
surgery, will be summarized descriptively by dose level/cohort and overall for the safety analysis 
set. 


 
 
 
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5.2.6.1. 
Prior and Subsequent Anti-cancer Medication 
Prior anti-cancer medications are defined as those taken by the patient prior to the administration 
of study drug. Subsequent anti-cancer medications are defined as those taken by the patient after 
the discontinuation of the study drug.  
Prior and subsequent anti-cancer medications will be coded to Anatomical Therapeutic 
Classification (ATC) therapeutic group (i.e., ATC Level 2) and PT using the World Health 
Organization Drug Dictionary (WHO-DD) version March 2024. 
The prior anti-cancer medications will be summarized by presenting the number and percentage 
of patients by PT and ATC. Patients taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC according to total column and PT within each ATC. If the frequencies tie, an 
alphabetic order will be applied.  
Similarly, the subsequent anti-cancer medications will be summarized. 
All prior and subsequent anti-cancer medications will be presented in patient listing. 
5.2.6.2. 
Prior and Subsequent Anti-cancer Radiotherapy 
Prior anti-cancer radiotherapy is defined as those taken by the patient prior to the administration 
of study drug.  
Subsequent anti-cancer radiotherapy is defined as those taken by the patient after the 
discontinuation of the study drug.  
The number and percentage of patients with at least one prior anti-cancer radiotherapy will be 
summarized.  
All prior and subsequent anti-cancer radiotherapy will be presented in patient listing.  
5.2.6.3. 
Prior and Subsequent Anti-cancer Procedure or Surgery 
Prior anti-cancer procedure or surgery are defined as those taken by the patient prior to the 
administration of study drug. Subsequent anti-cancer procedure or surgery are defined as those 
taken by the patient after the discontinuation of the study drug.  
Prior and subsequent anti-cancer procedure or surgery will be coded to SOC and PT using 
MedDRA (Medical Dictionary for Regulatory Activities) version 27.0 
The prior anti-cancer procedure or surgery will be summarized by presenting the number and 
percentage of patients by PT and SOC. Patients taking the same medication multiple times will 
only be counted once for that PT or SOC.  
Each summary will be ordered by descending order of incidence of SOC to total column and PT 
within each SOC. If the frequencies tie, an alphabetic order will be applied.  
Similarly, the subsequent anti-cancer procedure or surgery will be summarized.  
All prior and subsequent anti-cancer procedure or surgery will be presented in a patient listing. 


 
 
 
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5.2.7. 
Prior and Concomitant Medications 
Prior and concomitant medications (CMs) will be coded to Anatomical Therapeutic 
Classification (ATC) therapeutic group (i.e. ATC Level 2) and PT using the WHO-DD version 
March 2024. 
Medications taken and stopped prior to the first dose of study treatment are denoted “Prior”. 
Medications taken prior to the first dose of study treatment and continuing beyond the first dose 
of study treatment or those medications started on or after the first dose of study treatment but no 
later than 37 days after the last dose are denoted “Concomitant”.  
Medication with start date/time being partially or completely missing will be assumed to be 
concomitant if it cannot be definitely shown that the medication did not occur during the 
treatment period. 
The prior medications will be summarized by presenting the number and percentage of patients 
by PT and ATC. Patients taking the same medication multiple times will only be counted once 
for that PT or ATC. Each summary will be ordered by descending order of incidence of ATC 
according to total column and PT within each ATC. If the frequencies tie, an alphabetic order 
will be applied.  
Similarly, the concomitant medications will be summarized. 
All prior and concomitant medications will be presented in patient listing.  
 
5.2.8. 
Concomitant Procedure 
Medical or surgical procedures that started after first dose date but no later than 37 days after the 
last dose are denoted “Concomitant”.   
Concomitant medical or surgical procedures will be classified using the MedDRA version 27.0  
The concomitant medical or surgical procedures will be summarized by presenting the number and 
percentage of patients by PT and SOC. Patients having the same medical or surgical procedure 
multiple times will only be counted once for that PT or SOC. Each summary will be ordered by 
descending order of incidence of SOC according to total column and PT within each SOC. If the 
frequencies tie, an alphabetic order will be applied.  
All concomitant medical or surgical procedures will be presented in patient listing. 
5.2.9. 
Exposure of Study Treatment 
Exposure of study treatment (duration of exposure, number of cycles of treatment received, 
cumulative dose, dose intensity and relative dose intensity for each study drug,) will be 
summarized by dose level and overall for Part 1 as well as by cohort and overall for Part 2.   
 
 
Relative dose intensity will be also summarized using the following classifications:  


 
 
 
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- 
< 50%;  
- 
50 % - < 70% ;   
- 
70 % - < 90% ;  
- 
90 % - <110% ;  
- 
 >= 110 % 
 
Number of cycles treatment received will be also summarized using the following classifications: 
(1, 2, 3, 4, 5, 6, >6) 
 
The following summary for dose modification will be summarized separately for each drug 
(surufatinib and tislelizumab) by dose level, and overall for Part 1 as well as by cohort and overall 
for Part 2.  Dose reduction/increase is not allowed with tislelizumab. 
 
 Number of patients with any dose modification with surufatinib (including both drug 
interruption and dose reduction), and frequency of dose modification: 0, 1, 2, 3, 4, 5, 6, >6 
 Number of patients with any drug interrupted with surufatinib or tislelizumab (number of 
patients experienced drug interruption and reasons for drug interruption, and frequency of drug 
LQWHUUXSWLRQV     
 Number of patients with any drug withdrawn with surufatinib or tislelizumab (number of 
patients experienced drug withdrawn and reasons for drug withdrawn) 
 Number of patients with any dose reduced with surufatinib (Number of patients with any dose 
reduction and reasons for dose reduction; and frequency of dose reduction: 0, 1  2.  
5.2.10. 
Safety Analyses 
Safety data during the treatment period will be summarized. Treatment period is defined as the 
duration from the date of the first study drug administration until 37 days after last dose. 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.   
 
5.2.10.1. 
Dose-Limiting Toxicity (DLT) 
Adverse events will be assessed by the DLT criteria during the 21-day assessment window, 
which begins on the day of the administration of study treatment.  
All DLT analysis will be performed for the Part 1 dose escalation phase on the DLT evaluable 
analysis set. DLT analysis will be also done for the part 2 expansion phase on the safety analysis 
set. 


 
 
 
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The number of patients and percentage with DLTs or DLT-equivalent will be presented by dose 
level for part 1. Patients with DLTs or DLTs equivalent will be also summarized by SOC, PT, 
and highest CTCAE grade for each dose level. 
The same analysis (DLT-equivalent only) will be provided for Part 2 on the safety analysis 
population. 
DLTs or DLT-equivalent toxicities will also be presented in patient listings. 
5.2.10.2. 
Adverse Events 
An overall summary of the number and percentage of patients along with the number of adverse 
events for each dose level/cohort will be provided for the following categories of AEs: 
Group 
Summary Scope 
All TEAEs 
 CTCAE Grade ı3 AEs  
 Surufatinib-related AEs   
 Tislelizumab-related AEs  
 DLT 
 DLT-equivalent (DLTs which occur outside the DLT 
assessment window) 
 AEs Leading to Dose Reduction of Surufatinib 
 AEs Leading to Dose Interruption of Surufatinib 
 AEs Leading to Treatment Discontinuation of Surufatinib 
 AEs Leading to Dose Interruption of Tislelizumab 
 AEs Leading to Treatment Discontinuation of Tislelizumab 
 Surufatinib-related AEs Leading to Dose Reduction of 
Surufatinib 
 Surufatinib-related AEs Leading to Dose Interruption of  
Surufatinib 
 Surufatinib-related AEs Leading to Treatment 
Discontinuation  of Surufatinib 
 Tislelizumab-related AEs Leading to Dose Interruption of  
Tislelizumab  
 Tislelizumab-related AEs Leading to Treatment 
Discontinuation  of Tislelizumab  
 AEs Leading to Death 
Serious TEAEs 
 CTCAE Grade ı3 SAEs  
 Surufatinib-related SAEs  
 Tislelizumab-related SAEs  
 SAEs Leading to Dose Reduction of Surufatinib  
 SAEs Leading to Dose Interruption of Surufatinib 


 
 
 
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Group 
Summary Scope 
 SAEs Leading to Treatment Discontinuation of 
Surufatinib 
 SAEs Leading to Dose Interruption of Tislelizumab 
 SAEs Leading to Treatment Discontinuation of 
Tislelizumab  
 Surufatinib-related SAEs Leading to Dose Reduction of 
Surufatinib 
 Surufatinib-related SAEs Leading to Dose Interruption of 
Surufatinib 
 Surufatinib-related SAEs Leading to Treatment 
Discontinuation of Surufatinib 
 Tislelizumab-related SAEs Leading to Dose Interruption 
of Tislelizumab 
 Tislelizumab-related SAEs Leading to Treatment 
Discontinuation of Tislelizumab 
  SAEs Leading to Death 
Treatment-Emergent AESIs 
for Surufatinib 
 
 &7&$( *UDGH  $(6,V  
 Surufatinib -related AESIs 
 AESIs for Surufatinib Leading to Dose Reduction of 
Surufatinib 
 AESIs for Surufatinib Leading to Dose Interruption of 
Surufatinib 
 AESIs for Surufatinib Leading to Treatment 
Discontinuation of Surufatinib 
 AESIs for Surufatinib Leading to Dose Interruption of 
Tislelizumab 
 AESIs for Surufatinib  Leading to Treatment 
Discontinuation of Tislelizumab  
 Surufatinib-related AESIs for Surufatinib Leading to Dose 
Reduction of Surufatinib 


 
 
 
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Group 
Summary Scope 
 Surufatinib-related AESIs for Surufatinib Leading to Dose 
Interruption of Surufatinib 
 Surufatinib -related AESIs for Surufatinib Leading to 
Treatment Discontinuation of Surufatinib 
 AESIs for Surufatinib Leading to Death   
 
Treatment-Emergent imAEs 
for Tislelizumab 
 
 &7&$( *UDGH  LP$(V  
 Treatment-related imAEs to Tislelizumab 
 imAEs for Tislelizumab Leading to Dose Reduction of 
Surufatinib 
 imAEs for Tislelizumab Leading to Dose Interruption of 
Surufatinib 
 imAEs for Tislelizumab Leading to Treatment 
Discontinuation of Surufatinib  
 imAEs for Tislelizumab Leading to Dose Interruption of 
Tislelizumab 
 imAEs for Tislelizumab Leading to Treatment 
Discontinuation of Tislelizumab  
 Tislelizumab-related imAEs for Tislelizumab Leading to 
Dose Interruption of Tislelizumab 
 Tislelizumab-related imAEs for Tislelizumab Leading to 
Treatment Discontinuation of Tislelizumab 
 imAEs for Tislelizumab Leading to Death 
COVID-19-related TEAEs 
- 
&7&$( *UDGH    
 
 
The number and percent of patients experiencing a TEAE within each of the categories and sub-
categories listed in Table above will be also summarized by SOC, PT, and highest CTCAE grade 
for each dose level/cohort. 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 summary will be sorted in descending order of frequency of SOC according to the sum of 
column. Within SOC, sort by descending frequency of PT according to the sum of column. 


 
 
 
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All AEs, including AEs that started prior to the study drug, will be presented in patient listings. 
In addition, separate listings of all SAEs, AESIs, imAEs, AEs leading to death, AEs leading to 
dose reduction, AEs leading to dose interruption, and AEs leading to study drug discontinuation 
will be provided. 
5.2.10.3. 
Death 
Number of deaths, primary cause of death and whether autopsy was performed are summarized 
descriptively for each dose level/cohort.  Similarly, the deaths happening during the treatment 
period will also be tabulated.  
Data for deaths will be provided as patient list in which the on-treatment death will be flagged. 
5.2.10.4. 
Laboratory Evaluations 
For hematology, clinical chemistry and coagulation labs, the observed values and change from 
baseline will be summarized by visit using descriptive statistics.   
Toxicities for clinical labs will be characterized according to CTCAE, v5.0 (Appendix 2), and 
the frequency and percentage of patients with each CTCAE grade for each visit during the 
treatment period will be described. Moreover, any occurrence of Grade 3 or Grade 4 during the 
overall treatment period will be summarized, and shift in grade from baseline to the worst post-
baseline value will be summarized. Both the scheduled and unscheduled assessments will be 
used to identify the worst post-baseline values. 
Summary tables will be also provided for abnormal hepatic laboratory values by dose level (for 
part 1) and by cohort (for part 2). Abnormal hepatic laboratory values are based on the pre-
specified thresholds (section 4.3.3) 
Listings of all laboratory data with normal reference ranges, and CTCAE grades (when possible) 
will be provided.  
5.2.10.5. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline by visit.  
A listing of all ECG data will be provided.  
The criteria for potentially clinically significant findings are defined in Table 10.  
The frequency and percentage of patients with any potentially clinically significant findings 
during the treatment period will be presented. The supportive data will be provided in patient 
data listings. 
 
 


 
 
 
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5.2.10.6. 
Vital Signs 
For vital sign parameters (SBP, DBP, pulse rate, temperature, and weight) the observed values 
and change from baseline will be summarized using descriptive statistics at each visit during the 
treatment period. 
Additionally, the frequency and percentage of patients with any potentially clinically significant 
findings (defined in Table 10) during the overall treatment period will be presented. A listing of 
all vital sign data will be provided.  
Moreover, the minimum, and maximum, and their corresponding change from baseline vital sign 
values will be summarized descriptively overall treatment period. 
5.2.10.7. 
Performance Status 
The frequency and percentage of patients for each ECOG score level will be summarized by  
visit. Shift in grade from baseline to the maximum post-baseline score will be summarized.  
A listing of ECOG score for all patients will be provided. 
5.2.10.8. 
Echocardiogram 
Descriptive statistics for ECHO/MUGA will be summarized by visit. A by-patient listing of 
ECHO/MUGA values at each time point will be presented. 
5.2.10.9. 
Physical Examination 
A listing of physical examination data for all patients will be provided. 
 
 


 
 
 
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5.2.11. 
Efficacy Analyses 
No formal hypothesis testing is planned for this study.   
 
5.2.11.1. 
Primary Efficacy Analyses 
The number and percentage of patients in each category of derived BOR (CR, PR, Unconfirmed 
CR, Unconfirmed PR, SD, PD, or NE) will be summarized for the safety analysis set. 
ORR and ORRUNCONFIRMED will be summarized by dose level for Part 1 and by cohort for Part 2.   
The 95% CIs of ORR and ORRUNCONFIRMED will be calculated using the Clopper-Pearson exact 
binomial method for each dose level and cohort. 
Overall objective responses and best overall responses are provided in listings by patients and visit. 
 
5.2.11.2. 
Sensitivity Analysis for Efficacy Endpoint 
As a sensitivity analysis, ORR, DCR, CBR, DoR, and TTR will be presented for the response 
evaluable analysis set.   
 
5.2.11.3. 
Multiplicity Control  
Not applicable.  
 
 
5.2.11.4. 
Secondary Efficacy Analyses 
Progression-Free Survival 
PFS is defined in Table 10 and calculated as (date of death or radiographic PD or last assessment 
–start date of study treatment + 1)/30.4375. 
 
The number and percent of patients who had PFS event (PD or death), the number and percent of 
patients censored, and reasons for censoring will be presented for each dose level (Part 1) and 
cohort (Part 2) for the safety analysis set.   
 
Reasons for censoring include the following: 
 
a. No baseline or post-baseline tumor assessments  
b. Lost-to follow-up prior to progressive disease or death  
c. New anti-tumor therapy started prior to PD or death 
d. Death or PD occurred after two or more consecutive missed assessment 


 
 
 
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e. Withdrew consent prior to PD or death 
f.  Alive without disease progression at the data cut off date 
Kaplan-Meier plots will be produced and the median, 25% and 75% percentile will be estimated 
using Kaplan-Meier method with their corresponding 95% CIs calculated from a log-log 
transformation based on the method by Brookmeyer and Crowley (1982).  
In order to assess duration of follow-up for PFS, Kaplan Meier estimates will be calculated in the 
same way as in the analysis for primary PFS, while using different censoring rule which reverses 
censoring indicator of primary analysis of PFS instead, i.e. patients who progressed or died in PFS 
analysis will be censored at the date of PD (objective disease progression or death). Patients who 
are censored in PFS analysis will assigned as “eventā with the same duration for PFS. 
 
All PFS data will be provided in listings by patient. 
 
DCR and CBR 
DCR and CBR will be summarized by dose level for Part 1 and by cohort for Part 2.   
The 95% CIs of DCR and CBR will be calculated using the Clopper-Pearson exact binomial 
method for each dose level and cohort. 
DCR and CBR will be provided in listings by patients. 
 
DoR and TTR 
DoR and TTR will be summarized using Kaplan-Meier method. Both the unconfirmed and the 
confirmed DoR and TTR will be summarized. The median, 25% and 75% percentile will be 
estimated using Kaplan-Meier method with their corresponding 95% CI.  
 
Censoring reasons for DoR will be the same as for PFS. 
 
All confirmed and unconfirmed DoR and TTR data will be provided in listings by patient. 
 
 


 
 
 
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Overall Survival: 
OS will be summarized using Kaplan-Meier method.   Kaplan-Meier plot will be generated and 
median OS (if estimable) along with 95% CI and Q1 and Q3 percentiles will be calculated.  
Kaplan-Meier estimate with 95% CI at timepoints 6, 9, 12 months will be summarized.  
OS will be assessed in patients enrolled to the expansion Cohort A (CRC) and Cohort F (ATC) 
only. 
 
5.3. Other Analyses 
5.3.1. 
Pharmacokinetic Analysis 
Evaluation on PK will be performed on the PK population, which is defined as all subjects with at 
least one measurable concentration data point of surufatinib or tislelizumab. 
Concentration data of surufatinib in plasma and tislelizumab in serum will be tabulated and 
summarized for each cycle at which PK are collected. Descriptive statistics will include number 
of patients [n], arithmetic mean, standard deviation, coefficient of variation [CV%], median, 
minimum, and maximum as appropriate. 
For listing and presenting individual PK data, all concentrations will be presented in original units 
and to the same decimal place as reported by bioanalytical lab, e.g., ng/mL. The conventions 
presented in the table below will be used for the presentation of the descriptive statistics of PK 
concentrations. 
Variable 
Summarized with: 
Minimum, Maximum 
3 significant digits or based on actual measured values as needed 
Mean (arithmetic), Median 
3 significant digits 
StdDev 
3 significant digits 
CV% 
1 decimal point 
 
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 CSR. 
 


 
 
 
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5.3.1.1. 
Handling of Missing Concentration Data  
Missing concentration data for all subjects who are administered scheduled study treatments is 
considered as non-informative missing and will not be imputed. No concentration estimates will 
be provided for missing sample values. 
 
5.3.1.2. 
Handling of Dose Reduction or Interruption  
Any concentration data taken at or after the time of a dose reduced or interrupted of surufatinib, or 
a dose interrupted of tislelizumab will be listed with a flag but excluded from summary statistics. 
 
5.3.1.3. 
Handling of below the lower limit of quantification (BLQ) Data  
PK concentration summary, the following rules apply: 
x For surufatinib, PK concentrations below the lower limit of quantification (BLQ) in 
predose samples on C1D1 will be set to zero; all other PK concentrations BLQ will be set 
to 0.5*LLOQ. 
x For tislelizumab, all PK concentrations that are BLQ will be set to zero. 
x When more than half (>50%) of the values at a single time point are BLQ, mean and median 
values will be reported as BLQ. Standard deviation and %CV will not be reported; 
maximum and minimum values will be reported as observed (i.e., minimal will be BLQ). 
 
5.3.1.4. 
Handling of the Difference between the Scheduled (nominal time) and the 
Actual Sampling Times (actual time)  
For all sampling times, the actual sampling times relative to dosing will be calculated as the 
difference between the actual clock time of sampling and the actual clock time of dosing. Listing 
of PK sampling times will include planned nominal time of PK sample collection, allowed PK 
sampling window, actual time elapsed from the reference dose with the deviation from the nominal 
time, and measured concentrations of the drug. For surufatinib, the reference dose refers to the 
surufatinib dose administered prior to surufatinib PK sample collection. The dose administered on 
the day of PK visit may be used as the reference dose in case the date and time of the dose prior to 
surufatinib PK sample collection is not available (e.g. predose samples on Day 1 of Cycles 2, 5, 9, 
17). For tislelizumab, reference dose will be the tislelizumab dose during the same cycle of 
tislelizumab PK sample collection or last tislelizumab dose for EOT samples. 
The actual post-dose sampling times relative to dosing expressed in hours and rounded off to two 
decimal digits will be used.  For the visit when no dose administration is scheduled (e.g. no 
tislelizumab administration on C1D8 and C1D15), the actual sampling times will be calculated as 
the difference between the actual clock time of sampling and the actual clock time of the most 
recent dose administered prior to the visit (e.g. C1D1). If the actual time of sampling is missing, it 


 
 
 
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will be reported as NR (not recorded) in the listing, and actual time elapsed from the reference 
dose will be reported as NC (not calculated). 
 
5.3.2. 
Immunogenicity Analysis 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs to tislelizumab according to the following 
attributes and endpoints. ADA analysis set include all patients who received at least one dose of 
tislelizumab and that have one baseline ADA measurement and at least one post-baseline ADA 
measurement.  
ADA attributes: 
x Treatment-boosted ADA is defined as ADA positive at baseline that was boosted to a 4- 
fold or higher-level following drug administration. 
x Treatment-induced ADA is defined as ADA negative at baseline and ADA positive 
post-baseline. 
x Transient ADA response is defined as treatment-induced ADA detected only at 1 time 
point during treatment or follow-up, excluding last time point; or detected at 2 or more time 
points during treatment or follow-up, where the first and last positive samples are separated 
by less than 16 weeks and the last time point is negative. 
x Persistent ADA response is defined as treatment-induced ADA detected at 2 or more 
time points during treatment or follow-up, where the first and last ADA positive samples are 
separated by 16 weeks or longer; or detected only in the last time point. 
x Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological 
activity. 
 
ADA response endpoints: 
x ADA incidence (also known as treatment-emergent ADA) is defined as sum of treatment-
induced and treatment-boosted ADA-positive patients as a proportion of the ADA evaluable 
population. 
x ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point. 
 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidences of positive ADAs and 
neutralizing ADAs to tislelizumab will be reported for evaluable patients.  
The effect of immunogenicity on PK, efficacy, and safety may be evaluated if data allow. The 
results of this analysis may be reported separately from the CSR. 
 


 
 
 
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5.3.3. 
Other Exploratory Analyses 
PD-L1 Expression: 
The distribution of PD-L1 expression will be examined in all patients in Part 2.   
The potential association between PD-L1 expression and tislelizumab treatment effect will be 
explored.  Other potential predictive markers will be assessed. 
The exploratory analysis may be reported separately from the CSR. 
 


 
 
 
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6. PLANNED ANALYSIS  
6.1. Independent Data Monitoring Committee 
Safety monitoring and evaluation of the dose escalation part will be carried out by the Safety 
Review Committee (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, 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 and/or MTD. 
6.2. Interim Analysis 
There is no planned formal interim analysis. However, the accrued data from any cohort may be 
analyzed for internal decision-making purposes (for example, to provide information for a 
potential Phase 3 study design). 
An unplanned interim analysis was conducted based on data cut off date of 30 November 2021 to 
review the safety and efficacy for the dose escalation Part 1 of the study only. 
6.3. Final Analysis 
The final analysis will be conducted after Database Lock (DBL) for this study. 
 


 
 
 
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7. CHANGE FROM THE PROTOCOL 
There are no changes from the protocol-planned analyses. 


 
 
 
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REFERENCE 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982; 
29-41. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-247.  
 


 
 
 
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APPENDIX 1: STUDY SCHEDULE OF EVENTS 
 
 
Cycle/Period 
 
 
 
 
 
Screening 
 
Cycle 1 
 
Cycle 2 
 
Cycle 3+ 
 
EOT 
Efficacy 
Follow-up 
Survival 
Follow- 
up18 
 
 
 
Visit 
 
 
 
Day 1 
 
 
 
Day 8 
 
 
 
Day 15 
 
 
 
Day 1 
 
 
 
Day 15 
 
 
 
Day 1 
Within 
30 
Days 
After Last 
Dose 
 
Every 
12 Weeks 
From EOT 
 
Every 
12 Weeks 
From PD 
Visit window (days) 
-28 to -1  
±1 
±1 
±1 
±1 
±3 
±7 
±14 
±14 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
Tumor sample for PD-L1 testing2 
X 
 
 
 
 
 
 
 
 
 
Cohort F: Core needle biopsy19 
X 
 
 
 
X 
 
 
 
 
Medical history, disease history3 
X 
 
 
 
 
 
 
 
 
 
Demographics4 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
and concomitant procedures5 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Comprehensive physical exam6 
X 
 
 
 
 
 
 
X 
 
 
Limited physical exam7 
 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status8 
X 
X 
 
 
X 
 
X 
X 
 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory evaluations10 
Hematology 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
Blood chemistry 
X11 
 
X 
X 
X 
X 
X 
X 
 
 


 
 
 
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Blood amylase and lipase 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
Coagulation indicators 
X11 
 
X 
X 
X 
X 
X 
X 
 
 
CK and CK-MB 
X 
X 
 
 
X 
 
X 
X 
 
 
Thyroid test 
(FT3, FT4, TSH) 
X11 
 
 
 
 
 
Every 3 cycles starting 
from C4D1 (ie, C4D1, 
C7D1, C10D1) 
X 
 
 
Serum pregnancy test 
X11 
 
 
 
 
 
 
X 
 
 
Urine pregnancy test 
 
 
 
 
X 
 
X 
 
 
 
Urinalysis 
X11 
 
 
 
X 
 
X 
X 
 
 
Virological screening 
X 
 
 
 
 
 
 
 
 
 
PK and ADA assessments 
 
Refer to Table 9 
 
 
12-lead ECG12 
X11 
 
 
X 
X 
X 
X 
X 
 
 
ECHO/MUGA scan13 
X 
 
 
 
Every 12 weeks from C1D1 (±1 week) 
 
 
Tumor evaluation/imaging14 
X 
 
Q6W (±1 week) for the first 24 weeks from C1D1, then Q9W (±1 week) thereafter 
through EOT. 
X15 
 
Surufatinib administration 
 
QD, PO, based on dose escalation dose level in Part 1 and RP2D (300 mg) in 
Part 2 
 
 
 
Tislelizumab administration16 
 
X 
 
 
X 
 
X 
 
 
 
AEs/SAEs17 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Overall survival18 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes for the Schedule of Events 
1. A written informed consent form should be obtained prior to any protocol-specific procedure or test.  Procedural details for 
informed consent are available in Section 6.1.1 of the protocol. 
2. Submit formalin-fixed, paraffin-embedded tumor sample or a minimum of 10 unstained slides for PD-L1 analysis for all patients 


 
 
 
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enrolled in Part 2 of the study.  Procedural details for archived tumor sample are available in Section 6.1.14 of the protocol. 
3. Procedural details for medical history are available in Section 6.1.2. Tumor diagnosis and tumor treatment history are described in 
Section 6.1.3 of the protocol. 
4. Procedural details for patient demographics, including baseline characteristics, are available in Section 6.1.4 of the protocol. 
5. Procedural details for concomitant medications/treatments are available in Section 6.1.5 of the protocol. 
6. Procedural details for comprehensive physical examination are available in Section 6.1.6 of the protocol. 
7. Procedural details for limited physical examination are available in Section 6.1.7 of the protocol. 
8. Procedural details for ECOG performance status are available in Section 6.1.8 of the protocol. 
9. Procedural details for vital signs are available in Section 6.1.9 of the protocol. 
10. 
Procedural details for laboratory evaluations are available in Section 6.1.10 of the protocol. 
11. 
These tests should be completed within 7 days before the start of treatment; if completed more than 7 days before first dose, 
they must be repeated on C1D1 prior to dosing. 
12. 
ECG is to be performed prior to dosing of study drugs and PK sample collection and ECHO assessments at each relevant visit. 
Other procedural details for 12-lead ECG are available in Section 6.1.11 of the protocol. Unscheduled ECG or other cardiac 
examinations can be performed if clinically indicated. 
13. 
Procedural details for ECHO assessments are available in Section 6.1.12 of the protocol.  MUGA scans are acceptable if 
ECHO cannot be performed. 
14. 
Procedural details for tumor evaluation and imaging are available in Section 6.1.13 of the protocol. 
15. 
Any patient who discontinues study treatment for any reason other than disease progression should be followed with 
tumor evaluation/imaging until progression is documented or until a new anticancer treatment is initiated. 
16. 
Tislelizumab will be dosed on day 1 of every cycle starting at C1D1 (Q3W) as an IV infusion. 
17. 
AEs will be collected from the signing of the ICF until 30 days after the last dose or initiation of new antitumor therapy, 
whichever occurs first. The relevant AEs will be followed up until they are recovered to the baseline status, already in a stable 
state as assessed by the investigator, or until the start of new antitumor therapy, loss to follow-up, death, withdrawal of informed 
consent, or end of study. SAEs are collected from the signing of the ICF until 30 days after the last dose or initiation of new 
antitumor therapy, and after this period, only SAEs related to the investigational drug are collected. In addition, telephone 
contacts with patients should be conducted to assess AEs and concomitant medications (if appropriate; ie, is associated with an 


 
 
 
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imAE or is a new anticancer therapy) at 60 days and 90 days (±14 days) after the last dose of tislelizumab, regardless of whether or 
not patients started 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. 
18. 
All patients in dose expansion cohorts A and F may be followed for survival status every 12 weeks up to 2 years from last 
dose, until death, lost to follow up, or withdrawal of consent. Survival information can be obtained via phone and/or clinical 
visits. 
19. 
Cohort F: Mandatory core needle biopsies at screening, and on treatment (between C2D1 to C2D15). Procedural details for 
core needle biopsy are available in Section 6.1.14.1 of the protocol. 
 








 
 
 
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APPENDIX 3: AESI CATEGORIES AND PREFERRED TERM  
Categories and preferred terms for Surufatinib and Tislelizumab are listed below:  
AESI term 
Seraching strategy 
Hepatic disorders 
20000009 Cholestasis and jaundice of hepatic origin (SMQ)  
20000013 Hepatic failure, fibrosis and cirrhosis and other liver 
damage-related conditions (SMQ)  
20000010 Hepatitis, non-infectious (SMQ)  
20000008 Liver related investigations, signs and symptoms (SMQ) 
Hypertension 
20000147 Hypertension (SMQ)  
Haemorrhages 
20000039 Haemorrhage terms (excl laboratory terms) (SMQ)  
Acute renal failure 
20000003 Acute renal failure (SMQ)  
 
 
 
 
 


 
 
 
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APPENDIX 4: IMAE FOR TISLELIZUMAB (PREFERRED TERM) 
Treatment 
Category 
Preferred Term 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated adrenal insufficiency 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated adverse reaction 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated arthritis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated cholangitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated cholestasis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated cystitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated cytopenia 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated dermatitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated encephalitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated encephalopathy 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated endocrinopathy 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated enterocolitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated gastritis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated hepatic disorder 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated hepatitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated hyperthyroidism 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated hypophysitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated hypothyroidism 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated lung disease 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated myocarditis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated myositis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated nephritis 


 
 
 
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Treatment 
Category 
Preferred Term 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated neurological disorder 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated neuropathy 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated oesophagitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated pancreatitis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated renal disorder 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated thyroiditis 
Tislelizumab 
Immune-mediated AEs 
Immune-mediated uveitis 
Tislelizumab 
Skin Adverse Reactions 
Acute febrile neutrophilic dermatosis 
Tislelizumab 
Skin Adverse Reactions 
Angioedema 
Tislelizumab 
Skin Adverse Reactions 
Blister 
Tislelizumab 
Skin Adverse Reactions 
Cutaneous vasculitis 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis allergic 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis bullous 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis exfoliative 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis exfoliative generalised 
Tislelizumab 
Skin Adverse Reactions 
Drug eruption 
Tislelizumab 
Skin Adverse Reactions 
Eczema 
Tislelizumab 
Skin Adverse Reactions 
Erythema multiforme 
Tislelizumab 
Skin Adverse Reactions 
Fixed eruption 
Tislelizumab 
Skin Adverse Reactions 
Idiopathic urticaria 
Tislelizumab 
Skin Adverse Reactions 
Leukoderma 
Tislelizumab 
Skin Adverse Reactions 
Mucocutaneous ulceration 
Tislelizumab 
Skin Adverse Reactions 
Mucosal ulceration 
Tislelizumab 
Skin Adverse Reactions 
Oculomucocutaneous syndrome 


 
 
 
HUTCHMED Limited 
Study Protocol: 2020-012-GLOB1 
 
SAP Version 2.0 
 
 
CONFIDENTIAL 
Page 72 of 73 
Date: 19 September 2024 
 
 
 
 
Treatment 
Category 
Preferred Term 
Tislelizumab 
Skin Adverse Reactions 
Pruritus 
Tislelizumab 
Skin Adverse Reactions 
Rash 
Tislelizumab 
Skin Adverse Reactions 
Rash erythematous 
Tislelizumab 
Skin Adverse Reactions 
Rash follicular 
Tislelizumab 
Skin Adverse Reactions 
Rash macular 
Tislelizumab 
Skin Adverse Reactions 
Rash maculo-papular 
Tislelizumab 
Skin Adverse Reactions 
Rash papular 
Tislelizumab 
Skin Adverse Reactions 
Rash pruritic 
Tislelizumab 
Skin Adverse Reactions 
Rash pustular 
Tislelizumab 
Skin Adverse Reactions 
Rash vesicular 
Tislelizumab 
Skin Adverse Reactions 
Skin depigmentation 
Tislelizumab 
Skin Adverse Reactions 
Skin exfoliation 
Tislelizumab 
Skin Adverse Reactions 
Skin hypopigmentation 
Tislelizumab 
Skin Adverse Reactions 
Skin necrosis 
Tislelizumab 
Skin Adverse Reactions 
Stevens-Johnson syndrome 
Tislelizumab 
Skin Adverse Reactions 
Toxic epidermal necrolysis 
Tislelizumab 
Skin Adverse Reactions 
Urticaria 
Tislelizumab 
Skin Adverse Reactions 
Urticaria papular 
Tislelizumab 
Skin Adverse Reactions 
Urticaria vesiculosa 
Tislelizumab 
Skin Adverse Reactions 
Vitiligo 
Tislelizumab 
Skin Adverse Reactions 
Acute generalised exanthematous pustulosis 
Tislelizumab 
Skin Adverse Reactions 
Urticarial vasculitis 
Tislelizumab 
Skin Adverse Reactions 
Rash maculovesicular 
Tislelizumab 
Skin Adverse Reactions 
Urticaria chronic 
Tislelizumab 
Skin Adverse Reactions 
Mucocutaneous rash 


 
 
 
HUTCHMED Limited 
Study Protocol: 2020-012-GLOB1 
 
SAP Version 2.0 
 
 
CONFIDENTIAL 
Page 73 of 73 
Date: 19 September 2024 
 
 
 
 
Treatment 
Category 
Preferred Term 
Tislelizumab 
Skin Adverse Reactions 
Toxic skin eruption 
Tislelizumab 
Skin Adverse Reactions 
Dermatitis psoriasiform 
Tislelizumab 
Skin Adverse Reactions 
Epidermal necrosis 
Tislelizumab 
Skin Adverse Reactions 
Mucosal exfoliation 
Tislelizumab 
Skin Adverse Reactions 
Exfoliative rash 
Tislelizumab 
Skin Adverse Reactions 
Mucosal necrosis 
Tislelizumab 
Skin Adverse Reactions 
Drug reaction with eosinophilia and systemic symptoms 
Tislelizumab 
Skin Adverse Reactions 
Autoimmune dermatitis 
Tislelizumab 
Skin Adverse Reactions 
Nodular rash 
Tislelizumab 
Diabetes  
Diabetes mellitus 
Tislelizumab 
Diabetes  
Diabetes mellitus inadequate control 
Tislelizumab 
Diabetes  
Diabetes with hyperosmolarity 
Tislelizumab 
Diabetes  
Diabetic hyperglycaemic coma 
Tislelizumab 
Diabetes  
Diabetic hyperosmolar coma 
Tislelizumab 
Diabetes  
Diabetic ketoacidosis 
Tislelizumab 
Diabetes  
Diabetic ketoacidotic hyperglycaemic coma 
Tislelizumab 
Diabetes  
Diabetic ketosis 
Tislelizumab 
Diabetes  
Increased insulin requirement 
Tislelizumab 
Diabetes  
Insulin resistant diabetes 
Tislelizumab 
Diabetes  
Ketosis-prone diabetes mellitus 
Tislelizumab 
Diabetes  
Pancreatogenous diabetes 
Tislelizumab 
Diabetes  
Latent autoimmune diabetes in adults 
Tislelizumab 
Diabetes  
Type 1 diabetes mellitus 
Tislelizumab 
Diabetes  
Fulminant type 1 diabetes mellitus