Clinical trial NCT04579679
Conditions: Neuroendocrine Tumours Neuroendocrine Tumour of the Lung Small Intestinal NET
Keywords: VEGF
Sponsor: Hutchmed
Start date: 2021-08-13; Completion date: 2024-10-15
Enrollment: 78 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, open-label, multi-centre study of surufatinib in patients with low to intermediate grade (Grade 1 or Grade 2), well-differentiated neuroendocrine tumours (NETs).

Detailed description:
This is a Phase 2, open-label, multi-centre study of surufatinib in patients with low- to intermediate-grade (Grade 1 or Grade 2), well-differentiated NETs.

The study will enroll 4 cohorts of varying NETs, as follows:

* Cohort A - NET of lung origin
* Cohort B - NET of small bowel origin
* Cohort C - NET of non-small bowel, non-pancreas, and non-lung origin
* Cohort D - NET of any origin (DDI substudy)

All patients will be treated with oral surufatinib 300 mg QD in treatment cycles of 28 days starting on Cycle 1 Day 1.

Arms: arm 1: Cohorts A, B, and C: oral surufatinib 300 mg once daily in treatment cycles of 28 days starting at Cycle 1 Day1

Cohort D:

Surufatinib 300 mg once daily in treatment cycles of 28 days starting at Cycle 1 Day and single doses of drug cocktail on Day-2 and Day 15 Cycle 1
Interventions: intervention 1: Surufatinib
Intervention descriptions: intervention 1: Surufatinib 300 mg oral once daily

Protocol documents:
Prot_000.pdf: 
Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 1  
C O N FI D E N TI AL  
 
 
Cli nic al St u d y Pr ot oc ol  
A n O pe n -L a bel P h ase 2 St u d y of S ur uf ati ni b i n P atie nts wit h 
Ne ur oe n d ocri ne T u m ors i n E ur o p e  
 
 
I n vesti g ati o n al Pr o d uct(s): 
S ur ufati ni b  
Pr ot oc ol N u m ber:  
2 0 2 0 -0 1 2 -0 0 E U 1  
Cli nic al P h ase:  
2  
Iss ue D ate:  
0 1 Dece m b er  2 0 2 3  
A me n d me nt:  
6  
S p o ns or:  
H U T C H M E D Li mite d  
B uil di n g 4, 7 2 0 Cail u n R oa d  
C hi na ( S ha n g hai) Pil ot Free Tra de Z o 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)  
I N D 
 
E u dra C T 2 0 2 0 -0 0 6 1 1 8 -1 9  
N C T 0 4 5 7 9 6 7 9  
 
 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai n e d i n t his d oc u me nt is t he c o nfi de ntial a n d pr o pri etar y i nf or mati o n of 
H U T C H M E D Li mite d a n d e xce pt as ma y b e re q uire d b y a p plica ble la ws or re g ulati o n, ma y n ot 
be discl ose d t o ot hers wit h o ut pri or writte n pe r missi o n of H U T C H M E D Li mite d. 
 
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Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
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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.  Re-consent 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 Patients 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 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 3  
C O N FI D E N TI AL  
 
S P O N S O R’ S A P P R O V A L   
Title  
A n O pe n -La b el P hase 2 St u d y o f S ur ufati ni b i n Patie nts wit h Ne ur oe n d ocri ne T u m ors 
i n E ur o pe  
Pr ot oc ol N u m ber  
2 0 2 0 -0 1 2 -0 0 E U 1  
A m e n d m e nt  
6  
 
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 he si g nat ure ta ble bel o w. 
N a m e:  
Title:  
H U T C H M E D I nter nati o nal C or p.  
Si g n at ure:  
See a p pe n de d si g n at ure p a ge  
D ate:  [D D M o nt h Y Y Y Y ] 
P P D


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Surufatinib 
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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study 2020-012-00EU1 
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 of all personnel to whom study activities have been delegated 
• To control all study drugs 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 study drugs to those participants 
• To maintain records of each patient’s participation and all data required by the protocol 
 
Name: [Last name, first name] 
Title: [Title at institution] 
Institution: [Address] 
 
 
 
Signature: 
Date: [DD Month YYYY] 
 
 
 


Clinical Study Protocol 2020-012-00EU1 
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DOCUMENT HISTORY  
Amendment 
Date of Issue 
Original 
27 Aug 2020 
0.1 
12 Jan 2021 
1 
07 Feb 2021 
2 
23 Jun 2021 
3 
12 Aug 2021 
4 
01 March 2022 
5 
05 December 2022 
 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 6  
C O N FI D E N TI AL  
 
A M E N D M E N T S U M M A R Y   
T his 2 0 2 0 -0 1 2 -0 0 E U 1 A me n d me nt 6 re places A me n d me nt  5 (0 5 Dece m ber 2 0 2 2 ).  T his 
a me n d me nt is c o nsi dere d su bsta ntial base d o n t he criteria s et 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 h e C o u ncil of t he E ur o pea n U ni o n ( E U).  
T he pri mar y p ur p ose of A me n d me nt 6 is t o pr o vi de n otificati o n of te r mi nati o n of t his st u d y base d 
u p o n t he strate gic re -e val uati o n of t he cli nical de vel o p me nt pr o gra m f or s ur ufati ni b i n E ur o pe a n d 
t he U nite d States.  T his c ha n ge is n ot b ase d o n a n y c o ncer n f or p atie nt safet y or efficac y relati v e 
t o s ur ufati ni b treat me nt.  
 
 
T he maj or c ha n ges i nc or p orate d i n A me n d me nt 6 relati ve t o A me n d me nt 5 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 d e 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 9 . 
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 g e, Hea der, S p o ns or’s 
A p pr o val, a n d D oc u me nt Hist or y  
La n g ua ge was u p date d t o reflect 
A me n d me nt 6 . 
I nf or mati o n was u p date d t o 
ac k n o wle d ge t his d oc u me nt as 
Pr ot oc ol A me n d me nt 6 .  
S y n o psis, Secti o n 1. 2 Sc he d ule of 
e v e nts, Secti o n 4. 1 St u d y D esi g n, 
Secti o n 6. 1. 6. 4 E n d of 
T reat me nt/ Earl y T er mi nati o n, 
Secti o n 6. 3 St u d y T er mi nati o n  
La n g ua ge was a d de d detail i 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 c ycle, treat me nt 
disc o nti n uati o n a n d f oll o w -u p visit.  
T hese u p dates were ma de t o 
acc o m m o date t he pr ocess of st u d y 
ter mi nati o n.  
Secti o n 2. 1. 5 Be n efit/ Ris k 
Assess me nt  
Ta ble 4  was re m o ve d, a n d a 
refere n ce was a d de d t o t he c urre nt 
In vesti ga t or’s Br oc h ure  f or details of 
i de ntifie d ris ks  
T he s ur ufati ni b I n vesti gat or 
Br oc h ure is u p date d a n n uall y a n d 
t he ta ble was n o l o n ger c urre nt.  
Secti o n 4. 1 St u d y Desi g n , Secti o n 
9. 2. 1 Sa m ple S ize R ati o nale  
N u m ber of e nr olle d patie nts per 
c o h ort were u p date d  
T hese u p dates were ma de t o reflect 
t he c urre nt stat us of t he st u d y. 
Secti o n 7. 3. 2 Pr o hi bite d T hera pies  
A p pe n di x 5  Pr o hi bite d 
C o nc o mita nt Me dicati o ns T hat 
Ha v e a K n o w n Ris k of Q T 
Pr ol o n gati o n a n d / or T orsa d es de 
P oi ntes  
A d de d a refere nce t o 
htt p:// w w w.cre di ble me ds. or g . 
T his refere nce was a d de d t o g ui de 
t he st u d y pers o n nel t o t he m ost 
u p date d a n d c o m plete s o urce of 
i nf or mati o n.  
A p pe n di x 5  Pr o hi bite d 
C o nc o mita nt Me dicati o ns T hat 
Ha ve a K n o w n Ris k of Q T 
Pr ol o n gati o n a n d / or T orsa d es de 
P oi ntes  
U p date d t he list of me dicati o ns base d 
o n htt p:// w w w.cre di ble me ds. or g . 
U p dates ma de t o ali g n wit h t he 
m ost u p date d a n d c o m plete s o urce 
of i nf or mati 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 ....................................................................................................................... 11 
LIST OF FIGURES ..................................................................................................................... 12 
LIST OF APPENDICES .............................................................................................................. 12 
LIST OF ABBREVIATIONS ...................................................................................................... 13 
1 
SYNOPSIS ....................................................................................................................... 16 
1.1 
Study Schematic............................................................................................................ 19 
1.2 
Schedule of Events ........................................................................................................ 20 
2 
INTRODUCTION ........................................................................................................... 30 
2.1 
Background ................................................................................................................... 30 
2.1.1 
Target Indication and Population ............................................................................... 30 
2.1.2 
Description of Surufatinib.......................................................................................... 30 
2.1.3 
Supportive Nonclinical Data ...................................................................................... 31 
2.1.4 
Supportive Clinical Data ............................................................................................ 31 
2.1.4.1 
Clinical Pharmacokinetics ...................................................................................... 31 
2.1.4.2 
Clinical Efficacy ..................................................................................................... 32 
2.1.4.3 
Clinical Safety ......................................................................................................... 32 
2.1.5 
Benefit/Risk Assessment ........................................................................................... 33 
2.1.5.1 
Risk Assessment ..................................................................................................... 33 
2.1.5.2 
Benefit Assessment ................................................................................................. 33 
2.1.5.3 
Overall Benefit/Risk Conclusion ............................................................................ 33 
2.2 
Study Rationale ............................................................................................................. 33 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 35 
4 
STUDY PLAN ................................................................................................................. 36 
4.1 
Study Design ................................................................................................................. 36 
4.2 
Design Rationale ........................................................................................................... 37 


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5 
POPULATION ................................................................................................................ 39 
5.1 
Recruitment ................................................................................................................... 39 
5.2 
Definitions..................................................................................................................... 39 
5.3 
Inclusion Criteria .......................................................................................................... 39 
5.4 
Exclusion Criteria ......................................................................................................... 40 
5.5 
Exceptions to Eligibility Criteria .................................................................................. 41 
5.6 
Lifestyle Restrictions .................................................................................................... 41 
6 
STUDY CONDUCT ........................................................................................................ 42 
6.1 
Study Procedures .......................................................................................................... 42 
6.1.1 
Screening.................................................................................................................... 42 
6.1.1.1 
Informed Consent.................................................................................................... 42 
6.1.1.2 
Medical and Surgical History ................................................................................. 42 
6.1.1.3 
Demographics ......................................................................................................... 42 
6.1.1.4 
Eastern Cooperative Oncology Group Performance Status .................................... 42 
6.1.2 
Safety Assessments .................................................................................................... 42 
6.1.2.1 
Vital Signs Assessment ........................................................................................... 42 
6.1.2.2 
Physical Examination.............................................................................................. 43 
6.1.2.3 
Laboratory Test Evaluations ................................................................................... 43 
6.1.2.4 
Cardiac Monitoring ................................................................................................. 43 
6.1.2.5 
Electrocardiogram Monitoring................................................................................ 44 
6.1.3 
Efficacy Assessments................................................................................................. 45 
6.1.4 
Pharmacokinetic Assessments ................................................................................... 45 
6.1.4.1 
Sample Collection and Handling ............................................................................ 45 
6.1.4.2 
Analytical Procedures ............................................................................................. 46 
6.1.5 
Pharmacodynamic Assessments ................................................................................ 46 
6.1.6 
Study Visits and Assessments .................................................................................... 46 
6.1.6.1 
Screening................................................................................................................. 46 
6.1.6.2 
Pretreatment (Cohort D Only) ................................................................................ 46 
6.1.6.3 
Treatment Period ..................................................................................................... 46 
6.1.6.4 
End of Treatment/Early Termination ...................................................................... 47 
6.1.6.5 
End of Study ........................................................................................................... 47 
6.2 
Discontinuation or Withdrawal ..................................................................................... 47 


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6.2.1 
Individual Patients ..................................................................................................... 47 
6.2.1.1 
Treatment Discontinuation...................................................................................... 47 
6.2.1.2 
Withdrawal from Study........................................................................................... 48 
6.2.1.3 
Replacement of Patients .......................................................................................... 48 
6.2.1.4 
Patients Lost to Follow-up ...................................................................................... 48 
6.3 
Study Termination ........................................................................................................ 48 
7 
STUDY INTERVENTIONS ........................................................................................... 50 
7.1 
Description of Products................................................................................................. 50 
7.1.1 
Formulation, Storage, Preparation, and Handling ..................................................... 50 
7.1.2 
Dosing and Administration ........................................................................................ 50 
7.1.3 
Dose Modification ..................................................................................................... 52 
7.1.4 
Dose Modification for Important Identified Risks..................................................... 54 
7.2 
Treatment Assignment and Bias Minimization ............................................................ 56 
7.2.1 
Treatment Allocation ................................................................................................. 56 
7.2.2 
Randomization Strategy and Procedure ..................................................................... 56 
7.2.3 
Extent and Maintenance of Blinding ......................................................................... 56 
7.3 
Assessment and Verification of Compliance ................................................................ 56 
7.3.1 
Prior and Concomitant Therapies .............................................................................. 57 
7.3.2 
Prohibited Therapies .................................................................................................. 57 
7.3.3 
Permitted Therapies ................................................................................................... 57 
7.3.4 
Drug-Drug Interactions .............................................................................................. 58 
8 
SAFETY MONITORING ................................................................................................ 59 
8.1 
Definitions..................................................................................................................... 59 
8.2 
Documenting Adverse Events....................................................................................... 60 
8.2.1 
Assessment of Events ................................................................................................ 60 
8.2.1.1 
Severity ................................................................................................................... 60 
8.2.1.2 
Causality ................................................................................................................. 61 
8.2.2 
Diagnosis Versus Signs and Symptoms ..................................................................... 61 
8.2.3 
Adverse Event Occurring Secondary to Other Events ............................................... 61 
8.2.4 
Persistent or Recurrent Adverse Events ..................................................................... 61 
8.2.5 
Previously Existing Medical Condition ..................................................................... 62 
8.2.6 
Hospitalization, Prolonged Hospitalization, or Surgery ............................................ 62 


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8.2.7 
Worsening of Solid Tumor ........................................................................................ 62 
8.2.8 
Death .......................................................................................................................... 62 
8.3 
Reporting Adverse Events ............................................................................................ 63 
8.3.1 
Adverse Event Reporting Period ............................................................................... 63 
8.3.2 
Reporting Requirements for Serious Adverse Events ............................................... 63 
8.3.3 
Adverse Event Follow-Up Duration .......................................................................... 63 
8.3.4 
Post-Study Adverse Events ........................................................................................ 63 
8.4 
Adverse Events of Special Interest ............................................................................... 64 
8.5 
Clinical Laboratory Findings ........................................................................................ 64 
8.5.1 
Liver Function Abnormality ...................................................................................... 64 
8.6 
Pregnancy ...................................................................................................................... 64 
8.7 
Overdose ....................................................................................................................... 65 
9 
ANALYSIS ...................................................................................................................... 66 
9.1 
Hypothesis..................................................................................................................... 66 
9.2 
Population ..................................................................................................................... 66 
9.2.1 
Sample Size Rationale ............................................................................................... 66 
9.2.2 
Analysis Subsets ........................................................................................................ 67 
9.3 
Testing Procedures ........................................................................................................ 68 
9.3.1 
Analysis of the Primary Efficacy Endpoint ............................................................... 68 
9.3.2 
Analysis of Secondary Efficacy Endpoints................................................................ 68 
9.3.3 
Safety Analysis .......................................................................................................... 68 
9.3.4 
Pharmacokinetics Analysis ........................................................................................ 69 
9.3.4.1 
Pharmacokinetic Analysis for Cohorts A to C ........................................................ 69 
9.3.4.2 
Pharmacokinetic Analysis for Drug Interaction Evaluation (Cohort D) ................ 69 
9.3.5 
Pharmacodynamic (Electrocardiogram) Analysis ..................................................... 70 
9.3.5.1 
Corrected QT Intervals ........................................................................................... 71 
9.3.5.2 
Heart Rate, QRS, and PR Intervals ......................................................................... 71 
9.3.5.3 
T-wave and U-wave Morphology ........................................................................... 72 
9.4 
Planned Interim Analysis .............................................................................................. 72 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 73 
10.1 
Good Clinical Practice .................................................................................................. 73 
10.2 
Ethics Review ............................................................................................................... 73 


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10.3 
Informed Consent.......................................................................................................... 73 
10.4 
Data Privacy .................................................................................................................. 74 
10.5 
Disclosure ..................................................................................................................... 75 
10.6 
Data Quality Assurance ................................................................................................ 75 
11 
OVERSIGHT ................................................................................................................... 76 
11.1 
Independent Monitoring................................................................................................ 76 
11.1.1 
Safety Review Committee ......................................................................................... 76 
11.2 
Quality Control and Assurance ..................................................................................... 76 
11.2.1 
Monitoring ................................................................................................................. 76 
11.2.2 
Audits ......................................................................................................................... 77 
11.2.3 
Records ...................................................................................................................... 77 
11.2.3.1 
Data Capture and Management ............................................................................... 77 
11.2.3.2 
Source Documentation ............................................................................................ 77 
11.2.3.3 
Records Retention ................................................................................................... 78 
11.3 
Study Termination or Study Site Closure ..................................................................... 78 
12 
PUBLICATION POLICY ............................................................................................... 79 
13 
FINANCING AND INSURANCE .................................................................................. 80 
14 
REFERENCES ................................................................................................................ 81 
15 
APPENDICES ................................................................................................................. 83 
LIST OF TABLES  
Table 1 
Schedule of Events ............................................................................................... 20 
Table 2 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations 
(Cohorts A, B, and C) .......................................................................................... 24 
Table 3 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations 
(Cohort D) ............................................................................................................ 26 
Table 4 
Objectives and Endpoints for Study 2020-012-00EU1 ....................................... 35 
Table 5 
Cohort D Treatment Overview ............................................................................ 37 
Table 6 
Investigational Treatment Used in This Study ..................................................... 50 
Table 7 
Cohort D: Drug Cocktails .................................................................................... 50 
Table 8 
Dose Modification Sequence ............................................................................... 53 
Table 9 
Dose Modification for Hematologic and Nonhematologic Toxicity ................... 53 
Table 10 
Dose Modification for Hypertension ................................................................... 54 


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Table 11 
Dose Modification for Proteinuria ....................................................................... 55 
Table 12 
Dose Modification for Liver Function Impairment ............................................. 55 
Table 13 
Dose Modification for Hemorrhage ..................................................................... 56 
Table 14 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for N=20 
Patients ................................................................................................................. 66 
Table 15 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for N=35 
Patients ................................................................................................................. 67 
Table 16 
Eastern Cooperative Oncology Group Performance Status ................................. 84 
Table 17 
Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions) ................................................................................................................ 91 
Table 18 
Time Point Response: Patients with Non-Target Lesions Only .......................... 91 
Table 19 
Best Overall Response When Confirmation of CR and PR Required ................. 92 
Table 20 
Medications That Are Substrates, Inhibitors, or Inducers of CYP3A or Substrates 
of P-gp and BCRP ................................................................................................ 96 
Table 21 
Conversion of Urinalysis Results ...................................................................... 102 
LIST OF FIGURES  
Figure 1 
Study Schematic of Study 2020-012-00EU1 ....................................................... 19 
LIST OF APPENDICES  
Appendix 1 
Eastern Cooperative Oncology Group Performance Status ................................. 84 
Appendix 2 
Response Evaluation Criteria in Solid Tumors Version 1.1 ................................ 85 
Appendix 3 
Examples of Medications That Are Substrates, Inhibitors, or Inducers of CYP3A 
or Substrates of P-GP or BCRP ........................................................................... 96 
Appendix 4 
Guideline to Interpreting the Causality Question ................................................ 97 
Appendix 5 
Prohibited Concomitant Medications That Have a Known Risk of QT 
Prolongation and/or Torsades de Pointes ............................................................. 98 
Appendix 6 
Clinical Evaluation of Possible Drug-Induced Liver Injury .............................. 100 
Appendix 7 
Conversion of Urinalysis Results Table ............................................................ 102 
Appendix 8 
COVID-19 Risk Assessment ............................................................................. 103 
Appendix 9 
Amendment History ........................................................................................... 105 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 to 
infinity 
AUC0-24h 
Area under the plasma concentration-time curve from time 0 to 
24 hours 
AUC0-last 
Area under the plasma concentration-time curve from time 0 to 
time of last measurable concentration 
BCRP 
Breast cancer resistance protein 
BML 
Below measurable limit 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C 
Cycle 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CSF-1R 
Colony stimulating factor-1 receptor 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Observed analyte concentration just prior to the beginning or at 
the end of a dosing interval 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D 
Day(s) 
DCR 
Disease control rate 


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Abbreviation 
Definition 
DDI 
Drug-drug interaction 
DIC 
Disseminated intravascular coagulation 
DILI 
Drug-induced liver injury 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
epNET 
Extrapancreatic neuroendocrine tumor 
EU 
European Union 
FDG-PET 
18F-fluorodeoxyglucose positron emission tomography 
FGFR-1 
Fibroblast growth factor receptor-1 
γ-GGT 
gamma-glutamyl transferase 
GCP 
Good Clinical Practice 
h 
Hour(s) 
HR 
Hazard ratio 
HUVEC 
Human umbilical vein endothelial cell 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IV 
Intravenous 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute(s) 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NET 
Neuroendocrine tumors 


Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
Amendment 6 
 
 
 
HUTCHMED Limited 
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CONFIDENTIAL 
 
Abbreviation 
Definition 
ORR 
Objective response rate 
PD 
Progressive disease 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
pNET 
Pancreatic neuroendocrine tumor 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QTc 
Corrected QT interval(s) 
QTcF 
Corrected QT interval by Fridericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SMQ 
Standardized MedDRA Queries 
SRC 
Safety Review Committee 
SSA 
Somatostatin analogues 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
tmax 
Time to reach the maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
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 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 1 6  
C O N FI D E N TI AL  
 
1  
S Y N O P SI S   
Title  
A n O pe n -La bel P hase 2 St u d y of S ur ufati ni b i n Patie nts wit h Ne ur oe n d ocri ne 
T u m ors i n E ur o pe   
S h ort Title  
O pe n -La b el S ur ufati ni b i n E ur o pea n Patie nts wit h N E T  
Acr o n y m  
N ot a p plica ble  
P h ase  
2  
St u d y St at us as of Pr ot oc ol 
A m e n d m e nt 6  
T he pri mar y p ur p ose of A me n d me nt 6 is t o pr o vi de n otificati o n of ter m i nati o n 
of t his st u d y base d u p o n t he strate gic re -e val uati o n of t he cli nical de vel o p me nt 
pr o gra m f or s ur ufati ni b i n E ur o pe a n d t he U nite d States.  T his c ha n ge is n ot 
base d o n a n y c o ncer n f or patie nt safet y or efficac y relati ve t o s ur ufati ni b 
treat me nt.  
 
 
  
R ati o n ale  
Ne ur oe n d ocri ne t u m ors ( N E Ts ) are 
hi g hl y 
vasc ularize d t u m ors 
wit h  
o vere x pressi o n of a n gi o ge nic mar kers , i ncl u di n g vasc ular e n d ot helial gr o wt h 
fact or ( V E G F) a n d fi br o blast gr o wt h fact or rece pt or ( F G F R).  C urre nt t hera pies 
are n ot hi g hl y selecti ve a n d res ult i n ‘ off -tar get’ t o xicities.  S ur ufati ni b, a s mall 
m olec ule selecti ve i n hi bit or of V E G F rece pt or s 1, 2, a n d 3; fi br o blast gr o wt h 
fact or rece pt or 1 ( F G F R-1) , a n d c ol o n y sti m ulati n g fact or-1 rece pt or  ( C S F-1 R) , 
has de m o nstrate d efficac y i n 2 ra n d o mi ze d, d o u ble -bli n d, place b o -c o ntr olle d 
st u dies i n N E Ts of e xtra pa ncreatic ori gi n a n d pa ncreatic ori gi n, S A N E T -e p a n d 
S A N E T -p, res pecti vel y, w hic h were pre mat urel y ter mi nate d d ue t o s ur ufati ni b 
de m o nstrati n g s u peri or efficac y o ver place b o i n ter ms of t he pri mar y e n d p oi nt 
of pr o gressi o n -free s ur vi val ( P F S).  T his st u d y  ai ms t o e val uate t he a ntit u m or 
acti vit y of s ur ufati ni b i n patie nts 
wit h l ocall y a d va nce d or 
metastatic, 
well -differe ntiate d, l o w - t o i nter me diate-gra de N E Ts.  
T ar g et P o p ul ati o n  
A d ult patie nts ≥1 8 years of a ge w h o ha ve hist ol o gicall y or c yt ol o gicall y 
d oc u me nte d l ocall y a d va nce d or metastatic l o w- t o i nter me diate- gra de ( gra d e 1 
or 2) N E T a n d ha ve pr o gresse d o n at least 1 pri or li ne of t hera p y, b ut n o m ore 
t ha n 3 t hera pies: C o h ort A, N E T of l u n g ori gi n; C o h ort B, N E T of s mall b o wel 
ori gi n; C o h ort C, N E T of n o n -s mall b o wel, n o n-pa ncreas, a n d n o n -l u n g ori gi n; 
a n d C o h ort D, N E T of a n y ori gi n.  
I nter v e nti o n 
C o h orts A, B, a n d C : O ral s ur ufati ni b 3 0 0 m g  
C o h ort D : O ral s ur ufati ni b 3 0 0 m g a n d a dr u g c oc ktail of mi daz ola m 2. 5  m g, 
fe x ofe na di ne 3 0 m g, a n d r os u vastati n 1 0 m g 
N u m ber of Sites  
1 8  i n vesti gati o nal sites i n E ur o pe 
A p pr o xi matel y  4 i n vesti gati o nal sites i n t he U S  t o e nr oll patie nts i n C o h ort D 
O bjecti ves a n d E n d p oi nts   
O bjecti ves  
C orres p o n di n g E n d p oi nts  
Pri m ar y  
•  
T o e v al uate t he a ntit u m or acti vit y of 
s ur ufati ni b i n patie nts wit h l o w- t o 
i nter me diate-gra de ( g ra d e 1 or g ra d e 2), well-
differe ntiate d N E Ts  
Pri m ar y  
•  
Disease c o ntr ol rate ( D C R) at 6 m o nt hs  
Sec o n d ar y  
•  
T o c h aracteri ze t he p har mac o ki netics ( P K) of 
s ur ufati ni b i n patie nts wit h N E T 
Sec o n d ar y  
•  
O bser ve d plas ma c o nce ntrati o ns, esti mate d 
p o p ulati o n P K, a n d e x p os ure para meters of 
s ur ufati ni b 
C CI


Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
Amendment 6 
 
 
 
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CONFIDENTIAL 
 
• 
To evaluate the effect of surufatinib on cardiac 
repolarization, as detected by changes in 
electrocardiogram (ECG) corrected QT 
intervals (QTc), and the potential relationship 
with surufatinib plasma concentrations 
• 
QTc and plasma concentrations of surufatinib 
at specified time points 
• 
To further characterize the antitumor activity of 
surufatinib in patients with NET 
• 
Objective response rate (ORR), time to 
response, duration of response (DoR), and PFS 
• 
Cohort D only: To evaluate the effects of repeat 
dosing of surufatinib on the single-dose PK of 
cytochrome P450 (CYP)3A4, P-glycoprotein 
(P-gp), and breast cancer resistance protein 
(BCRP) substrates in patients with NET 
• 
Exposure parameters of CYP3A4, P-gp, and 
BCRP substrates 
• 
To evaluate the safety and tolerability of 
surufatinib in patients with NET 
• 
Frequency and severity of adverse events 
(AEs), physical examination findings, vital 
signs, laboratory tests, ECG, and 
echocardiogram/multigated acquisition 
Brief Summary 
This is a phase 2, open-label, multicenter study of surufatinib in patients with locally advanced or metastatic, low- 
to intermediate-grade (grade 1 or grade 2), well-differentiated NETs.  The study will enroll 4 cohorts of varying 
NETs, as follows: 
• 
Cohort A – NET of lung origin 
• 
Cohort B – NET of small bowel origin 
• 
Cohort C – NET of non-small bowel, non-pancreas, and non-lung origin 
• 
Cohort D – NET of any origin (drug-drug interaction [DDI] substudy) 
Condition/Disease 
NETs 
Study Duration 
18 months (including 12 months of enrollment) 
Treatment Duration 
Until disease progression or other discontinuation criteria are met 
Health 
Measurement/Observation 
DCR at 6 months 
Visit Frequency 
Cycle 1: Every week (±1 day, except days 1 and 2) 
Cycle 2: Every 2 weeks (±3 days) 
Cycle 3 and onwards: Every 4 weeks (±3 days) 
End of Treatment: 30±7 days after the last dose 
Number of Participants 
Total: Approximately 91 patients  
Per cohort: Approximately 20 patients in Cohorts A and C, approximately 
35 patients in Cohort B, and 16 patients in Cohort D 
Intervention Groups and 
Duration 
On study duration (including screening and follow-up): treatment until disease 
progression plus 4-week screening period and 30-day (±7 days) follow-up 
Cohorts A, B, and C: oral surufatinib 300 mg once daily (QD) in treatment 
cycles of 28 days starting on cycle 1 day 1 
Cohort D:  
• 
Day -2: A single dose of drug cocktail consisting of midazolam 2.5 mg, 
fexofenadine 30 mg, and rosuvastatin 10 mg 
• 
Cycle 1 day 1 to cycle 1 day 14: Oral surufatinib 300 mg QD 
• 
Cycle 1 day 15 (+1 week): Oral surufatinib 300 mg QD and a single 
dose of the drug cocktail 


Clinical Study Protocol 2020-012-00EU1 
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Amendment 6 
 
 
 
HUTCHMED Limited 
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CONFIDENTIAL 
 
• 
Cycle 1 day 16 and beyond: Oral surufatinib 300 mg QD in treatment 
cycles of 28 days 
In general, dose modification is allowed no more than twice, from 300 mg QD 
to 250 mg QD and then to 200 mg QD.  Full details for individual toxicities are 
provided in the protocol. 
Independent Monitoring 
The sponsor will review study safety data every 6 months or more frequently if 
safety concerns arise. 


Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
Amendment 6 
 
 
 
HUTCHMED Limited 
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CONFIDENTIAL 
 
 
 
1.1 
Study Schematic  
The study schematic is presented in Figure 1. 
Figure 1 
Study Schematic of Study 2020-012-00EU1  
 
DDI=drug-drug interaction; NET=neuroendocrine tumor; PD=progressive disease. 
1. 
Single dose of drug cocktail consisting of midazolam 2.5 mg, fexofenadine 30 mg, and rosuvastatin 10 mg. 
2. 
Patients will continue to receive surufatinib treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, lost to follow-up, the patient is no longer 
receiving clinical benefit in the opinion of the investigator, the start of subsequent anticancer therapy, or the sponsor ends the study. 
 


Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
Amendment 6 
 
 
 
HUTCHMED Limited 
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CONFIDENTIAL 
 
 
 
1.2 
Schedule of Events  
The schedule of events is presented in Table 1. 
Table 1 
Schedule of Events  
Study Visit 
 
Procedure 
Screening 
Pretreatment1 
Treatment2 
Treatment 
Completion3 
Cycle 1 
Cycle 2 
Cycle 3 
and 
Onward 
 
Day -28 
to Day  
-1 
Day -7 
to Day 
-1 
Day -2 
Day -1 
Day 1 
Day 8 
(±1 D) 
Day 15 
(±1 D)4 
Day 22 
(±1 D) 
Day 1 
(±3 D) 
Day 15 
(±3 D) 
Day 1  
(±3 D) and 
Then 
Every 
4 Weeks 
30±7 D After 
Completion 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
Vital signs6 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination7 
X 
 
 
 
 
 
 
 
 
 
 
 
Limited physical 
examination7 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology8 
 
X9 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation assay 
(aPTT, PT/INR) 
 
X9 
 
 
 
X 
 
X 
X 
 
Serum chemistry10 
 
X9 
 
 
 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 2020-012-00EU1 
Surufatinib 
Amendment 6 
 
 
 
HUTCHMED Limited 
Page 21 
CONFIDENTIAL 
 
 
 
Study Visit 
 
Procedure 
Screening 
Pretreatment1 
Treatment2 
Treatment 
Completion3 
Cycle 1 
Cycle 2 
Cycle 3 
and 
Onward 
 
Day -28 
to Day  
-1 
Day -7 
to Day 
-1 
Day -2 
Day -1 
Day 1 
Day 8 
(±1 D) 
Day 15 
(±1 D)4 
Day 22 
(±1 D) 
Day 1 
(±3 D) 
Day 15 
(±3 D) 
Day 1  
(±3 D) and 
Then 
Every 
4 Weeks 
30±7 D After 
Completion 
Lipid panel11 
X 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy tests12 
 
X9 
 
 
 
 
 
 
X 
 
X 
X 
Urinalysis13 
X9 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Thyroid function test14 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Echocardiogram/MUGA 
X 
 
 
 
 
Every 12 weeks (±7 D) after the first dose 
12-lead ECG15 
 
X9 
 
 
Refer to Table 2 for 
Cohorts A, B, and C and 
Table 3 for Cohort D 
 
X 
 
X 
X 
Tumor assessment16 
X 
 
 
 
Every 8 weeks for the first 24 weeks from C1D1 (±7 D), then every 12 weeks thereafter (±14 D) 
Meal 
 
 
X17 
 
X 
 
X17, 
 
 
 
 
 
PK plasma sampling 
 
 
X17 
X17 
Refer to Table 2 for Cohorts A, B, and C and Table 3 for Cohort D 
 
Surufatinib 
administration 
 
 
 
 
X 
 
Cocktail drug 
administration1 
 
 
X 
 
 
 
X 
 
 
 
 
 
Prior and concomitant 
medications19 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; C=cycle; 
CT=computed tomography; D=day(s); ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; INR=international 
normalized ratio; IV=intravenous; MUGA=multigated acquisition; PD=progressive disease; PK=pharmacokinetic; PT=prothrombin time; QTc=corrected QT interval; 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 2 2  
C O N FI D E N TI AL  
 
 
 
 
R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors.  
1. 
Da y -2 a n d da y -1 a n d c orres p o n di n g assess me nts are o nl y a p plica ble f or patie nts i n C o h ort D.  
2. 
D uri n g C 1, t he visit wi n d o w will be ± 1 da y ( u nless ot her wise n ote d).  Fr o m C 2 o n war d, t he visit wi n d o w will be ± 3 da ys ( u nless ot her wise n ote d).  
3. 
All p atie nts o n acti ve treat me nt at t he ti me of A me n d me nt 6 are re q uire d t o ret ur n t o t he st u d y site f or a f oll o w-u p wit hi n 3 0 ± 7 da ys af ter t he last d ose of s ur ufati ni b 
recei ve d.  Treat me nt wit h s ur ufati ni b s h o ul d be disc o nti n ue d o n Da y 2 8 of t he last c ycle t hat ca n be f ull y c o m plete d n o later t ha n
.  All treat me nt 
c o m pleti o n assess me nts descri 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. 
Patie nts w h o disc o nti n ue st u d y treat me nt f or a n y reas o n nee d t o ret ur n t o t he st u d y site f or a f oll o w -u p wit hi n 3 0 ± 7 da ys after t he last d ose of s ur ufati ni b .  A n 
o n g oi n g A E relate d t o s ur ufati ni b will be f oll o we d u ntil t he e ve nt has res ol ve d t o baseli ne gra de  , t he i n vesti gat or e val uates t he A E as sta ble, or ne w a ntit u m or 
treat me nt is i nitiate d , t he patie nt is l ost t o f oll o w-u p, t he patie nt wit h dra ws i nf or me d c o nse nt, or it is deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he 
ca use of t he e ve nt.  
4. 
F or t he first a p pr o xi matel y 4 0 patie nts of C o h orts A, B, a n d C a n d all patie nts i n C o h ort D, visits f or C 1 D 1 5 ma y be sc h e d ule d u p t o 1 wee k after  b ut n o t b ef ore 
C 1 D 1 5.  T his is t o e ns ure t hat s ur ufati ni b reac hes stea d y state ( 1 4 da ys after first d ose).  
5. 
A si g ne d I C F s h o ul d be o btai ne d pri or t o a n y pr ot oc ol -s pecific pr oce d ure or test.  Tests c o m plete d wit hi n 2 8 da ys pri or t o e nr oll me nt ca n be use d f or scree ni n g a n d 
d o n ot nee d t o be re peate d, wit h t he e xce pti o n of certai n la b orat or y tests.  
6. 
Vital si g ns i ncl u de s yst olic a n d diast olic bl o o d press ure, heart rate, res pirat or y rate, a n d b o d y te m perat ure.  F or patie nts recei vi n g a nti h y perte nsi ve me dicati o ns wit h 
eit her a baseli ne hist or y of h y perte nsi o n or ne w o nset of h y perte nsi o n d uri n g t he st u d y, bl o o d press ure s h o ul d be m o nit ore d per i nstit uti o nal sta n dar d practice. 
7. 
C o m plete p h ysical e x a mi nati o n refers t o t he e xa mi nati o n of all b o d y s yste ms, i ncl u di n g wei g ht. L i mite d p h ysical e x a mi nati o n i ncl u des vital si g ns, a n y c h a n ge fr o m 
baseli ne a b n or malities, a n y ne w a b n or malities, wei g ht, a n d e val uati o n of patie nt -re p orte d s y m pt o ms.  I n or der t o assess c ha n ges fr o m baseli ne a n d scree n f or ne w 
a b n or malities, t he li mite d p h ysical e xa mi nati o n s h o ul d assess f or ne w or c ha n ge d s ki n lesi o ns, e nlar ge d l y m p h n o des, pal pa ble masses, he p at o me g al y, a n d 
s ple n o me g al y.  
8. 
T he set he mat ol o g y asse ss me nts at t hese visits c o nsist of c o m plete bl o o d c o u nt, i ncl u di n g he m o gl o bi n, he mat ocrit, w hit e bl o o d cell c o u nt wit h differe ntial, re d bl o o d 
cell c o u nt, a n d platelet c o u nt.  
9. 
T hese tests are t o be c o m plete d wit hi n 7 da ys bef ore t he start of s ur ufati ni b treat me nt.  
1 0. T he c h e mistr y pa nel i ncl u des bl o o d urea nitr o ge n, creati ni ne, s o di u m, p otassi u m, c hl ori de, bicar b o nate, calci u m, ma g nesi u m, p h os p hate, gl uc ose, t otal bilir u bi n, 
direct bilir u bi n, A L T, A S T, A L P, lactic de h y dr o ge nase, a m ylase, t otal pr otei n, al b u mi n, a n d uric aci d.  
1 1. Li pi d pa n el i ncl u des t otal c h olester ol a n d tri gl yceri des a n d is t o be o btai ne d d uri n g scree ni n g, C 3 D 1 ( ± 3 da ys), t he n e v er y 4  wee ks ( ± 3 da ys).  
C CI


Clinical Study Protocol 2020-012-00EU1 
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Amendment 6 
 
 
 
HUTCHMED Limited 
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CONFIDENTIAL 
 
 
 
12. Women of childbearing potential will receive a serum pregnancy test during screening within 7 days prior to surufatinib treatment and within 30±7 days after 
treatment completion.  In addition, serum or urine pregnancy tests will be performed on C2D1 (±3 days) and continue on D1 (±3 days) at each 4-week cycle 
thereafter.  If pregnancy is suspected, additional tests should be completed.  In the case of menopausal women, the date of menopause onset should be recorded. 
13. Urinalysis includes pH, glucose, protein, and blood. If protein is ≥2+ during screening and/or the period of study treatment, a 24-hour urine test should be conducted 
within 1 week. If 24-hour urine is required at screening, protein must be ≤1g to be eligible.  
14. Includes free triiodothyronine, free thyroxine, and thyroid-stimulating hormone.  In the absence of symptoms, the investigator may determine if assessing thyroid 
function every 2 to 3 cycles is sufficient.  
15. Triplicate ECGs (using Holter monitor) will be collected in patients enrolled in cohorts A, B, and C on C1D1 and C1D15 (+1 week) in for QTc evaluation according 
to the time points outlined in Table 2.  Safety ECG will be conducted on C2D1 and C3D1.  From C4 onward, ECG will only be performed as clinically indicated. 
16. The baseline tumor assessment can be completed within 28 days prior to enrollment.  All measurable and evaluable lesions should be assessed and documented at 
this visit, using physical examination and image-based evaluation.  Screening assessments include CT scans with oral and IV contrast of the chest, abdomen, and 
pelvis.  Bone scans and CT scan of the neck should also be performed if clinically indicated.  Tumor response will be assessed using RECIST version 1.1 
(Appendix 2 [Section 15]).  The same imaging procedure used to define measurable lesions at baseline must be used throughout the study for each patient.  At the 
investigator’s discretion, other methods of assessment of measurable disease as per RECIST version 1.1 (Appendix 2 [Section 15]) may be used.  Patients 
discontinuing surufatinib for reasons other than PD are to continue tumor assessments until documented disease progression, start of new antitumor therapy, or 
withdrawal of informed consent. 
17. Meals are applicable for all patients in Cohort D; refer to Table 3 for specific details and time points.  
18. Concomitant medication includes any prescribed or over-the-counter medicines.  All medication used by patients within 7 days before screening and 30 days after 
study completion should be recorded.  At each visit, all medication used since the last record should be recorded. 


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CONFIDENTIAL 
 
Table 2 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations 
(Cohorts A, B, and C)  
Study 
Visit 
Time 
Relative 
to Dosing 
Study 
Drug 
Intake1 
Patients Assigned to Holter Monitoring 
All Other Patients 
Meal 
PK 
Samples2 
Triplicate 
ECG for 
QTc 
Evaluation 
(Holter 
Monitor) 
Safety ECG 
(Standard 
Equipment) 
PK 
Samples2 
Safety ECG 
(Standard 
Equipment) 
 
C1D1 
-30 min 
 
X5 
 
 
 
 
 
Predose3 
 
 
 
X 
 
 
X 
0 h 
X 
 
 
 
 
 
 
1 h (±5 
min) 
 
 
X 
X 
 
X 
(anytime 
between 
1 and 4 
h) 
 
2 h (±5 
min) 
 
 
X 
X 
 
3 h (±5 
min) 
 
 
X 
X 
 
3.5 h 
 
X6 
 
 
 
4 h (±5 
min) 
 
 
X 
X 
 
C1D8 
Predose3 
 
 
X 
 
 
X 
 
0 h 
X 
 
 
 
 
 
 
 
C1D15 
(+1 week 
window)4 
-30 min 
 
X5 
 
 
 
 
 
Predose3 
 
 
X 
X 
 
X 
 
0 h 
X 
 
 
 
 
 
 
1 h (±5 
min) 
 
 
X 
X 
 
 
 
2 h (±5 
min) 
 
 
X 
X 
 
X 
X 
3 h (±5 
min) 
 
 
X 
X 
 
 
 
3.5 h 
 
X6 
 
 
 
 
 
4 h (±5 
min) 
 
 
X 
X 
 
 
 
C1D22 
Predose3 
 
 
X 
 
 
X 
 
0 h 
X 
 
 
 
 
 
 
C2D1 
Predose3 
 
 
X 
 
 
X 
 
0 h 
X 
 
 
 
 
 
 
2 h (±5 
min) 
 
 
X 
 
X 
X 
X 
C3D17 
Predose3 
 
 
X 
 
 
X 
 
0 h 
X 
 
 
 
 
 
 


Clinical Study Protocol 2020-012-00EU1 
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CONFIDENTIAL 
 
2 h (±5 
min) 
 
 
X 
 
X 
X 
X 
C4D1 and 
every 
other 
cycle 
thereafter7 
Predose3 
 
 
X 
 
 
X 
 
0 h 
X 
 
 
 
 
 
 
C=Cycle; D=Day; ECG=electrocardiogram; eCRF=electronic case report form; h=hour; min=minute; PK=pharmacokinetic(s); 
QTc=corrected QT interval. 
1. 
On PK sampling days, study drug must be taken at the investigative site under the supervision of the 
investigator or designee and should not be taken at home on the morning of the visits.  The date and time of 
the dose administered on the day of PK collection and 1 day before PK collection must be recorded on the 
eCRF. 
2. 
The actual date and time of the PK samples must be recorded on the eCRF. 
3. 
Predose PK and ECG must be performed within 30 minutes before study drug administration.  
4. 
Visits for C1D15 may be scheduled up to 1 week after but not before C1D15.  This is to ensure that 
surufatinib reaches steady state (14 days after first dose). 
5. 
Breakfast should be consumed within 30 minutes.  Dosing should occur within 5 minutes after completion 
of breakfast but no more than 30 minutes after the start of breakfast. 
6. 
Lunch to be given at 3.5 hours.  
7. 
PK samples will no longer be required on C3D1 and beyond. Refer to Section 6.1.4.1 for more details.


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Table 3 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations (Cohort D)  
Phase 
Cycle Day 
Time 
Relative 
to Dosing 
Study Drug Intake1 
PK Samples2,3 
Meal 
ECG 
Drug 
Cocktail4 
Surufatinib 
Midazolam 
Fexofenadine 
Rosuvastatin 
Surufatinib 
Pretreatment 
D -2 
-30 min 
 
 
 
 
 
 
X5 
 
Predose6 
 
 
X 
X 
X 
 
 
 
0 
X 
 
 
 
 
 
 
 
15 min  
(±2 min) 
 
 
X 
 
 
 
 
 
30 min 
(±2 min) 
 
 
X 
X 
 
 
 
 
1 h 
(±5 min) 
 
 
X 
X 
X 
 
 
 
2 h 
(±10 min) 
 
 
X 
X 
X 
 
 
 
3 h 
(±10 min) 
 
 
X 
X 
X 
 
 
 
4 h 
(±10 min) 
 
 
X 
X 
X 
 
X7 
 
5 h 
(±20 min) 
 
 
X 
X 
X 
 
 
 
6 h 
(±20 min) 
 
 
X 
X 
X 
 
 
 
8 h 
(±20 min) 
 
 
X 
X 
X 
 
 
 
10 h 
(±20 min) 
 
 
X 
X 
X 
 
 
 
D -1 
24 h 
(±30 min) 
 
 
X 
X 
X 
 
 
 


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Table 3 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations (Cohort D)  
Phase 
Cycle Day 
Time 
Relative 
to Dosing 
Study Drug Intake1 
PK Samples2,3 
Meal 
ECG 
Drug 
Cocktail4 
Surufatinib 
Midazolam 
Fexofenadine 
Rosuvastatin 
Surufatinib 
36 h 
(±30 min) 
 
 
 
 
X 
 
 
 
Treatment 
 
C1D1 
48 h/ 
predose6 
 
 
 
 
X 
 
 
X 
0 h 
 
X 
 
 
 
 
 
 
C1D15 
(+1 week 
window)8 
-30 min 
 
 
 
 
 
 
X5 
 
Predose6 
 
 
X 
X 
X 
X 
 
X 
0 
X9 
X9 
 
 
 
 
 
 
15 min 
(±2 min) 
 
 
X 
 
 
 
 
 
30 min 
(±2 min) 
 
 
X 
X 
 
X 
 
 
1 h 
(±5 min) 
 
 
X 
X 
X 
X 
 
 
2 h 
(±10 min) 
 
 
X 
X 
X 
X 
 
X 
3 h 
(±10 min) 
 
 
X 
X 
X 
X 
 
 
4 h 
(±10 min) 
 
 
X 
X 
X 
X 
X7 
 
5 h 
(±20 min) 
 
 
X 
X 
X 
X 
 
 
6 h 
(±20 min) 
 
 
X 
X 
X 
X 
 
 
8 h 
(±20 min) 
 
 
X 
X 
X 
X 
 
 


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Table 3 
Schedule of Events for Pharmacokinetic and Electrocardiogram Evaluations (Cohort D)  
Phase 
Cycle Day 
Time 
Relative 
to Dosing 
Study Drug Intake1 
PK Samples2,3 
Meal 
ECG 
Drug 
Cocktail4 
Surufatinib 
Midazolam 
Fexofenadine 
Rosuvastatin 
Surufatinib 
10 h 
(±20 min) 
 
 
X 
X 
X 
X 
 
 
C1D16 
24 h/ 
predose6  
(±30 min) 
 
X 
X 
X 
X 
X6 
 
 
36 h 
(±30 min) 
 
 
 
 
X 
 
 
 
C1D17 
48 h/ 
predose6  
(±30 min) 
 
 
 
 
X 
 
 
 
0 h 
 
X 
 
 
 
 
 
 
C2D1 
 
 
Predose6 
 
 
 
 
 
X 
 
 
0 h 
 
X 
 
 
 
 
 
 
2 h 
 
 
 
 
 
X 
 
X 
C3D110 
 
 
Predose6 
 
 
 
 
 
X 
 
 
0 h 
 
X 
 
 
 
 
 
 
2 h 
 
 
 
 
 
X 
 
X 
C4D1 and 
every 
other cycle 
thereafter10 
Predose6 
 
 
 
 
 
X 
 
 
0 h 
 
X 
 
 
 
 
 
 
C=cycle; D=day; ECG=electrocardiogram; eCRF=electronic case report form; h=hour(s); min=minute(s); PK=pharmacokinetic(s). 
1. 
On PK sampling days, study drug must be taken at the investigative site under the supervision of the investigator or designee and should not be taken at home on the 
morning of the visits.  The date and time of the dose administered on the day of PK collection must be recorded on the eCRF. 
2. 
The actual date and time of the PK samples must be recorded on the eCRF. 
3. 
Relative to drug cocktail administration. 
4. 
Dosing of the cocktail components will be done sequentially in the following order: midazolam, fexofenadine, and rosuvastatin.  
5. 
Breakfast should be consumed within 30 minutes.  Dosing should occur within 5 minutes after completion of breakfast but no more than 30 minutes after the start of 
breakfast. 


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6. 
Predose PK blood sample and ECG (when required) must be taken within 15 minutes before surufatinib administration. 
7. 
Lunch to be given after the 4-hour PK blood sample. 
8. 
Visits for C1D15 may be scheduled up to 1 week after but not before C1D15.  This is to ensure that surufatinib reaches steady state (14 days after first dose). 
9. 
Surufatinib and the drug cocktail should be taken at approximately the same time.  Surufatinib should be taken prior to intake of the drug cocktail. 
10.  PK samples will no longer be required on C3D1 and beyond. Refer to Section 6.1.4.1 for more details 
 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 3 0  
C O N FI D E N TI AL  
 
2  
I N T R O D U C TI O N  
2. 1  
B ac k gr o u n d   
2. 1. 1  
T ar get I n dic ati o n a n d P o p ul ati o n   
U p o n  i m ple me ntati o n of t his pr ot oc ol a me n d me nt, 
 
 
 T he ter mi nati o n of t his st u d y is base d u p o n t he 
strate gic re-e v al uati o n of t he cli nical de v el o p me nt pr o gra m f or s ur ufati ni b i n E ur o pe a n d t he 
U nite d States.  T his c ha n ge is n ot base d o n a n y c o ncer n  f or patie nt safet y or efficac y relati ve t o 
s ur ufati ni b treat me nt.  
A n gi o ge nesis pla ys a ke y r ole i n t he pat h o ge nesis of ne ur oe n d o cri ne t u m ors ( N E Ts )  
(Terris  et al 1 9 9 8 ), w hic h are rare, hi g hl y vasc ular t u m ors wit h o vere x pressi o n of a n gi o g e nic 
mar kers , i ncl u di n g vasc ular e n d ot helial gr o wt h fact or ( V E G F) a n d fi br o bl ast gr o wt h fact or.  T h e 
pr o g n osis of patie nts wit h N E Ts varies acc or di n g t o a n u m ber of dif fere nt fact ors, i ncl u di n g 
l ocati o n of t he pri mar y t u m or, hist ol o gical gra de, a n d t u m or sta ge at dia g n osis, wit h patie nts wit h 
N E Ts ori gi nati n g i n t he pa ncreas ha vi n g t he w orst pr o g n osis a n d 5 -year s ur vi val at 8. 7 % f or t h ose 
wit h 
p o orl y 
differe ntiate d 
hi g h -gra de t u m ors 
at 
di a g n osis 
( Half da nars o n  et al 2 0 0 8 , 
Ma n  et al 2 0 1 8 ).  Treat me nt o pti o ns f or ma na gi n g l oc ore gi o nal a n d metastatic N E Ts c o nsist 
pri maril y of c yt ore d u cti ve s ur ger y a n d s yste mic a ntit u m or t hera p y ( N C C N 2 0 1 9 , Pa vel  et al 2 0 2 0 , 
S ha h  et al 2 0 1 8 ).  S mall m olec ule dr u gs, i ncl u di n g s u niti ni b a n d s orafe ni b, tar geti n g t he vasc ular 
e n d ot helial gr o wt h fact or rece pt or ( V E G F R) t yr osi ne ki nase si g nali n g pat h wa y ha ve c o ntri b ute d 
si g nifica ntl y t o treati n g ca ncer (Es c u dier  et al 2 0 0 7 , M otzer  et al 2 0 0 7 ).  H o we ver, m ost of t he 
earl y g e nerati o n s mall m olec ule V E G F R t yr osi n e ki nase i n hi bit ors ( T KIs) i n hi bit ma n y ki nases 
ot her t ha n V E G F R, res ulti n g i n ‘ off -tar g et’ t o xicities.  A nti V E G F R a ge nt s u niti ni b a n d 
ma m malia n tar get of ra p a m yci n i n hi bit or e ver oli m us, a p pr o ve d f or t he tr eat me nt of p a ncreatic 
ne ur oe n d ocri ne t u m or ( p N E T -) i n t he U nite d States ( U S) a n d t he E ur o pea n U ni o n ( E U ), ha v e 
s h o w n i m pr o ve me nt i n pr o gressi o n-free s ur vi v al ( P F S), wit h a n o bjecti ve res p o nse rate ( O R R) of 
j ust u n der 1 0 % i n patie nts wit h p N E Ts (Ra y m o n d  et al 2 0 1 1 , Ya o  et al 2 0 1 3 ).  C urre ntl y, t here is 
n o a p pr o ve d tar gete d t hera p y f or ot her t y pes of N E Ts besi des p N E Ts a n d e xtra p a ncreatic  
ne ur oe n d ocri ne t u m or (e p N E Ts) ( n o nf u n cti o ni n g) i n t he U S a n d t he E U.  
2. 1. 2  
Descri pti o n of S ur uf ati ni b   
S ur ufati ni b is a s m all m olec ule ki nas e i n hi bit or t hat pri maril y tar g ets t u m or a n gi o ge nesis .  It 
p ote ntl y i n hi bits V E G F R 1, 2, a n d 3, fi br o blast gr o wt h fact or rece pt or 1 ( F G F R-1), a n d c ol o n y 
sti m ulati n g fact or-1 rece pt or ( C S F -1 R) ki nase wit h half ma xi mal i n hi bit or y c o nce ntr ati o n (I C 5 0) 
of 1 t o 2 4 n M .  S ur ufati ni b was f o u n d t o ha ve hi g her ki nase s electi vit y t ha n s u niti ni b a n d s h o we d 
a si milar i n hi bit or y effect o n  V E G F R 2 ( K D R) b ut a wea ker effect o n ot her ki nases , s uc h as 
P D G F R β, F L T 3, a n d Y E S, c o m pare d wit h s u niti ni b .  F or f urt her det ails, refer t o t he I n vesti gat or’s 
Br oc h ure (I B).  
T he d osi n g re gi me n f or t his st u d y is orall y a d mi nistere d s ur ufati ni b 3 0 0 m g o nce da il y ( Q D).  See 
Secti o n  7. 1. 2  f or f urt her details.  T h e o pti mal d ose a n d d osi n g sc he d ule f or s ur ufati ni b were  
deter mi ne d i n 2 p hase 1 st u dies; 1  c o n d ucte d i n C hi na 
 a n d t he ot her is bei n g 
c o n d ucte d i n t h e U S ( 2 0 1 5 -0 1 2 -0 0 U S 1) .  A f o o d -effect st u d y 
 was als o 
C CI
C CI
C CI


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 3 1  
C O N FI D E N TI AL  
 
c o n d ucte d t o g ui de d osi n g i n cli nical st u dies .  A d diti o nall y, a p hase 1 b/ 2 
 a n d 
p hase 3 ( 2 0 1 5 -0 1 2 -0 0 C H 4, k n o w n as S A N E T -e p, a n d 2 0 1 5 -0 1 2 -0 0 C H 3, k n o w n as S A N E T -p) 
st u dies f urt her e val u ate d t he rec o m me n de d p h ase 2 d ose a n d c o nfir me d t h at s ur ufati ni b 3 0 0 m g 
Q D pr o vi de d safe a n d effecti ve t hera p y i n patie nts wit h a d va nce d N E Ts .  T his is als o t he sta n dar d 
d ose  a n d d osi n g sc he d ule i n all ot her c o m plete d, o n g oi n g, a n d pla n ne d st u dies i n patie nts wit h 
a d va nce d ca n cer .  R efer t o t he I B f or f ull details o n d osi n g deter mi nati o n.  
2. 1. 3  
S u p p orti ve N o ncli nic al D at a   
I n vitr o ass a ys de m o nstrate d t hat  
 
 
 
 
  I n vi v o dat a o n V E G F R 2 p h os p h or ylati o n ha ve i n dicate d t hat if t he c o v era g e o n 
c o m plete tar get i n hi biti o n laste d f or m ore t ha n 8 h o urs, s ur ufati ni b c o ul d si g nifica ntl y  s u p press 
t u m or gr o wt h, a n d if t he c o vera g e laste d f or m ore t ha n 1 6 h o urs, s ur ufati ni b mi g ht i n d uce t u m or 
re gressi o n.  I n safet y p har mac ol o g y st u dies, t he res ults s h o we d s ur ufati ni b ha d l o w ris k i n t he 
car di o vas c ular, res pirat or y, a n d ce ntr al ner v o us s yste ms .   
I n vitr o res ults s u g gest t hat 
 
 
 
 
 
 
 
 
. 
Refer t o t he I B f or f ull details o n n o ncli nical fi n di n gs.  
2. 1. 4  
S u p p orti ve Cli nic al D at a   
S ur ufati ni b is c urre ntl y i n cli nical de v el o p me nt i n m ulti ple ca ncer i n dicati o ns at vari o us sta g es .  
As of 1 1 Fe br uar y 2 0 2 0, 8 cli nical st u dies ha ve bee n c o m plete d (i ncl u di n g 3 i n healt h y v ol u nteers 
a n d 5 i n patie nts wit h ca ncer); 5 cli nical st u dies i n patie nts wit h ca ncer are  o n g oi n g .  Refer t o t he 
I B f or f urt her i nf or mati o n.  
2. 1. 4. 1  
Cli nical P har mac o ki netics   
I n C hi nese p atie nts wit h ca ncer, s ur ufati ni b was a bs or be d ra pi dl y, wit h c o nce ntrati o n reac hi n g 
ma xi m u m le vel after 1. 0 t o 2. 0 h o urs of d osi n g .  Mea n plas ma half -life ra n gi n g fr o m 1 4. 9 t o 
2 0. 2  h o urs was o bser ve d .  F oll o wi n g m ulti ple d oses of s ur ufati ni b Q D, plas ma s ur ufati ni b 
c o nce ntr ati o n reac he d st ea d y state b y 1 4  d a ys after d osi n g, wit h e x p os ure acc u m ulati n g 1. 2 - t o 
2. 4 -f ol d at stea d y state c o m pare d t o d a y 1 ( St u dies 
).  
Preli mi na r y p har mac o ki n etic ( P K) res ults fr o m t he U S patie nt p o p ulati o n (St u d y 2 0 1 5 -0 1 2 -0 0 U S 1 
[ o n g oi n g]) s h o we d t hat s ur ufati ni b e x p os ure, i n ge neral, i ncreas e d pr o p orti o nall y wit h a n 
i ncreasi n g d os e fr o m 5 0 t o 4 0 0 m g Q D .  T here were n o mea ni n gf ul differe nces i n s u r ufati ni b 
e x p os ure bet w ee n C hi nes e a n d U S patie nts.  
C CI
C CI
C CI
C CI
C CI


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A study for a single oral 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 reach the maximum plasma 
concentration (tmax). 
2.1.4.2 
Clinical Efficacy  
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 
surufatinib versus 3.8 months placebo; hazard ratio [HR] of 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 versus 
3.7 months placebo; HR of 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, disease control rate (DCR), duration of response (DoR), and time to response (TTR).  In 
the ongoing Study 2015-012-00US1, a total of 32 patients with progressive NETs were enrolled 
(16 pNET and 16 epNET).  In the pNET cohort, 3 patients achieved a confirmed partial response 
(PR), and 1 patient achieved unconfirmed PR, and an ORR of 18.8% was observed.  In the epNET 
cohort, 1 patient achieved an unconfirmed PR.  All patients had previously received everolimus 
and/or sunitinib (Dasari et al 2020).  As the treatment of advanced NETs in China generally 
follows the same paradigm as that in Western countries, supported by emerging 
Study 2015-012-00US1 data, the patient populations in SANET-ep and SANET-p received prior 
therapies that were consistent with contemporaneously available treatments in the EU, and the 
efficacy data are applicable to EU populations. 
2.1.4.3 
Clinical Safety  
As of 30 June 2020, the safety database includes 955 patients (792 in monotherapy and 163 in 
combination therapy) and 128 healthy patients who received surufatinib as monotherapy or 
combination therapy in completed or ongoing studies.  Refer to the IB for full safety information.  
Of the 792 patients who received at least 1 dose of monotherapy of surufatinib, 781 (98.6%) 
patients reported treatment-emergent adverse events (TEAEs), and 757 (95.6%) patients reported 
treatment-related TEAEs.  Treatment-related TEAEs reported in ≥20% of patients included, by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term, proteinuria, 
hypertension, diarrhoea, blood bilirubin increased, blood thyroid-stimulating hormone increased, 
aspartate aminotransferase (AST) increased, hypertriglyceridemia, occult blood positive, and 
alanine aminotransferase (ALT) increased.  A total of 568 (71.7%) patients reported TEAEs of 
grade ≥3 regardless of causality, of which hypertension and proteinuria occurred in >10% of 
patients.  Approximately one-third of patients experienced a serious adverse event (SAE), and the 
most common (frequency of ≥1%) were gastrointestinal hemorrhage, intestinal obstruction, 
hepatic function abnormal, proteinuria, pneumonia, acute kidney injury, jaundice cholestatic, 
abdominal pain, and anaemia.  The reported fatal SAEs that were considered related to study 
treatment (31 patients) included hypovolaemic shock, diarrhoea, gastrointestinal haemorrhage, 


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disseminated intravascular coagulation (DIC) and hepatic encephalopathy, liver injury, cerebral 
haemorrhage, and death.  A total of 142 (17.9%) patients reported TEAEs leading to drug 
discontinuation, of which proteinuria and hepatic function abnormal were reported in ≥1% of 
patients.  
2.1.5 
Benefit/Risk Assessment  
2.1.5.1 
Risk Assessment  
Overall, nonclinical and clinical study results have demonstrated that surufatinib has an acceptable 
safety profile and is well tolerated.  Identified risks for surufatinib are hepatic disorder, 
hemorrhage, hypertension, and acute kidney injury.     
Details regarding identified risks for surufatinib can be found in the current Investigator’s 
Brochure.  
2.1.5.2 
Benefit Assessment  
Surufatinib is a selective, small molecule, kinase inhibitor of VEGFR1, 2, and 3; FGFR-1, and 
CSF-1R kinase that may fulfill a critical unmet need for patients with NETs.  Efficacy data from 
the randomized, double-blind, placebo-controlled, phase 3 studies SANET-ep and SANET-p have 
demonstrated encouraging antitumor activity in terms of PFS, ORR, DCR, DoR, and TTR.  The 
primary endpoint of PFS showed clinically meaningful and statistically significant improvement 
in both studies (SANET-ep: HR 0.334, p<0.0001; and SANET-p: HR 0.491, p=0.0011).  The 
favorable data resulted in early termination of SANET-ep- and SANET-p at the interim analysis 
upon recommendation of their respective, independent data monitoring committees.  Surufatinib 
can provide another treatment option to patients with NETs who have poor prognosis and few 
treatment options available.   
2.1.5.3 
Overall Benefit/Risk Conclusion  
Based on the summary of efficacy and safety data, the proposed safety management actions, the 
limited life expectancy of patients with advanced malignancies, and the lack of effective 
alternative treatments, the overall benefit/risk assessment supports the administration of 
surufatinib to patients with NETs as an investigational treatment. 
2.2 
Study Rationale  
This study primarily aims to demonstrate similar efficacy of surufatinib as seen in SANET-ep and 
SANET-p in European patients with locally advanced or metastatic, well-differentiated, low- to 
intermediate-grade NETs reflective of the tumor types seen in the European population.  Current 
NET therapies are not highly selective and result in unintended ‘off-target’ toxicities.  Improving 
kinase selectivity is a key focus for newer generation TKIs.  Surufatinib, a small molecule, 
selective inhibitor of VEGFR1, 2, 3, FGFR-1, and CSF-1R, has demonstrated efficacy in 2 
randomized, double-blind, placebo-controlled studies in NETs of extrapancreatic origin and 
pancreatic origin (Section 2.1.4.2), which were prematurely terminated by their respective, 
independent data monitoring committees following a preplanned interim analysis due to 
surufatinib demonstrating superior efficacy over placebo in terms of the primary endpoint of PFS.  


Clinical Study Protocol 2020-012-00EU1 
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In vitro studies indicated that surufatinib has the potential to inhibit CYP3A4 in a time-dependent 
manner and cause reversible inhibition of P-glycoprotein (P-gp) and BCRP at clinically relevant 
concentrations (see the IB for details).  In addition to the overall study purpose, the present study 
aims to further assess the in vivo significance of these nonclinical findings in European and US 
patients with NETs of any origin using a cocktail approach in a specific drug-drug interaction 
(DDI) cohort. 


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3 
OBJECTIVES AND ENDPOINTS  
The purpose of this study is to evaluate the antitumor activity of surufatinib in patients with locally 
advanced or metastatic, well-differentiated, low- to intermediate-grade NETs as determined by 
DCR at 6 months. 
Table 4 describes the study objectives and endpoints. 
Table 4 
Objectives and Endpoints for Study 2020-012-00EU1  
Tier 
Objectives 
Endpoints 
Primary 
• 
To evaluate the antitumor activity of 
surufatinib in patients with low- to 
intermediate-grade (grade 1 or 
grade 2), well-differentiated NET 
• 
DCR at 6 months 
Secondary 
• 
To characterize the PK of surufatinib 
in patients with NET 
• 
Observed plasma concentrations, 
estimated population PK, and exposure 
parameters of surufatinib 
• 
To evaluate the effect of surufatinib 
on cardiac repolarization, as detected 
by changes in ECG QTc, and the 
potential relationship with surufatinib 
plasma concentrations 
• 
QTc and plasma concentrations of 
surufatinib at specified time points 
• 
To further characterize the antitumor 
activity of surufatinib in patients with 
NET 
• 
Additional efficacy endpoints 
o 
ORR 
o 
TTR 
o 
DoR 
o 
PFS 
• 
Cohort D only: To evaluate the 
effects of repeat dosing of surufatinib 
on the single-dose PK of CYP3A4, 
P-gp, and BCRP substrates in 
patients with NET 
• 
Cohort D only: Exposure parameters of 
CYP3A4, P-gp, and BCRP substrates 
• 
To evaluate the safety and tolerability 
of surufatinib in patients with NET 
Safety assessments include the following: 
• 
Frequency and severity of AEs 
• 
Physical examination findings 
• 
Vital signs 
• 
Laboratory tests 
• 
ECG 
• 
Echocardiograms/MUGA 
AEs=adverse events; BCRP=breast cancer resistance protein; CYP=cytochrome P450; DCR=disease control rate; 
DoR=duration of response; ECG=electrocardiogram; MUGA=multigated acquisition; NET=neuroendocrine tumor; 
ORR=objective response rate; PFS=progressive-free survival; P-gp=P-glycoprotein; PK=pharmacokinetic; QTc=corrected QT 
interval; TTR=time to response.  


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 3 6  
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4  
S T U D Y P L A N   
4. 1  
St u d y Desi g n   
T his is a p hase 2, o pe n -l a bel, m ultice nter st u d y of s ur ufati ni b i n patie nts wit h l ocall y a d va n ce d, or 
metastatic  l o w- t o i nter m e diate -gra d e ( g ra d e 1 or g ra de 2), well-differe ntiate d N E Ts .  T he st u d y 
will e nr ol l 4  c o h orts of v ar yi n g N E Ts, as f oll o ws:  
•  C o h ort A –  N E T of l u n g ori gi n  
•  C o h ort B –  N E T of s mall b o wel ori gi n  
•  C o h ort C –  N E T of n o n -s mall b o wel, n o n-pa ncreas, a n d n o n -l u n g ori gi n 
•  C o h ort D –  N E T of a n y ori gi n ( D DI s u bst u d y) 
T he st u d y pla n ne d t o e nr oll a p pr o xi m atel y 2 0 pati e nts eac h i n C o h orts A a n d C , a p pr o xi matel y 3 5 
patie nts  i n C o h ort B , a n d 1 6 patie nts i n C o h ort D res pecti vel y . At t he ti me of pr ot oc ol a me n d me nt 
pre parati o n ( 1 6  N o v e m b er 2 0 2 3 ), C o h ort B h a d e nr olle d 3 2  p atie nts a n d C o h ort D ha d e nr olle d 
6  patie nts.  C o h ort A ha d  e nr olle d 2 0 patie nts a n d C o h ort C ha d e nr olle d 3 2 patie nts .  
All patie nts will be treat e d wit h a d ose of oral s ur ufati ni b 3 0 0  m g Q D i n treat me nt c y cles of 
2 8  da ys starti n g o n cycl e  1 d a y 1 .  All p atie nts will u n der g o c o ntin u o us safet y m o nit ori n g a n d 
t u m or assess me nt o n a r o uti ne basis.  Patie nts e nr olle d t o C o h orts A, B, a n d C o nl y will u n der g o 
electr ocar di o gra m ( E C G) m o nit ori n g via a H olter m o nit or o n d a y 1 a n d d a y 1 5 ( + 1 wee k) of t he 
first c ycle of treat me nt.  T he g oal wi ll be t o o btai n c o m plete H olter m o nit or  data f or a p pr o xi matel y  
4 0 patie nts .  T he n u m ber of s u bjects u n der g oi n g H olter assess me nts ma y be i ncrease d t o e ns ure 
f ull, usa ble d ata is a vaila ble.  Patie nts will c o nti n u e t o recei ve s ur ufati ni b treat me nt u ntil dise ase 
pr o gressi o n, deat h,  u n acce pta ble t o xicit y, wit h dr a wal of c o nse nt, l ost t o f oll o w -u p, t he patie nt is 
n o l o n ger recei vi n g cli nical be nefit i n t he o pi ni o n of t he i n vesti gat or, t he start of s u bse q ue nt 
a ntica ncer t hera p y, or t he s p o ns or e n ds t he st u d y . 
Base d u p o n t he strate gi c re -e v al uati o n of t h e cli nical de vel o p me nt pr o gra m f or s ur ufati ni b i n 
E ur o pe a n d t he U nite d States, t he st u d y will be ter mi nate d.  T his c ha n ge is n ot base d o n a n y 
c o ncer n  f or p atie nt safet y or efficac y relati ve t o s ur ufati ni b treat me nt.  
 
 
. 
D DI s u bst u d y ( C o h ort D): Patie nt s wit h N E Ts of a n y ori gi n  
A p pr o xi matel y 1 6 a d diti o nal patie nts wit h N E T s of a n y ori gi n will be e nr olle d t o C o h ort D f or t he 
D DI s u bst u d y  at st u d y sites selecte d b y t he s p o ns or.  T he pri mar y o bjecti ve of t his c o h ort is t o 
i n vesti gate t he p ote ntial D DI bet wee n s ur ufati ni b a n d a dr u g c o c ktail c o nt ai ni n g selecti ve pr o bes 
of C Y P 3 A 4 ( mi daz ola m), P -g p (fe x ofe n a di ne), a n d B C R P (r os u vastati n) s u bstrates .  Treat me nt 
c ycles f or C o h ort  D  are o utli ne d i n Ta ble  3 .  T he D DI dr u g c oc ktail will be gi ve n o n d a y -2 d uri n g 
t he pretreat me nt p hase, a n d assess me nt of P K pr ofiles of t he pr o be s u bstrates will be c o n d ucte d at 
baseli ne o n d a ys -2 a n d -1 (ie, d uri n g t he 4 8-h o ur peri o d be f ore starti n g treat me nt wit h s ur ufati ni b) 
a n d after re peate d d osi n g wit h s ur ufati ni b at a d ose of 3 0 0 m g Q D f or at least 1 4  da ys (s ur ufati ni b 
stea d y state o n cycle 1 d a y 1 5 [ + 1 wee k]) .  Patie nts e nr olle d t o t his c o h ort will n ot ha ve t o u n der g o 
H olter m o nit ori n g.  
F or t his D DI c o h ort, t he m ost critical q uesti o n will be a ns were d wit h t he c o m pleti o n of cycle  1 
d a y 1 7 .  T heref ore, o nce all patie nts i n t his c o h ort ha ve c o m plete d t he re q uire d st u d y pr oce d ures 
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up to cycle 1 day 17, an interim data cutoff is planned to evaluate the short-term safety and the PK 
profile.  An interim PK report for Cohort D will be written on the basis of this data cutoff date. 
Table 5 
Cohort D Treatment Overview  
Phase 
Cycle Day 
Dose Regimen 
Pretreatment 
D -2 
A single dose of drug cocktail consisting of the 
following: 
• 
Midazolam 2.5 mg 
• 
Fexofenadine 30 mg 
• 
Rosuvastatin 10 mg 
Treatment 
C1D1 to C1D14 
Surufatinib 300 mg QD 
Treatment 
C1D15 (+1 week) 
A single dose of surufatinib 300 mg and a single 
dose of drug cocktail consisting of the following: 
• 
Midazolam 2.5 mg 
• 
Fexofenadine 30 mg 
• 
Rosuvastatin 10 mg 
Treatment 
C1D16 and beyond 
Surufatinib 300 mg QD 
C=cycle; D=day(s); QD=once daily. 
The safety of all enrolled patients will be closely and continuously monitored from the time of 
informed consent until 30±7 days after the last dose.  Any SAEs that occur after the informed 
consent form (ICF) is signed, but before the first dose of study drug is taken, should also be 
reported.  All adverse events (AEs) will be graded in accordance with the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.  In addition, 
safety will be monitored by a Safety Review Committee (SRC), as described in Section 11.1.1. 
Tumor assessments will be conducted according to the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 criteria (Appendix 2 [Section 15]) at screening, every 8 weeks for 
the first 24 weeks from cycle 1 day 1 (±7 days), and then every 12 weeks thereafter (±14 days).  
Confirmation of complete response (CR) and PR is required at least 4 weeks after the criteria for 
response are first met. 
See Section 1.1 for the study schematic. 
4.2 
Design Rationale  
The open-label design of Cohorts A, B, and C was chosen to confirm that the safety and efficacy 
seen in a Chinese patient population (established in 2 randomized, double-blind, placebo 
controlled studies [SANET-p and SANET-ep]) can be demonstrated in European subjects.  
Because surufatinib has already proven to be a valid treatment option for NETs and no other 
treatment options are available to patients, an open-label design was appropriate for this study.  
Introducing a placebo control group would raise problems of ethics, acceptability, and feasibility.  
In this study, the drug interaction potential of surufatinib will be assessed in Cohort D using a 
cocktail containing selective probes of CYP3A, P-gp, and BCRP.  This cocktail approach is 
considered an advantageous strategy to obtain actual and reliable information on multiple enzyme 
and transporter protein activities within 1 study and minimize intra-individual variability.  The 
probe drugs are selected in accordance with the existing guidelines (EMA 2012, FDA 2020) and 


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drug interaction studies reported in the literature.  The absence of any in vivo interaction between 
the individual cocktail probes is crucial.  The combination of midazolam and fexofenadine in a 
cocktail for DDI assessment has been reported (Bosilkovska et al 2014, Duran et al 2020).  
Although rosuvastatin (BCRP) has not been evaluated in a cocktail, co-administration of 
rosuvastatin is not expected to interact with midazolam and fexofenadine based on their well 
characterized DDI profiles.  To date, none of the drugs are reported to have the propensity to 
significantly affect the PK of other drugs via interaction with metabolic enzyme or transporter. 
To evaluate the effect of surufatinib as a time-dependent inhibitor of CYP3A, multiple doses of 
surufatinib to reach a clinically relevant concentration are necessary in order to achieve full effects 
on enzyme inhibition.  The need for repeat-dose administration to reach steady state conditions for 
surufatinib precludes the conduct of this study in healthy subjects because of potential tolerability 
concern in healthy volunteers.  Therefore, this study will be conducted in patients with NETs.  
The surufatinib dose selected for this study is 300 mg QD, the therapeutic dose demonstrated to 
be efficacious and have good tolerability in patients with NETs.  The doses of the drug cocktail 
proposed in this study are similar to those used by other cocktail drug interaction studies in the 
literature.  The drug cocktail will be administered after intake of a light breakfast, which should 
be completed within approximately 30 minutes (see Section 7.1.2).  This provision is not expected 
to affect the PK results as conditions will be maintained across the 2 treatment periods, and most 
of these probe drugs can be given with or without food, or exhibit no significant food effect, 
according to the literature. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
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5  
P O P U L A TI O N   
5. 1  
Recr uit me nt   
T his st u d y will e nr ol l a p pr o xi matel y 9 1  patie nts fr o m 1 8  i n vesti gati o nal sites i n E ur o pe a n d 
a p pr o xi matel y  4 i n vesti g ati o nal sites i n t he U S.  T he U S sites will e nr oll p atie nts t o C o h ort D o nl y.  
U p o n i m ple me ntati o n of P r ot oc ol A me n d me nt 5  ( 0 5 Dece m b er 2 0 2 2), t he e nr oll me nt was halte d.  
U p o n i m ple me ntati o n of t his pr ot oc ol a me n d me nt, 
 
 
 
 
5. 2  
Defi niti o ns   
Patie nts e nter t he scree ni n g peri 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 a ut h ori z e d re prese ntati ve.  
A scree n fail ure is a c o ns e 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 tr eat me nt assi g n me nt.  Scree n fail ures 
ma y be res cree ne d o nce.  
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 i ncl u de d i n t his st u d y, eac h p atie nt m ust satisf y al l t he f oll o wi n g criteria: 
1.  Has hist ol o gicall y or c yt ol o gicall y d oc u me nte d, l ocall y a d va n ce d, or met astatic l o w- t o 
i nter me diate-gra de ( g ra d es 1  t o 2) N E T s an d h as pr o gresse d o n at least 1 pri or li ne of 
t hera p y b ut n o m ore t ha n 3 t hera pies: 
a. C o h ort A: N E T of l u n g ori gi n  
b.  C o h ort B: N E T of s mall b o wel ori gi n  
c. C o h ort C: N E T of n o n -s mall b o wel, n o n-pa ncreas, a n d n o n -l u n g ori gi n  
d.  C o h ort D ( D DI s u bst u d y): N E T of a n y ori gi n  
2.  Has ra di ol o gic e vi d e nce of pr o gressi ve t u m or wit hi n 1 2 m o nt hs of st u d y e nr ol lme nt  
3.  Is willi n g an d a bl e t o pr o vi de i nf or me d c o nse nt  
4.  Is ≥1 8 y ears of a ge 
5.  Has meas ur a ble lesi o ns acc or di n g t o R E CI S T v ersi o n 1. 1 ( A p pe n di x  2  [ Secti o n 1 5 ]) 
6.  Has a bs ol ute ne utr o p hil c o u nt of ≥1. 5 × 1 0 9/ L, platelet c o u nt of ≥1 0 0 × 1 09/L, a n d 
he m o gl o bi n of ≥9 g/ d L  
7.  Has ser u m t otal bilir u bi n of < 1. 5 ti mes t he u p per li mit of n or mal ( U L N)  
8.  Has pr otei n uria of < 2 + b y uri nal ysis, or 2 4 -h o ur uri ne c ollecti o n of ≤1 g of pr otei n, or 
uri ne pr otei n: uri ne -creati ni ne rati o  of  ≤1. 9  
9.  Has A L T, A S T, or al k ali ne p h os p hatase  ( A L P) le vels of ≤2. 5 ti mes t he U L N  
e. Patie nts wit h k n o w n li ver metastases ma y h a ve A L T, A S T, a n d A L P of ≤3 × t he U L N  
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10. Has serum creatinine of <1.5 times ULN or creatinine clearance of ≥60 mL/min as 
estimated by the Cockcroft-Gault formula 
11. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix 1 [Section 15]) 
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 (<1% per year) when used consistently and correctly, starting during the 
screening period, continuing throughout the entire study period, and for 90 days after 
taking the last dose of study drug.  Such methods include oral, progestogen-only, 
hormonal contraception (combined estrogen/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, intrauterine hormone-releasing system, 
bilateral tubal ligation, vasectomized partner, or sexual abstinence in line with the 
preferred and usual lifestyle of the subject. 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.  The same criteria are applicable to 
male patients involved in this clinical study if they have a partner of childbearing 
potential, and male patients must always use a condom.  
A female is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (ie, ≥12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of the ovaries and/or uterus). 
5.4 
Exclusion Criteria  
If a patient meets any of the following criteria, he or she is ineligible for this study: 
1. Has an AE due to previous antitumor therapy that has not recovered to CTCAE grade ≤1, 
except alopecia and peripheral neurotoxicity with CTCAE grade ≤2 caused by platinum 
chemotherapy 
2. Major surgery within previous 4 weeks or radiation therapy within 2 weeks prior to the 
start of treatment (prior palliative radiotherapy for metastatic lesions is permitted if there 
is at least 1 measurable lesion that has not been irradiated) 
3. Prior VEGF/VEGFR-targeted therapy, including, but not limited to sunitinib, axitinib, 
and cabozantinib 
4. Has uncontrollable hypertension, defined as systolic blood pressure of ≥140 mmHg 
and/or diastolic blood pressure of ≥90 mmHg, despite antihypertensive medication 
5. Prothrombin time (PT)/International normalized ratio (INR) of >1.5 or activated partial 
thromboplastin time (aPTT) of >1.5×ULN (for patients on Coumadin or Coumadin-like 
products, please refer to Section 7.3.3) 
6. Has gastrointestinal disease or condition within 6 months prior to first dose 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 could, in the 
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7. Has a history or presence of a serious hemorrhage (>30 mL within 3 months) or 
hemoptysis (>5 mL of blood within 4 weeks) within 6 months of first dose of study drug  
8. Has 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 of ≥2 according to the 
New York Heart Association classification, ventricular arrhythmia that needs drug 
treatment, and left ventricular ejection fraction (LVEF) of <50% 
9. Has a mean corrected QT interval by Fridericia (QTcF) of ≥480 ms 
10. Has used medication known to cause QT prolongation or torsades de pointes within 
2 weeks of screening (see Appendix 5 [Section 15]) 
11. Has brain metastases 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) 
12. Has a 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 
13. Has arterial thrombosis or deep venous thrombosis within 6 months prior to first dosing, 
or thromboembolic events (including stroke and/or transient ischemic attack) within 
6 months prior to the first dose of study drug 
14. Use of strong or moderate inducers or inhibitors of CYP3A4 within 2 weeks before the 
first dose of surufatinib (see Appendix 3 [Section 15] for examples) 
15. For Cohort D, use of medications that are known substrates, inhibitors, or inducers of 
CYP3A or substrates of P-gp or BCRP within 3 weeks before the first dose of the drug 
cocktail (see Appendix 3 [Section 15] for examples)   
16. Prior history of other cancers, except those treated with curative intent for in situ non-
melanoma skin cancer, breast or cervical cancer, or those treated with curative intent and 
no evidence of disease in the last 5 years prior to enrollment in the study 
17. Has a clinically meaningful ongoing infection (eg, requiring intravenous treatment with 
anti-infective therapy) 
a. See Appendix 8 (Section 15)for procedures specific to subjects with suspected or 
confirmed coronavirus disease 2019 (COVID-19) 
18. Has clinical symptoms consistent with pancreatitis 
19. Has a history of allergies to any ingredient of surufatinib or its capsule shell, including 
tartrazine (E 102) 
20. Pregnant or breastfeeding females will not be entered into this study due to risks of fetal 
and teratogenic adverse events as seen in animal/human studies (pregnancy tests must be 
obtained in females who are of reproductive potential) 
5.5 
Exceptions to Eligibility Criteria  
Exceptions to the eligibility criteria will not be permitted. 
5.6 
Lifestyle Restrictions  
Patients must follow the contraception requirements outlined in the inclusion criteria (Section 5.3). 


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6 
STUDY CONDUCT  
The following procedures will be performed according to the schedule in Table 1.  During cycle 1, 
the visit window will be ±1 day (unless otherwise noted).  From cycle 2 onward, the visit window 
will be ±3 days (unless otherwise noted). 
6.1 
Study Procedures  
6.1.1 
Screening  
6.1.1.1 
Informed Consent  
All patients (or legally authorized representative; see Section 10.3) must sign the ICF prior to any 
study-related examinations or protocol procedures.  All patients who sign ICF are to be entered 
into the Interactive Web Response System.  The system will generate a patient identification 
number, which will be assigned to the patient.  ICFs for patients who are not subsequently enrolled 
will be maintained at the study site. 
6.1.1.2 
Medical and Surgical History  
A complete medical and surgical history, including the patient’s medical history, surgical 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. 
6.1.1.3 
Demographics  
Demographic characteristics, including year of birth, sex, ethnic group, and any relevant lifestyle 
habits, should be recorded at screening and in the applicable electronic case report form (eCRF) 
(as permitted by local regulations). 
6.1.1.4 
Eastern Cooperative Oncology Group Performance Status  
Patient performance status will be graded according to the ECOG performance status scale at study 
visits as detailed in Table 1.  It is recommended that ECOG performance status scores be evaluated 
by the same investigator throughout the study.  Details on the ECOG assessment and grading scale 
are available in Appendix 1 (Section 15). 
6.1.2 
Safety Assessments  
6.1.2.1 
Vital Signs Assessment  
Vital signs will include measurements of body temperature, heart rate, respiratory rate, and systolic 
and diastolic blood pressure while the patient is in a seated position.  The patient should be seated 
for approximately 5 minutes before the measurement of the blood pressure.  
For patients receiving antihypertensive medications with either a baseline history of hypertension 
or a new onset of hypertension during the study, blood pressure should be monitored per 
institutional standard practice.  


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6.1.2.2 
Physical Examination  
A complete physical examination at screening should include the evaluation of head, eye, ear, 
nose, 
and 
throat; 
and 
cardiovascular, 
dermatological, 
musculoskeletal, 
respiratory, 
gastrointestinal, and neurological systems as well as weight.  Height will be measured at screening 
only. 
At subsequent visits, a limited physical examination will be performed to assess vital signs, weight, 
any changes from baseline abnormalities, any new abnormalities, and evaluation of patient-
reported symptoms.  New or worsened abnormalities should be recorded as AEs if appropriate.  In 
order to assess changes from baseline and screen for new abnormalities, the limited physical 
examination should assess for new or changed skin lesions, enlarged lymph nodes, palpable 
masses, hepatomegaly, and splenomegaly.  Patient-reported symptoms require a physical 
examination directed to address the symptoms. 
As part of tumor assessment, physical examinations should also include the evaluation of the 
presence and degree of enlarged lymph nodes, skin lesions, hepatomegaly, and splenomegaly. 
6.1.2.3 
Laboratory Test Evaluations  
Samples for hematology, serum chemistry, urinalysis, and pregnancy testing will be evaluated at 
the study site’s local laboratory.  Laboratory assessments will include the following: 
• Hematology: Complete blood count, including red blood cell count, hemoglobin, 
hematocrit, white blood cell count with differential, and platelet count  
• Coagulation assay: (PT/INR and aPTT) 
• Serum chemistry: Blood urea nitrogen, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, magnesium, phosphate, glucose, total bilirubin, direct bilirubin, ALT, 
AST, ALP, lactic dehydrogenase, amylase, total protein, albumin, and uric acid 
• Lipid panel: Total cholesterol and triglycerides 
• Pregnancy tests: Serum pregnancy test at screening (within 7 days before the start of 
surufatinib treatment) and within 30±7 days after treatment completion for all women of 
childbearing potential, including those who have had a tubal ligation; in addition, serum or 
urine pregnancy tests will be performed on day 1 of cycle 2 and each subsequent cycle 
• Urinalysis: Urinalysis includes pH, glucose, protein, and blood.  If there is a result of 
≥2+ protein on urinalysis, then a 24-hour urine protein test should be done within 1 week; for 
urinalysis results conversions, please refer to Appendix 7 (Section 15). 
• Thyroid function: Thyroid-stimulating hormone, free triiodothyronine, and free 
thyroxine.  In the absence of symptoms, the investigator may determine if assessing thyroid 
function every 2 to 3 cycles is sufficient. 
6.1.2.4 
Cardiac Monitoring  
LVEF is assessed via echocardiogram or multigated acquisition (MUGA) at screening and every 
12 weeks (±7 days) thereafter.  The modality of the cardiac function assessments must be 
consistent within a patient, that is, if the echocardiogram is used for the screening assessment, then 
the echocardiogram should also be used for subsequent scans, if required.  The patients should also 
be examined using the same machine and operator whenever possible. 


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6.1.2.5 
Electrocardiogram Monitoring  
Twelve-lead ECGs should be performed according to the time points in Table 2 for Cohorts A, B, 
and C and Table 3 for Cohort D.  The QTcF will be closely monitored.  
In addition, a continuous 12-lead Holter monitor will be used for corrected QT interval (QTc) 
evaluation during cycle 1 in patients enrolled across Cohorts A, B, and C.   The results will be sent 
for central reading (see below in Continuous 12-Lead Holter Monitor for QTc Evaluation for 
details).  Vital signs will be measured (Section 6.1.2.1), a symptom-directed physical examination 
will be conducted (Section 6.1.2.2), and safety -related blood samples (Section 6.1.2.3) will be 
collected as per the time points in Table 1; these should always be completed before the start of 
any ECG recordings. 
Continuous 12-Lead Holter Monitor for QTc Evaluation 
Continuous ECG recordings using 12-lead Holter monitoring will be collected to evaluate the 
effects of surufatinib on ventricular repolarization.  The assessments will be conducted at predose 
and postdose on cycle 1 day 1 and cycle 1 day 15 (+1 week) at specific time points summarized in  
Table 2. 
Patients should reside in a quiet setting without distractions (eg, television, cell phones, and staff 
talking) at each scheduled time point for ECG measurements.  Patients should rest in a supine 
position for at least 10 minutes before and 5 minutes after the scheduled time point and should 
refrain from talking or moving their arms or legs.  Skin preparation should be optimal to obtain 
high quality ECGs; if deemed appropriate, the chest should be shaved and prepared with light 
abrasion. 
Continuous digital 12-lead Holter ECGs will be recorded as described in the ECG/Holter manual.  
Good quality 12-lead ECG selection and extraction will occur during a 10-minute timeframe, 
starting 5 minutes before and ending 5 minutes after the scheduled ECG time point.  All Holter 
recorder devices (as supplied by the central ECG laboratory) will be of the same brand and model 
with the same software and will have been recently serviced and calibrated.  Documentation 
describing the brand, type, software, and service/calibration history of Holter recorders will be 
provided by the central ECG laboratory and archived at the site as well as in the sponsor’s study 
file.  Transfer of the Holter recordings and extraction of the ECG tracings will be performed as 
described in the ECG/Holter manual. 
Ten-second digital ECG tracings will be extracted from the Holter device in triplicate by the central 
ECG laboratory according to the following principles: 
• The actual time of dosing will be communicated to the central ECG laboratory on the 
Holter acquisition form completed by the site. 
• Using visual inspection or automated tools, as appropriate, the central ECG laboratory 
will identify a period of stable heart rate on the continuous Holter tracing within ±5 minutes 
of the nominal ECG time point (determined relative to the actual dosing time for an 
individual patient).  Three 10-second ECGs will be extracted in close succession from this 
identified segment. 
• The scheduled time points for triplicate ECG extraction are summarized in Table 2. 


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Unless warranted by a specific safety endpoint of the study, the Holter tracings will not be routinely 
analyzed for rhythm and conduction abnormalities.  These analyses will only be performed on 
individual patient’s Holter if warranted by TEAEs (eg, syncope). 
6.1.3 
Efficacy Assessments  
Tumor evaluation of disease for all patients will be done during the screening period, every 
8 weeks for the first 24 weeks from cycle 1 day 1 (±7 days) and then every 12 weeks thereafter 
(±14 days) until disease progression, death, unacceptable toxicity, withdrawal of consent, lost to 
follow-up, the patient is no longer receiving clinical benefit in the opinion of the investigator, the 
start of subsequent anticancer therapy, or the sponsor ends the study (Section 6.2.1.1). 
At screening, patients will have radiological assessments by cross-sectional imaging of the chest, 
abdomen, and pelvis (computed tomography [CT], magnetic resonance imaging [MRI], or a 
combination of CT/MRI) in order to identify lesions.  Using CT scans with oral or intravenous 
(IV) contrast (unless contraindicated) is preferred; MRI scans are allowed if CT contrast is 
contraindicated.  Bone scans and CT scan of the neck should also be performed if clinically 
indicated.  At the investigator’s discretion, CT scans may be repeated at any time if progressive 
disease (PD) is suspected.  In addition, other radiographic procedures (such as radionuclide bone 
scans), as deemed appropriate by the investigator, will be performed to assess sites of neoplastic 
involvement.  Assessments throughout the study should be made using the same modality as that 
used at screening.  Tumor response will be evaluated locally using physical examination and 
image-based evaluation by the investigator to support treatment decisions, as well as the primary 
endpoint of antitumor activity.  Tumor response will be evaluated using RECIST version 1.1 
(Appendix 2 [Section 15]).  Confirmation of CR and PR is required at least 4 weeks after the 
criteria for response are first met. 
Investigators will assign target and nontarget lesions in accordance with RECIST version 1.1 
guidelines (Appendix 2 [Section 15]) at screening.  These lesions will be followed locally 
throughout the study to determine continuation of treatment. 
6.1.4 
Pharmacokinetic Assessments  
6.1.4.1 
Sample Collection and Handling  
For Cohorts A, B, and C, PK samples for measurement of plasma concentrations of surufatinib 
will be collected according to the schedule in Table 2. 
For Cohort D, PK samples will be collected according to the schedule in Table 3.  Separate blood 
samples will be collected for measurement of plasma concentrations of each probe substrate (plus 
metabolite, where applicable) and surufatinib. 
For all cohorts, the exact times and dates of PK blood sampling should be recorded on the eCRF.  
In addition, the dates and times of surufatinib administered on the day of PK sample collection and 
1 day before PK sample collection must be recorded on the eCRF.  For Cohort D, the dates and 
times of the drug cocktail administered on the day of PK sample collection must be recorded on 
the eCRF. 
Detailed information regarding collection, handling, storage, and shipment of plasma samples is 
provided in the laboratory manual.  


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Upon implementation of Protocol Amendment 5, for all cohorts, PK samples for measurement of 
plasma concentrations of surufatinib will not be collected on C3D1 and beyond. For Cohort D, PK 
samples for measurement of plasma concentrations of each probe substrate (plus metabolite, where 
applicable) and surufatinib up to C2D1 will remain unchanged. For all cohorts, PK samples for 
measurement of plasma concentrations of surufatinib were not to be collected on C3D1 and 
beyond.  
6.1.4.2 
Analytical Procedures  
Plasma samples will be analyzed to determine concentrations of surufatinib, midazolam, 
1-OH-midazolam, fexofenadine, rosuvastatin, and N-desmethyl rosuvastatin, as appropriate, using 
a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry method. 
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. 
6.1.5 
Pharmacodynamic Assessments  
Continuous ECG recordings using 12-lead Holter monitoring will be collected from patients 
enrolled in the study (excluding Cohort D) to evaluate the effects of surufatinib on ventricular 
repolarization.  Details are described in Section 6.1.2.5. 
6.1.6 
Study Visits and Assessments  
6.1.6.1 
Screening  
Followed informed consent, all screening evaluations must be completed and reviewed by the 
investigator and Clinical Monitor to confirm that patients meet all eligibility criteria before the 
first administration of surufatinib.  
Screening will be performed within 28 days of the first dose day of study drug.  Results of 
standard-of-care tests performed prior to obtaining informed consent and within 28 days prior to 
study entry may be used (except hematology, coagulation test, clinical chemistry, and urinalysis); 
such tests do not need to be repeated for screening. 
6.1.6.2 
Pretreatment (Cohort D Only)  
Day -2 and day -1 and corresponding assessments of the pretreatment phase are only applicable 
for patients in Cohort D. Patients will be given a breakfast meal to consume within 30 minutes of 
dosing.  Predose baseline PK samples will be taken before the patient receives the drug cocktail of 
DDI substrates.  Postdosing samples will be taken at the time points described in Table 3, and a 
second meal (lunch) will be given 4 hours postdose, after collection of the 4-hour PK blood sample. 
6.1.6.3 
Treatment Period  
All visits beyond cycle 1 must occur within ±3 days from the scheduled date, unless otherwise 
noted (see Table 1).  All assessments will be performed on the day of the specified visit, unless a 
time window is specified.  If scheduled study assessments cannot be obtained because of a holiday, 
these assessments should be obtained at the soonest following date, unless the soonest following 
date is within 7 days of other regularly scheduled study assessments. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 4 7  
C O N FI D E N TI AL  
 
6. 1. 6. 4  
E n d of Treat me nt/ Earl y Ter mi nati o n   
Patie nts w h o disc o nti n ue st u d y treat me nt f or a n y reas o n nee d  t o ret ur n t o t he cli nic at 3 0 ± 7 da ys 
after t he last d ose of s ur ufati ni b f or a f oll o w-u p visit .  O n g oi n g A Es t h o u g ht t o be relate d t o 
s ur ufati ni b will be f oll o we d u ntil 1  of t he criteria i n Secti o n 8. 3. 3  are met.  
U p o n i m ple me ntati o n of t his P r otoc ol A me n d me nt 6, treat me nt wit h s ur ufati ni b f or all patie nts 
o n acti ve treat me nt s h o ul d be disc o nti n ue d o n Da y  2 8 of t he last c ycle t h at ca n be f ull y 
c o m plete d n o later t ha n 
   
6. 1. 6. 5  
E n d of St u d y   
A patie nt is c o nsi dere d t o ha ve c o m plete d t he st u d y o nce he or s h e has c o m plete d t he last visit or 
t he last sc he d ule d pr o ce d ure as o utli ne d i n Ta ble 1 . 
T he st u d y will be c o nsi d ere d c o m plete d o n ce t h e last patie nt has c o m plet e d t he last visit or last 
sc he d ule d pr o ce d ure. 
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 nts  
6. 2. 1. 1  
Treat me nt Disc o nti n uati o n   
T he i n vesti gat or has t he ri g ht t o disc o nti n ue a patie n t fr o m treat me nt f or a n y me dical c o n diti o n 
t hat t he i n vesti gat or deter mi nes ma y je o par dize t he patie nt’s safet y if h e or s he c o nti n ues i n t h e 
st u d y a n d f or reas o ns of n o nc o m plia nce (e g, misse d d oses, visits), pre g na n c y, or if t he i n vesti gat or 
deter mi nes it  is i n t he best i nterest of t he patie nt.  
A n y patie nt w h o disc o nti n ues treat me nt b ut d o es n ot wit h dra w i nf or m e d c o nse nt s h o ul d be 
e nc o ura g e d t o ret ur n t o t he st u d y site f or a tr eat me nt c o m pleti o n visit .  See Ta ble 1  f or t he 
assess me nts t hat are t o be perf or me d f or patie nts w h o pre mat urel y wit h dra w fr o m t he st u d y d uri n g 
t he treat me nt peri o d.  T h e pri mar y reas o n f or disc o nti n uati o n m ust be rec or de d o n t he a p pr o priate 
e C R F.  Patie nts disc o nti n ui n g s ur ufati ni b f or reas o ns ot her t ha n pr o gressi o n of t he u n d erl yi n g 
mali g na nc y are t o  c o nti n ue t u m or assess me nts per Ta ble 1  u ntil d oc u me ntati o n of disease 
pr o gressi o n, start of n e w a ntit u m or t hera p y, or wit h dra wal of i nf or me d c o nse nt.  
Patie nts ma y be disc o nti n ue d fr o m treat me nt f or a n y of t he f oll o wi n g reas o ns:  
1.  Disease pr o gressi o n (acc or di n g t o R E CI S T v ersi o n 1. 1; A p pe n di x  2  [ Secti o n 1 5 ]).  If t he 
patie nt is e x perie n ci 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 patie nt 
ma y c o nti n ue st u d y treat me nt be y o n d ra di o gr a p hic pr o gressi o 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 discreti o n of t he i n vesti gat or a n d ma y 
i ncl u de b ot h o bjecti ve a n d s u bjecti ve data.  T h e c o nti n uati o n decisi o n s h o ul d be ma de b y 
t he i n vesti gat or i n c o ns ultati o n wit h t he s p o ns or. 
2.  Deat h  
3.  U nacce pta ble t o xicit y  
4.  Wit h dra wal of c o nse nt  
5.  Patie nt is l ost t o f oll o w -u p  
6.  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  
7.  Use of ot her a ntit u m or treat me nt d uri n g t he st u d y  
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8. Study is terminated by the sponsor 
9. Pregnancy 
10. Poor patient compliance at the investigator’s discretion 
11. End of this study 
Patients must be discontinued if they experience certain high-grade AEs, recurrent AEs, or AEs 
that warrant withdrawal of study treatment as determined by the Principal Investigator, as outlined 
in Section 7.1.3 
6.2.1.2 
Withdrawal from Study  
All patients have the right to withdraw from the study at any time.  During the treatment period 
and follow-up period, a patient who withdraws consent to continue participation in the study will 
not be followed for any reason after consent has been withdrawn.  Every effort should be made to 
obtain information on patients who discontinue study treatment but who do not withdraw consent 
to continue participation in the study.  If a participant withdraws consent for disclosure of future 
information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
If a participant withdraws from the study, he 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 eligible for response assessment (defined as those subjects who have at least 
one post-baseline assessment unless any clinical PD or death occurred before the first assessment) 
may be replaced. 
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 should be documented in the patient’s medical record. 
Should the patient continue to be unreachable, he or she will be considered to be withdrawn from 
the study or lost to follow-up. 
6.3 
Study Termination  
The sponsor has the right to stop the study at any time.  Should the sponsor decide to terminate the 
study, the investigator(s) will be notified in writing. 
The reasons for stopping the study may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 


Cli nic al St u d y Pr ot oc ol 2 0 2 0 -0 1 2 -0 0 E U 1  
S ur uf ati ni b  
A m e n d m e nt 6  
 
 
 
H U T C H M E D Li mit e d  
P a g e 4 9  
C O N FI D E N TI AL  
 
•  I n t he cas e of patie nt e nr ol lme nt bei n g  u nsatisfact or y , the e nr ollme nt of ne w patie nts will 
be st o p pe d.  Pa tie nts alrea d y e nr olle d will be tr eat e d a n d f oll o we d i n acc or da nce wit h t he 
pr ot oc ol .   
•  A n y ot her reas o n c o nsist e nt wit h a p plica ble la ws, re g ulati o ns, a n d G o o d Cli nical Practice 
(G C P ). 
As of t he i m ple me ntati o n of Pr ot oc ol A me n d me nt 6, 
 
 
a n d ha ve a f oll o w u p visit 3 0 ± 7 da ys after last d os e of s ur ufati ni b as descri be d i n  Secti o n  6. 1. 6. 4 .  
T he st u d y will be ter mi nate d eit her 3 0 ± 7 da ys aft er t he last patie nt has recei ve d s ur ufati ni b, or at 
t he p oi nt at w hic h all A Es c o nsi dere d b y t he I n vesti gat or t o be relate d t o s ur ufati ni b ha ve 
res ol ve d or are n o l o n ger bei n g f oll o we d. 
 
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7 
STUDY INTERVENTIONS  
7.1 
Description of Products  
Surufatinib is a study drug formulated as an off-white powder in a capsule with a strength of 50 mg 
per capsule (Table 6).  
Table 6 
Investigational Treatment Used in This Study  
Product 
Dosage Form 
Strength 
Dose 
Frequency 
Route 
Surufatinib 
Capsule 
50 mg 
300 mg 
Daily 
Oral 
The drug cocktail (midazolam, fexofenadine, and rosuvastatin) for Cohort D will be provided by 
the sponsor.  The description of the individual products used in the cocktail is summarized in 
Table 7. 
Table 7 
Cohort D: Drug Cocktails  
Product 
Dosage Form 
Dose 
Frequency 
Route 
Midazolam 
Oral liquid 
2.5 mg 
Single dose 
Oral 
Fexofenadine 
Tablet or oral suspension 
30 mg 
Single dose 
Oral 
Rosuvastatin 
Tablet 
10 mg 
Single dose 
Oral 
7.1.1 
Formulation, Storage, Preparation, and Handling  
The surufatinib 50-mg strength is presented as a size 3, hard gelatin capsule.  The capsules are 
packaged in white, high-density polyethylene bottles.  Refer to the IB and pharmacy manual for 
further details. 
Study drugs should be sealed and stored in a secure, limited access area between 10°C and 30°C, 
protected from light and moisture.  Midazolam, fexofenadine, and rosuvastatin should be stored as 
directed by the label.  The temperature log should be recorded and filed in the study binder.  
Surufatinib capsules should not be used beyond the expiration date provided by the manufacturer.  
All study drugs required for this study will be provided by the sponsor.  The recipient will 
acknowledge receipt of the study drug by returning the appropriate documentation form indicating 
shipment content and condition.  Damaged supplies will be replaced.  Accurate records of all study 
drug received at, dispensed from, returned to, and disposed by the study site should be recorded 
by using the Drug Inventory Log. 
The study drugs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the sponsor with the appropriate documentation, as 
determined by the study site.  If the study site chooses to destroy the study drug, the method of 
destruction must be documented. 
7.1.2 
Dosing and Administration  
The starting dose of surufatinib is 300 mg QD, which is the maximum tolerated dose and 
recommended phase 2 dose determined by the 2015-012-00US1 study, same as the dose used in 
2 phase 3 randomized trials conducted in China.  There is no dose escalation in this study.  The 
dose may be reduced as described in Section 7.1.3.  


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It is recommended that surufatinib be taken with approximately 240 mL water within 1 hour after 
breakfast.  Patients will take six 50-mg capsules for the 300-mg QD dose.  When predose PK blood 
samples need to be collected on the days of PK sample collection, patients must take the study 
drug after sampling. 
If patients miss a dose in the morning, a replacement dose can be taken before 10:00 PM on the 
same day.  Otherwise, the patients should not make up the missed dose but should resume 
scheduled doses the next day per the protocol.  The missed dose should be reported to investigators 
and recorded on the eCRF. 
On the day of PK sampling during cycles 1 to 3, patients should avoid high-fat, high-calorie meals 
for the entire day.  No caffeine-containing foods or drinks, grapefruit, starfruit, Seville oranges or 
their products, tobacco and tobacco-containing products, or alcohol will be allowed. 
Special instructions for the patients in Cohorts A, B, and C assigned to Holter monitoring: 
• On cycle 1 day 1 and cycle 1 day 15 (+1 week), intake of surufatinib must occur at the 
study site under overnight fasted conditions at the morning appointment under supervision of 
site personnel. 
• A light breakfast (ie, a low-fat meal [eg, 2 slices of white bread, 2 tablespoons of jam, 
and 1 cup of low-fat milk]) will be given on cycle 1 day 1 and cycle 1 day 15 (+1 week). 
Breakfast should be consumed within 30 minutes.  Surufatinib will be given within 5 minutes 
after completion of breakfast but no more than 30 minutes after the start of breakfast. 
• A lunch of approximately 500 to 600 calories (eg, turkey sandwich or chicken and 
vegetable soup with 2 slices of bread plus 1 cup of decaffeinated tea or coffee) will be given 
on cycle 1 day 1 and cycle 1 day 15 (+1 week) approximately 3.5 hours postdose. 
• On other days up to cycle 1 day 14, surufatinib should be taken between 8:00 AM and 
10:00 AM. 
• From cycle 1 day 16 onwards, surufatinib will be taken following the usual instructions. 
Special instructions for Cohort D 
• The dose and schedule for administration of surufatinib and drug cocktail is provided in 
Table 5.  
− On day -2 and cycle 1 days 1, 15, and 16, study drugs must be taken at the 
investigative site under the supervision of the investigator or designee.  
− On day -2 and cycle 1 day 15 (+1 week), times of intake of study drugs and meals 
(start and stop times of breakfast and start time of lunch consistent across dosing days) 
must be recorded on the eCRF.  
• No fruit juice (including apple juice) will be allowed on day -2 and cycle 1 day 15 
(+1 week). 
• On day -2 and cycle 1 day 15 (+1 week), the patient must fast overnight for at least 
10 hours before the morning when safety laboratory tests and PK blood samples are 
collected.  
− Intake of water is allowed until 2 hours before surufatinib/drug cocktail intake.  From 
2 hours after dosing, intake of water is allowed.  


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− A light breakfast (ie, a low-fat meal [eg, 2 slices of white bread, 2 tablespoons of jam, 
and 1 cup of low-fat milk]) will be given at the site.  Breakfast should be consumed 
within 30 minutes. 
− Surufatinib and the drug cocktail will be given within 5 minutes after completion of 
breakfast but no more than 30 minutes after the start of breakfast.  
• Surufatinib and the drug cocktail should be taken at approximately the same time.  They 
will be taken orally with a small amount of noncarbonated water, approximately 240 mL in 
total for surufatinib/the drug cocktail.  If needed, an additional 120 mL of water may be 
consumed.  
− Predose PK and ECG (when required) samples must be collected within 15 minutes 
before dosing. 
− Surufatinib should be taken prior to intake of the drug cocktail.  Dosing of the 
cocktail components will be done sequentially in the following order: midazolam, 
fexofenadine, and rosuvastatin.  On cycle 1 day 15 (+1 week).  
• Patients will fast until approximately 4 hours postdose, followed by a standard lunch of 
approximately 500 to 600 calories (eg, turkey sandwich or chicken and vegetable soup with 
2 slices of bread plus 1 cup of decaffeinated tea or coffee).  After that, patients may resume 
their usual diet. 
• From cycle 1 day 16 onwards, surufatinib will be taken following the usual instructions. 
• When surufatinib is self-administered at home (ie, cycle 1 day 2 through cycle 1 day 14 
and cycle 1 day 17 onwards), it should be taken within 1 hour after breakfast during the 
morning hours. 
• In case of severe sedation by oral midazolam, the benzodiazepine antagonist flumazenil 
may be used by the IV route. 
7.1.3 
Dose Modification  
The dose modification sequence by starting dose is shown in Table 8.  A patient is normally 
allowed to have dose reductions no more than twice; ie, dose reductions from 300 mg QD to 250 
mg QD and then to 200 mg QD.  However, if the investigator judges that a dose lower than 200 mg 
QD is required for safety reasons and that the patient could still benefit from study drug treatment 
at such a lower dose, then the dose may be further lowered to 200 mg QD, 3 weeks on and 1 week 
off, during each subsequent 4-week cycle. 
The severity of AEs will be graded according to the NCI CTCAE version 5.0.  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 eCRF. 
• 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 or 


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interruption.  In addition, no dose reductions or interruptions will be required for anemia 
(non-hemolytic) because it can be satisfactorily managed. 
• To recover from acute toxicity, unless otherwise indicated, the treatment 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 treatment.  Continuation/resumption of surufatinib treatment 
after an interruption of more than 21 days must be discussed with the medical monitor or his 
or her designee. 
• Where several toxicities with different grades or severity occur at the same time, the dose 
modifications should be according to the highest grade observed. 
Table 8 
Dose Modification Sequence  
Daily Starting Dose 
300 mg 
-1 dose 
250 mg 
-2 dose 
200 mg 
-3 dose 
200 mg on reduced schedule1 
QD=once daily. 
1. Dosing schedule 200 mg QD, 3 weeks on/1 week off, every 4-week cycle. 
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 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 to ≤grade 1.  Patients with a grade 3 nonhematologic toxicity 
that does not resolve to ≤grade 1 within 14 days should permanently discontinue the study drug. 
Table 9 
Dose Modification for Hematologic and Nonhematologic Toxicity  
NCI CTCAE Version 5.0 Toxicity Grading 
Action 
Grade 1 or 2 
None 
Grade 3 or 4 
Expected manageable/reversible with dose reduction 
Hold1 
Toxicity remains grade 3 >14 days 
Discontinue treatment 
Toxicity lasts ≤14 days and resolves to ≤grade 1 
Reduce 1 dose level 
Reoccurrence of grade 3 toxicity 
Reduce 1 dose level or discontinue treatment1 
Reoccurrence of grade 4 toxicity 
Discontinue treatment 
Not expected manageable/irreversible with dose 
reduction 
Discontinue treatment 
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute. 
Note: Patients who experience gastrointestinal perforation should be permanently discontinued from study treatment. 
1. 
Treatment should be withheld until toxicity recovers to ≤grade 1.  For patients who cannot recover within 21 days, 
the study treatment should be discontinued permanently. 


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7.1.4 
Dose Modification for Important Identified Risks  
Dose modifications for important identified risks are provided in Table 10 (hypertension), 
Table 11 (proteinuria), Table 12 (liver function impairment), and Table 13 (hemorrhage). 
Table 10 
Dose Modification for Hypertension  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1:  
Pre-hypertension (systolic blood 
pressure 120 to 139 mmHg or 
diastolic blood pressure 80 to 
89 mmHg) 
None 
None 
Grade 2:  
Stage 1 hypertension (systolic 
blood pressure 140 to 159 mmHg 
or diastolic blood pressure 90 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; 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 
blood pressure ≥160 mmHg or 
diastolic blood pressure 
≥100 mmHg); medical intervention 
indicated; more than 1 drug or 
more intensive therapy than 
previously used indicated 
If blood pressure >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 to 
grade 1 or baseline level within 
21 days, surufatinib treatment could 
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); urgent 
intervention indicated 
Discontinue surufatinib treatment 
Emergency medical intervention 
 


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Table 11 
Dose Modification for Proteinuria  
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1:  
1+ proteinuria; urinary protein 
<1.0 g/24 hours 
None 
Follow-up per planned schedule 
Grade 2: 
2+ or 3+ proteinuria; urinary 
protein 1.0 to 2.0 g (excluding 
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+; urinary protein 2.0 
to 3.5 g (excluding 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 
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 2+ proteinuria, 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 instance 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/resumption of surufatinib treatment should be 
discussed with the medical monitor.  Surufatinib treatment should be discontinued if a patient develops nephrotic 
syndrome. 
 
Table 12 
Dose Modification for Liver Function Impairment  
Grade and Definitions 
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 to 
5ULN 
Maintain the original dose, provide 
supportive care of complications of 
liver impairment, and observe for 
1 week.  If the ALT and AST is 
stable or declining, continue with 
the original dose treatment. 
If the ALT and/or AST continue to 
rise significantly, then interrupt 
surufatinib; resume treatment at a 
lower dose if transaminase 
elevation resolves to ≤grade 1 
within 21 days; otherwise, 
discontinue treatment. 
Check total bilirubin.1 Provide 
supportive care and increase the 
frequency of liver function 
monitoring to 1 to 2 times a week 


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Table 12 
Dose Modification for Liver Function Impairment  
Grade and Definitions 
Dose Adjustment 
Suggested Actions 
Grade 3: 
ALT >5ULN or AST >5ULN 
Hold surufatinib; resume treatment 
at the lower dose if resolves to 
≤grade 1 within 21 days; otherwise, 
discontinue treatment. 
Check total bilirubin.1 Provide 
supportive care and increase the 
frequency of liver function monitor 
to twice a week; consult expert if 
necessary. 
Grade 4: 
ALT >20×ULN or AST >20×ULN 
Discontinue treatment 
Check total bilirubin.1 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, 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 6 (Section 15) for important additional information. 
 
Table 13 
Dose Modification for Hemorrhage  
Grade and Definitions 
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 or higher 
Discontinue treatment 
Immediate medical intervention to 
identify and treat the source of 
bleeding 
7.2 
Treatment Assignment and Bias Minimization  
7.2.1 
Treatment Allocation  
All patients in this study will receive surufatinib 300 mg QD.  Patients will be assigned to 1 of the 
4 cohorts as determined by NET origin.  
7.2.2 
Randomization Strategy and Procedure  
This is not a randomized study. 
7.2.3 
Extent and Maintenance of Blinding  
Not applicable to this open-label study. 
7.3 
Assessment and Verification of Compliance  
The investigator is responsible for ensuring the patient’s treatment compliance.  The sponsor will 
provide supervision through on-site or remote monitoring visits made by its representatives.  The 
investigators should maintain complete and accurate records of drug use.  The dosing regimen and 
patient’s actual dosing should be recorded in the original treatment records as well as on the eCRF.  
At each treatment visit, the investigators or study staff should comprehensively assess the patient’s 
treatment compliance according to the drug dispensing and return status at each visit and the actual 


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dosing conditions, such as missed doses and overdosing reported by the patient.  The patient must 
return all drug bottles and remaining capsules at the end of the study.  The investigational sites 
must return all remaining supplies and drugs to the sponsor or provide evidence of destruction at 
the conclusion of the study. 
7.3.1 
Prior and Concomitant Therapies  
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient within 7 days before screening and 30 days after study completion should be recorded.  
At each visit, all medication used since the last record should be recorded. 
7.3.2 
Prohibited Therapies  
Any therapy intended for the treatment of cancer (with the exceptions noted in Section 7.3.3), 
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. 
Concomitant use of somatostatin analogues (SSAs) by patients with nonfunctioning NETs is not 
permitted and must have been discontinued before administration of the first dose of the study 
drug. 
Medications that are strong or moderate 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 (Section 15). 
Concomitant use of medications that are known to cause QT prolongation and/or torsades de 
pointes is not permitted.  See Appendix 5 (Section 15) for a table of current medications in this 
category and also consult the current list at http://www.crediblemeds.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 and only after meeting the following 
criteria: 
• Radiation related toxicities resolves to ≤grade 2 
• No disease progression observed 
7.3.3 
Permitted Therapies  
Patients who use hormonal therapy with gonadotropin-releasing hormone agonists for 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 at study entry: 
• Patients who are receiving Coumadin or Coumadin-like products should have their 
PT/INR monitored and maintained at the lower end of the therapeutic range (eg, close to 2.0 
if the therapeutic range is 2.0 to 3.0). 


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• Patients who require low-molecular-weight heparin should receive the prophylactic dose 
and monitoring as specified by the appropriate product information label. 
Patients who develop arterial thromboembolic events should discontinue the study treatment.  If a 
patient experiences a venous thromboembolic event while still receiving study treatment, it may 
still be possible for him or her to remain on study treatment under adequate monitoring and dose 
modification.  
• Patients who have functioning NETs and have been on a stable dose of a 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. 
All supportive measures consistent with optimal patient care will be given throughout the study. 
All concomitant medications should be reported to the investigator and recorded on the appropriate 
eCRF. 
7.3.4 
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 or 
moderate 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 (Section 15). 
In vitro, surufatinib is shown to have the potential to inhibit CYP3A, P-gp, and 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 dose reduction of the CYP3A, P-gp, or BCRP substrate medication should 
be considered.  Examples of the medications that are sensitive substrates of CYP3A, P-gp, and 
BCRP are listed in Appendix 3 (Section 15). 
For patients who participate in Cohort D, medications known to induce or inhibit CYP3A, P-gp, 
or BRCP must be discontinued or substituted 3 weeks prior to study visit day -2 until after cycle 1 
day 17.  Examples of these medications are listed in Appendix 3 (Section 15).  Moreover, patients 
should not use midazolam, fexofenadine, rosuvastatin, and any acid-reducing agents from 1 week 
before day -2 until after the last PK sample is collected on cycle 1 day 17.  All fruit juice is 
temporally disallowed on day -2 and cycle 1 day 15 (+1 week) as clinically relevant juice-drug 
interactions have been reported (Chen et al 2018). 


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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 the 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 30±7 days after the last study treatment administration.  AEs and SAEs 
ongoing at the end of treatment will be followed until resolution.  Any new SAE possibly related 
to the study treatment occurring any time after the end of treatment should be reported.  The NCI 
CTCAE (version 5.0) will be used to grade all AEs and laboratory abnormalities. 
8.1 
Definitions  
• Adverse event – An AE is any untoward medical occurrence in a clinical study patient 
temporally associated with the use of a study intervention, whether or not considered related 
to the intervention.  An AE can therefore be any of the following: 
− Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study intervention, whether or 
not considered related to the study intervention  
− Any new disease or exacerbation of an existing disease (a worsening in the frequency 
or severity of a known condition).  Recurrence of an intermittent medical condition (eg, 
headache) not present at baseline 
− Any deterioration in a laboratory value or other clinical test (eg, ECG, x-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
− AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (eg, screening invasive procedures such as 
biopsies) 
− Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concomitant medication.  Overdose per se will not be reported as an AE/SAE unless 
it is an intentional overdose taken with possible suicidal/self-harming intent.  Such 
overdoses should be reported regardless of sequelae. 
• Serious adverse event – An event is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
− Death 
− A life-threatening AE (an event is considered life-threatening if, in the view of either 
the investigator or sponsor, its occurrence places the patient or 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 
− Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 


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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. 
• Adverse event 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 can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it. 
8.2 
Documenting Adverse Events  
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. 
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?” 
When documenting an AE or SAE, the preferred medical terminology or concept should be used.  
Abbreviations and spoken language should be avoided.  Only 1 medical concept should be 
recorded in the event field on the eCRF.  All AEs (including SAEs) should be recorded on the 
eCRF on the AE page.  
All AEs (including SAEs) should be recorded on the AE eCRF, and the check box for ‘Serious’ 
should be ticked for entries that fit the criterion of serious.  The investigator should also complete 
an SAE report and submit this to the sponsor or its designee within 24 hours of knowledge of the 
event.  
8.2.1 
Assessment of Events  
8.2.1.1 
Severity  
For each AE and SAE recorded on the applicable eCRF, the investigator will make an assessment 
of severity through clinical description by referring to the 5-grade determination standard in the 
NCI CTCAE version 5.0.  The NCI CTCAE version 5.0 shows specific criteria for a large number 
of commonly reported specific AEs by MedDRA preferred term.  If a specific AE cannot be found 
in the NCI CTCAE version 5.0, then the investigator should name the AE and report the severity 
based on the general guideline shown in the list below. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)* 


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• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL** 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Activities of daily living 
• *Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc 
• **Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden 
8.2.1.2 
Causality  
A guideline to the interpretation of the causality question is found in Appendix 4 (Section 15) to 
the clinical study protocol. 
The investigator will assess a causal relationship between the study drug and each AE and will 
answer “yes” or “no” to the question “Do you consider that there is a reasonable possibility that 
the event may have been caused by the study drug?”  
For SAEs, a causal relationship will also be assessed for other medication and study procedures 
and additional study drug.  Note that for SAEs that could be associated with any study procedure, 
the causal relationship is implied to be “yes.” 
8.2.2 
Diagnosis Versus Signs and Symptoms  
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(eg, record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the eCRF.  If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
8.2.3 
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.  For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are separated 
from the initiating event in time should be recorded as independent events on the eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the eCRF. 
8.2.4 
Persistent or Recurrent Adverse Events  
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points.  Such events should only be recorded once in the eCRF unless the severity changes.  
If a persistent AE becomes more or less severe, it should be recorded again on an AE/SAE eCRF.  


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A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on an AE/SAE eCRF. 
8.2.5 
Previously Existing Medical Condition  
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the Medical and Surgical History eCRF. 
A pre-existing medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such events on 
an AE/SAE eCRF, it is important to convey the concept that the pre-existing condition has changed 
by including applicable descriptors (eg, “more frequent headaches”). 
8.2.6 
Hospitalization, Prolonged Hospitalization, or Surgery  
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE.  These scenarios include a planned hospitalization or prolonged 
hospitalization to: 
• Perform an efficacy measurement for the study 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical condition 
that has not changed 
• Receive scheduled therapy for the target disease of the study 
8.2.7 
Worsening of Solid Tumor  
Worsening and/or progression of the patient’s solid tumor should not be recorded as an AE or SAE 
unless it resulted in death within the AE reporting period.  These data will be captured as efficacy 
assessment data only. 
8.2.8 
Death  
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
should be recorded on an AE/SAE eCRF and expeditiously reported to the sponsor or its designee.  
This includes death attributed to tumor progression. 
When recording a death event, the underlying condition that caused or primarily contributed to the 
fatal outcome should be reported as an AE with death being the outcome of the event on the 
AE/SAE eCRF.  If the primary cause of death is unknown and cannot be ascertained at the time of 
reporting, record “Unknown Death” on the AE/SAE eCRF. 
If the death is attributed to progression of cancer, record “Cancer Progression” as the AE term on 
the eCRF. 


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8.3 
Reporting Adverse Events  
8.3.1 
Adverse Event Reporting Period  
All AEs that occur after informed consent is signed and through 30±7 days following the last 
administration of study treatment will be collected.  After this period, investigators should report 
only SAEs that are thought to be related to prior study treatment. 
8.3.2 
Reporting Requirements for Serious Adverse Events  
Investigators will submit reports of all SAEs, regardless of attribution, to the sponsor or its 
designee within 24 hours of learning of the events.  
For initial SAE reports, investigators should record all case details that can be gathered on the SAE 
report form.  Relevant follow-up information should be submitted to the sponsor or its designee as 
soon as it becomes available and/or upon request. 
Any life-threatening (ie, imminent risk of death) or fatal AE that is attributed by the investigator 
to the study drug will be telephoned to the medical monitor immediately, followed by submission 
of written case details on the SAE report form within 24 hours. 
8.3.3 
Adverse Event Follow-Up Duration  
The investigator should follow-up all unresolved AEs and SAEs until the events are resolved or 
stabilized, new antitumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws informed consent, or it has been determined that the study treatment or participation is 
not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) should be documented on 
the appropriate AE/SAE eCRF and in the patient’s medical record to facilitate source data 
verification.  For SAEs, if, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded in the additional case details section of the AE 
eCRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE report 
(eg, hospital discharge summary, consultant report, or autopsy report) may be followed up by 
telephone, fax, email, and/or a monitoring visit to obtain. 
8.3.4 
Post-Study Adverse Events  
At the last scheduled visit, the investigator should instruct each patient to report to the investigator 
any subsequent SAEs that the patient’s personal physician believes could be related to prior study 
treatment.  
The investigator should notify the sponsor or its designee of any death or other SAE occurring at 
any time after a patient has discontinued or terminated study participation if it is felt to be related 
to prior study treatment.  The sponsor or its designee should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly/birth defect in a 
subsequently conceived offspring of a patient that participated in this study. 


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8.4 
Adverse Events of Special Interest  
The AEs of special interest for surufatinib include hepatic disorder, proteinuria, hypertension, 
thyroid dysfunction, hemorrhage, and acute renal failure.  Depending on the nature of the event, 
rapid communication by the study sponsor to other parties (eg, regulators) might also be warranted. 
8.5 
Clinical Laboratory Findings  
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (eg, abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, or further 
diagnostic investigation). 
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 AE/SAE eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be recorded as 
“hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
8.5.1 
Liver Function Abnormality  
The finding of an elevated ALT or AST (>3×baseline value) in combination with either an elevated 
total bilirubin (>2×ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury; these findings meet the 
definition for Hy’s law and are associated with an increased risk of drug-induced liver injury 
(DILI).  Therefore, investigators must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST >3×baseline value in combination with total bilirubin 
>2×ULN (of which 35% is direct bilirubin) 
• Treatment-emergent ALT or AST >3×baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF and reported to the sponsor or its designee within 
24 hours after learning of the event as an SAE.  See Appendix 6 (Section 15) for important 
additional information. 
8.6 
Pregnancy  
A female patient must be instructed to stop taking the study drug and immediately inform the 
investigator if she becomes pregnant during the study.  The investigator should report all 
pregnancies related to maternal or paternal exposure within 24 hours to the sponsor or its designee.  
The investigator should counsel the patient and discuss the risks of continuing with the pregnancy 


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and the possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Pregnancies occurring up to 30 days after the completion of the study drug must 
also be reported to the investigator. 
Abortion, whether therapeutic or spontaneous, should always be classified as serious (as the 
sponsor considers these medically significant), recorded on an AE/SAE eCRF and expeditiously 
reported to the sponsor or its designee. 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male 
patient exposed to the study drug should be recorded and reported as an SAE. 
8.7 
Overdose  
For this study, any dose of surufatinib greater than 400 mg daily will be considered an overdose.  
No specific information is available on the treatment of overdose of surufatinib.  In the event of 
overdose, further surufatinib administration should be held, and the patient should be observed 
closely for signs of toxicities.  Appropriate supportive treatment should also be provided if 
clinically indicated.  In the event of accidental or intentional overdose, the investigator or other 
site personnel should inform sponsor study representatives immediately or no later than 24 hours.  
An overdose with associated AEs/SAEs should be recorded as the AE diagnosis/symptoms on the 
relevant AE/SAE modules in the eCRF and on the study drug eCRF module. 
An overdose with no associated signs or symptoms should only be reported on the study drug 
eCRF module. 


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9 
ANALYSIS  
All statistical analysis will be performed under the direction of the sponsor’s personnel.  Details 
of the statistical analysis and data reporting will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized prior to the database lock.  
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and the final analysis of the study will be conducted at the time of analysis of the last cohort.  An 
interim analysis is planned for Cohort D only.  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. 
Data will be summarized using descriptive statistics (continuous data) and/or contingency tables 
(categorical data) for demographic and baseline characteristics, efficacy measurements, safety 
measurements, and PK measurements.  Time to event variables will be summarized descriptively 
using Kaplan-Meier medians and quartiles.  Analyses will be performed using SAS® (Version 9.1 
or higher). 
9.1 
Hypothesis  
No formal hypothesis testing is planned for this study.  For efficacy endpoints DCR and ORR, the 
study will provide the estimates and the associated 95% confidence interval (CI) for precision. 
9.2 
Population  
9.2.1 
Sample Size Rationale  
Taking into account study feasibility, given that these tumors are relatively rare, it is planned to 
enroll approximately 20 patients each in Cohorts A and C and approximately 35 patients in 
Cohort B. Twenty patients in Cohorts A and C and 35 patients in Cohort B can provide adequate 
precision for the estimate of DCR at a specific time point. 
Table 14 shows the range of DCR and the corresponding 95% CIs for a sample size of 20 patients.  
Table 15 shows the range of DCR and the corresponding 95% CIs for a sample size of 35 patients.  
Table 14 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for 
N=20 Patients  
Number of Cases 
Estimated DCR 
95% CI Lower Limit 
95% CI Upper Limit 
0 
0 
0.00 
0.17 
5 
0.25 
0.09 
0.49 
10 
0.50 
0.27 
0.73 
12 
0.60 
0.36 
0.80 
14 
0.70 
0.46 
0.88 
16 
0.80 
0.56 
0.94 
18 
0.90 
0.68 
0.99 
20 
1.0 
0.83 
1.0 
CI=confidence interval; DCR=disease control rate. 
95% Clopper-Pearson Interval for binomial distribution. 


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Table 15 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for 
N=35 Patients  
Number of Cases 
Estimated DCR 
95% CI Lower Limit 
95% CI Upper Limit 
0 
0.00 
0.00 
0.10 
5 
0.14 
0.05 
0.30 
10 
0.29 
0.15 
0.46 
15 
0.43 
0.26 
0.61 
20 
0.57 
0.39 
0.74 
25 
0.71 
0.54 
0.85 
30 
0.86 
0.70 
0.95 
35 
1.00 
0.90 
1.00 
CI=confidence interval; DCR=disease control rate. 
95% Clopper-Pearson Interval for binomial distribution. 
Cohort D: Previously published clinical data indicate that the intra-patient coefficient of variation 
(CV) ranges from approximately 16% to 22% for area under the plasma concentration-time curve 
from time 0 to infinity (AUC0-∞) with respect to the probe drugs to be investigated in the study 
(Haberer 2014).  Assuming an intra-patient CV of 22% among the probe drugs for AUC0-∞, a 
sample size of 14 patients would be sufficient for the point estimate of the geometric mean ratio 
of AUC0-∞ of test versus reference to fall within 87% and 115% of the true value with 90% 
confidence.  Assuming a 15% dropout rate, approximately 16 patients will be enrolled to ensure a 
minimum of 14 completers.  
At the time of this protocol amendment preparation (16 November 2023), Cohort B had enrolled 
32 patients and Cohort D had enrolled 6 patients. Cohort A had enrolled 20 patients and Cohort C 
had enrolled 32 patients.  
9.2.2 
Analysis Subsets  
The following analysis populations have been defined for the study: 
• Safety Analysis Set – All Treated Population: This population includes all patients who 
have received at least 1 dose of surufatinib.  Safety data will be evaluated based on the actual 
dose initially received.  PFS will also be analyzed based on this population. 
• PK Analysis Set: This population will include all patients who received at least 1 dose of 
surufatinib and have at least 1 PK sample obtained and analyzed. 
− PK Population: all patients who received at least 1 dose of the study drug and have 
at least 1 measurable plasma concentration data point 
− PK Evaluable Population: all patients who received at least 1 dose of the study drug 
and have a sufficient PK profile to derive at least 1 PK parameter 
• Pharmacodynamic (ECG) Set: This population will include all patients who received at 
least 1 dose of study drug and have baseline and at least 1 postdose ECG measurement. 
• Efficacy Analysis Set: This population includes all patients who have received at least 
1 dose of surufatinib and have had at least 1 post-baseline tumor assessment unless death 
occurs before first post-baseline assessment.  All efficacy endpoints will be analyzed based 
on this analysis set except PFS, which will be analyzed based on the safety analysis set. 


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Additional populations may be defined in the SAP. 
9.3 
Testing Procedures  
9.3.1 
Analysis of the Primary Efficacy Endpoint  
The primary endpoint of DCR at 6 months is defined as the proportion of patients at 6 months 
whose best overall response from baseline is either a CR, PR, or SD per RECIST version 1.1 
(Appendix 2 [Section 15]).  To be assigned a status of PR or CR, changes in tumour measurements 
must be confirmed by repeat assessments performed at least 4 weeks after the criteria for response 
are first met. The estimated DCR and the corresponding 95% CIs based on the Clopper-Pearson 
method will be provided for each cohort.  
9.3.2 
Analysis of Secondary Efficacy Endpoints  
The ORR is defined as the proportion of patients with a best overall response or CR or PR per 
RECIST version 1.1 (Appendix 2 [Section 15]).  To be assigned a status of PR or CR, changes in 
tumor measurements must be confirmed by repeat assessments performed at least 4 weeks after 
the criteria for response are first met.  The estimated ORR and the corresponding 95% CIs based 
on the Clopper-Pearson method will be provided for each cohort. 
The TTR is defined as the time between the start date of study drug until first documented response 
(CR or PR) according to RECIST version 1.1 (Appendix 2 [Section 15]).  Time to response will 
be summarized for patients with best overall response of CR or PR. 
The DoR is defined as the time from the first time that the objective response reaches CR or PR, 
whichever comes first, until the occurrence of PD or death (if the death of the patient occurs before 
recording the PD). Duration of response will be summarized for patients with best overall response 
of CR or PR. 
The PFS is defined as the time from the start of study drug to date of objective disease progression 
as defined by RECIST version 1.1 or death, whichever comes first. 
The TTR, DoR, and PFS will be summarized using the Kaplan-Meier method, including estimated 
median (in months) with 95% CI, 25th, and 75th percentiles and Kaplan-Meier estimated 
probabilities with corresponding 95% CIs at pre-defined landmark times as defined in the SAP.  
Censoring reasons for PFS and DoR will be summarized.  
9.3.3 
Safety Analysis  
An AE is considered a TEAE if the onset date is on or after the start of study treatment or if the 
onset date is missing, or if the AE has an onset date before the start of study treatment but worsened 
in severity after the study treatment until 37 days after the last dose of study treatment.  After this 
period, treatment-related SAEs will also be considered as TEAEs. 
TEAEs, TEAEs leading to drug modification or discontinuation, changes in laboratory results, 
changes in ECGs/echocardiograms and MUGA, and changes in vital signs will be summarized by 
disease cohort. Exposure to study drug will be summarized. Physical examination findings will be 
listed. 
All AE data will be listed by individual patient and cohort.  All AEs will be coded with MedDRA 
and graded using the NCI CTCAE (version 5.0) severity grading system.  The frequency of AEs 


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will be summarized by MedDRA System Organ Class and Preferred Term, and NCI CTCAE 
grade. 
Changes in laboratory data will be summarized by grade for each visit using the NCI CTCAE 
version 5.0.  Selected vital signs and selected laboratory data may be plotted over time for each 
patient. 
9.3.4 
Pharmacokinetics Analysis  
9.3.4.1 
Pharmacokinetic Analysis for Cohorts A to C  
Descriptive statistics (including, but not limited to, arithmetic mean, standard deviation, CV, 
median, minimum, maximum, and geometric mean) will be provided for the observed 
concentration for surufatinib. 
9.3.4.2 
Pharmacokinetic Analysis for Drug Interaction Evaluation (Cohort D)  
The following PK parameters will be determined: 
Surufatinib: 
Cycle 1 day 15 (+1 week): 
• Maximum plasma concentration (Cmax), tmax, area under the plasma concentration-time 
curve from time 0 to 24 hours (AUC024h), observed analyte concentration just prior to the 
beginning or at the end of a dosing interval (Ctrough) 
Midazolam and its metabolite 1-OH-midazolam, fexofenadine, and rosuvastatin and its 
metabolite N-desmethyl rosuvastatin: 
Day -2 and cycle 1 day 15 (+1 week): 
• Cmax, tmax, area under the plasma concentration-time curve from time 0 to time of the last 
measurable concentration (AUC0-last), AUC0-∞, elimination half-life 
• Total apparent clearance (only for parent compounds midazolam, fexofenadine, and 
rosuvastatin) 
• Ratio Cmax, metabolite/parent, Ratio AUC0-last, metabolite/parent, Ratio AUC0-∞, metabolite/parent 
(metabolite/parent=1-OH-midazolam/midazolam, N-desmethyl rosuvastatin/rosuvastatin; not 
for fexofenadine) 
• Ratio Cmax, test/reference, Ratio AUC0-last, test/reference, Ratio AUC0-∞, test/reference 
(test/reference=probe drug in presence of surufatinib/probe drug alone) 
Additional PK parameters may be included if deemed appropriate.  PK analysis will be performed 
using actual blood collection times relative to dosing times recorded in the raw data.  If an actual 
blood collection time or a dosing time is missing, the nominal time may be used.  Details of the 
PK analysis, including data handling rules and software used to perform the PK analysis, will be 
provided in the SAP. 
Descriptive statistics will be calculated for the plasma concentrations of surufatinib and for the 
probe drugs and their metabolites (midazolam and its metabolite 1 OH-midazolam, fexofenadine, 
rosuvastatin and its metabolite N-desmethyl rosuvastatin) and for the derived PK parameters, as 


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applicable.  Statistics include sample size (n), arithmetic mean, standard deviation, CV, geometric 
mean, median, minimum, and maximum. 
For each patient, plasma concentration-time data will be graphically presented.  Similarly, graphs 
of the mean plasma concentration-time profiles and overlay graphs with combined individual 
plasma concentration-time profiles will be produced.  PK parameters will be subjected to an 
exploratory graphical analysis, including various transformations in order to obtain a general 
overview. 
Statistical analysis will be performed for the PK parameters (Cmax, AUC0-last, and AUC0-∞) of each 
of the following analytes of the drug cocktail: 
• midazolam and its metabolite 1-OH-midazolam 
• fexofenadine 
• rosuvastatin and its metabolite N-desmethyl rosuvastatin 
The test/reference treatments are defined as cycle 1 day 15 (+1 week; the drug cocktail in the 
presence of surufatinib at steady state)/day -2 (the drug cocktail alone). 
The primary PK parameters of interest for statistical analysis are Cmax, AUC0-last, and AUC0-∞ of 
the parent compounds of the drug cocktail.  For each analyte, all patients who have the primary 
PK parameters of interest from both pretreatment and treatment phases will be included in the 
statistical analysis. 
Linear mixed-effects models will be applied to log-transformed PK parameters data with treatment 
as the fixed effect and patient as the random effect.  The least square means and intra-patient 
coefficients of variation will be derived from the model.  The geometric mean ratios and the 90% 
CI of the PK parameters of each probe drug with and without coadministration of surufatinib will 
then be constructed through back-transformed results based on the model. 
The PK parameters of the metabolites of the compounds and the ratios of metabolite to parent for 
Cmax, AUC0-last, and AUC0-∞ will be analyzed in a similar way as planned above. 
Additional statistical analysis will be performed if deemed appropriate and will be addressed in 
the SAP. 
9.3.5 
Pharmacodynamic (Electrocardiogram) Analysis  
Patients who 1) receive at least 1 dose of study drug and 2) have baseline and at least 1 postdose 
ECG measurement will be evaluable for pharmacodynamic (ECG) evaluation.  Patients who had 
reduced dosage, prolonged dose interruption of >2 days in cycle 1, any dose interruption within 
7 days before cycle 1 day 15 (+1 week), or were discontinued from the study prior to the 
completion of ECG data collection (cycle 1 day 15 [+1 week]) will be excluded.  For each of the 
ECG parameters, the average values from the 3 readings of a triplicate ECG set will be used in the 
analysis. 
For all ECG parameters, the baseline will be defined as the mean values of the triplicate ECG 
measurements taken at predose on cycle 1 day 1. 


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9.3.5.1 
Corrected QT Intervals  
The terminology QTc is used in this section as a general notation for QTc using any of the specified 
methods. 
The QT interval data will be corrected for heart rate using 2 correction methods (Fridericia – QTcF 
and Bazett – QTcB).  For each QTc correction method, the relationship between QTc and RR 
interval at baseline will be evaluated graphically by plotting the logarithm of baseline QTc values 
against the logarithm of corresponding RR intervals.  Fridericia will be used as the primary 
correction method for statistical analysis.  If the correlation between QTc and RR intervals remains 
significant using the Fridericia correction method, an alternative correction method may be 
considered for statistical analysis in addition to QTcF. 
For the statistical analysis based on the primary correction method (QTcF), the mean changes from 
baseline (ΔQTc) at each time point will be summarized (mean, standard deviation, median and 
range, and 2-sided 90% CI).  Mean values for the difference and 2-sided 90% CI for mean 
difference will be calculated at each time point. 
The primary analysis will focus on the maximum mean change from baseline in QTc (ΔQTc) on 
cycle 1 day 15 (+1 week), which will be estimated by the mean QTc change at around tmax, the 
time when the Cmax is reached (ie, steady state).  The same analysis will be performed for ΔQT 
data using other correction methods if data warrant.  The mean change from baseline in QTc 
(±standard deviation) over time will be plotted. 
In addition, QTc will be categorized based on International Council for Harmonisation (ICH) E14 
guidelines.  Tables will present the number and percentage of patients meeting or exceeding the 
following categories: 
• QTc prolongation: 
− Absolute values >450 to ≤480 msec 
− Absolute values >480 to ≤500 msec 
− Absolute values >500 msec 
• QTc change from baseline: 
− Increase from baseline >30 to ≤60 msec 
− Increase from baseline >60 msec 
9.3.5.2 
Heart Rate, QRS, and PR Intervals  
For each treatment and time point of measurement, heart rate, QRS interval, and PR interval, as 
well as the change from baseline in heart rate, QRS, and PR (Δheart rate, ΔQRS, ΔPR), will be 
summarized using descriptive statistics (mean, standard deviation, median, range, and 90% CI).  
The number and percentage of patients with heart rate >100 bpm will be tabulated for each time 
point.  The number and percentage of patients with QRS >110 msec will be tabulated for each time 
point.  The number and percentage of patients with PR >200 msec will be tabulated for each time 
point. 


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9.3.5.3 
T-wave and U-wave Morphology  
The number and percentage of patients having T-wave morphology changes from baseline and/or 
the occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality will be summarized.  Patients with abnormal ECG findings will be 
listed.  Additional analyses will be performed if deemed necessary. 
9.4 
Planned Interim Analysis  
For Cohort D only, once the last patient enrolled to this cohort has completed the required study 
procedures up to Cycle 1 Day 17, an interim analysis is planned to evaluate the short-term safety 
and the PK profile.  An interim PK report for Cohort D will be written on the basis of this data 
cutoff date. 
 


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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be conducted in accordance with the protocol; consensus ethics 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 Independent Ethics Committee/Institutional Review Board (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.  The IRB/IEC will be notified of SAEs or other 
significant safety findings by IEC/IRB procedures.  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 Code of Federal Regulations (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 
Informed Consent  
• Investigators or designees must obtain the signed ICF from patients prior to conducting 
any study-related procedures. 
• The investigator or his or her representative will explain the nature of the study to the 
participant or to their legally authorized representative and answer all questions regarding the 
study. 
• Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the IEC/IRB or study 
center. 


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• Patients must be informed that they may withdraw consent to participate in the study 
without any limitations.  If the patient cannot sign the ICF, a legally acceptable representative 
of the patient must sign the ICF.  
• If the patient and the legally acceptable representative are not able to read and write, an 
impartial witness should be present throughout the whole process of providing informed 
consent.  Once the patient and the legally acceptable representative give their oral consent, 
the ICF should be signed by the impartial witness to confirm that the patient and the legally 
acceptable representative fully understand the study and their right to withdraw informed 
consent without any limitations. 
• Informed consent should be recorded on the eCRF.  
• The investigator is responsible for answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be 
relevant to the patient’s willingness to continue his or her participation in the study. 
• 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 (including 
patients who have already received the study drug). 
• A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 28 days from the previous ICF signature date. 
10.4 
Data Privacy  
All information about the study drug (such as patent application, formulation, manufacturing 
process, and basic study information) is considered confidential as long as it is unpublished. 
All information obtained in the study is considered confidential.  The sponsor will open the 
information to investigational personnel and any other regulatory authority when necessary.  To 
ensure the completeness of the study analysis data, investigational personnel are accountable for 
providing all results and data to the sponsor. 
Investigators must guarantee the privacy of patients by not disclosing patient-related information 
to third parties without authorization.  eCRFs and other documents submitted to the sponsor should 
not contain the patient’s name.  
• 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 his or her data to be used 
as described in the informed consent.  
• 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. 


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10.5 
Disclosure  
Final study results will be published on a public clinical study website according to applicable 
local guidelines and regulations. 
10.6 
Data Quality Assurance  
• To ensure the safety of 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 printed case report forms (CRFs) 
or eCRFs 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 eCRF. 
• Guidance on completion of case report forms (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, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals 
(eg, contract research organizations [CROs]). 
 


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11 
OVERSIGHT  
11.1 
Independent Monitoring  
The sponsor will review study safety data every 6 months, or more frequently, if safety concerns 
arise.  In addition, a SRC will monitor patient safety as described below.   
11.1.1 
Safety Review Committee  
Patient safety will be monitored by a SRC.  The SRC is charged with evaluating safety data and 
determining if enrollment may continue as planned.  The SRC membership will be comprised of 
sponsor medical representative(s), CRO medical representative(s), and investigators.  The details 
of roles and responsibilities will be outlined in the SRC Charter.  Safety review meetings will be 
conducted at least once every 6 months, but may be conducted more frequently if safety concerns 
arise.   
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 eCRFs with the investigators and their 
staff.  During the study, the field monitor will visit the site or remotely monitor regularly to check 
the completeness of patient records, the accuracy of entries on the eCRFs, the adherence of the 
protocol to GCP, and the progress of enrollment and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications.  Key study personnel including the 
investigator must be available to assist the field monitor during these visits. 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries.  The sponsor’s monitoring standards require full verification 
of the informed consent, adherence to the inclusion/exclusion criteria, and documentation of SAEs.  
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. 


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11.2.2 
Audits  
Authorized representatives of the sponsor, 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 eCRF 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 eCRFs is complete and accurate and that entry and updates are performed 
in a timely manner. 
At all times, the Principal Investigator has final responsibility for the accuracy and authenticity of 
all clinical and laboratory data entered in the EDC.  Patient source documents are the 
investigator’s/physician’s patient records maintained at the study site.  In cases where the source 
documents are the hospital or the physician’s chart, the information collected in the EDC must 
match those charts. 
The completed pages of the EDC system are the sole property of the sponsor and should not be 
made available in any form to third parties without written permission from the sponsor, except 
for authorized representatives of the sponsor or appropriate regulatory authorities. 
11.2.3.2 
Source Documentation  
• The investigator/institution should maintain accurate source documents and study records 
for all patients that support the information entered in the 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 


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


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


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


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14 
REFERENCES  
Bosilkovska et al 2014  
Bosilkovska M, Samer CF, Déglon J, Rebsamen M, Staub C, Dayer P, et al. Geneva cocktail for 
cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol 
Ther. 2014;96(3):349-59. 
Chen et al 2018  
Chen M, Zhou SY, Fabriaga E, Zhang PH, Zhou Q. Food-drug interactions precipitated by fruit 
juices other than grapefruit juice: an update review. J Food Drug Anal. 2018;26(2S):S61-S71. 
doi:10.1016/j.jfda.2018.01.009. 
Dasari et al 2020  
Dasari A, Li D, Sung M, Tucci C, Kauh J, Kania M, et al. Efficacy and safety of surufatinib in 
United States patients with neuroendocrine tumors. Presented at ASCO 2020; May 29-Jun 2, 2020.  
Duran et al 2020  
Duran I, Carles J, Bulat I, Hellemans P, Mitselos A, Ward P, et al. Pharmacokinetic drug–drug 
interaction of apalutamide, part 1: clinical studies in healthy men and patients with castration-
resistant prostate cancer. Clin Pharmacokinet. 2020. doi:10.1007/s40262-020-00882-2. 
EMA 2012  
EMA Guideline on the investigation of drug interactions (2012). Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500
129606.pdf. Accessed 20 June 2020. 
Escudier et al 2007  
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced 
renal clear-cell carcinoma. N Engl J Med. 2007;356(2):125-34. 
FDA 2020  
FDA Guidance for Industry Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and 
Transporter-Mediated 
Drug 
Interactions 
(January 
2020). 
Available 
at: 
https://www.fda.gov/media/134581/download. Accessed 20 June 2020. 
FDA 2009  
Food and Drug Administration. FDA guidance for industry – drug-induced liver injury: 
premarketing 
clinical 
evaluation. 
Published 
July 
2009. 
Available 
from: 
https://www.fda.gov/media/116737/download. 
Haberer 2014  
Haberer LJ, McSherry I, Cargill A, McCarthy L. Effects of vercirnon on the activity of CYP3A4, 
CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe 
substrates. Eur J Clin Pharmacol. 2014;70(1):37-45. 


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Halfdanarson et al 2008  
Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): 
incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19(10):1727-
33. 
Man et al 2018  
Man D, Wu J, Shen Z, Zhu X. Prognosis of patients with neuroendocrine tumor: a SEER database 
analysis. Cancer Manag Res. 2018;10:5629-38. 
Motzer et al 2007  
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib 
versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-24. 
NCCN 2019  
National Comprehensive Cancer Network. Neuroendocrine and adrenal tumors, version 1.2019. 
www.NCCN.org/patients. Published March 5, 2019. 
Pavel et al 2020  
Pavel M, Öberg K, Falconi M, Krenning EP, Sundin A, Perren A, et al. Gastroenteropancreatic 
neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment, and 
follow-up. J Ann Oncol. 2020;31(7):844-60. 
Raymond et al 2011  
Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib malate 
for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-13. 
Shah et al 2018  
Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. 
Neuroendocrine and adrenal tumors, version 2.2018: featured updates to the NCCN guidelines. 
J Natl Compr Canc Netw. 2018;16(6):693-702. 
Terris et al 1998  
Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, et al. Expression of 
vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathol. 
1998;32:133-8. 
Yao et al 2013  
Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic 
neuroendocrine tumors: the clinical experience. Cancer Res. 2013;73(5):1449-53. 


Si g nat ure Pa ge f or 
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A p pr o val Tas k
0 3- Dec- 2 0 2 3 1 1: 5 7: 5 9 G M T + 0 0 0 0
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SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN  
An Open-Label Phase 2 Study of Surufatinib in Patients with Neuroendocrine Tumours in 
Europe 
 
 
 
Protocol Number: 
2020-012-00EU1 
 
 
Name of Test Drug: 
Surufatinib 
 
 
Phase: 
Phase 2  
 
 
 
Sponsor Name: 
HUTCHMED Limited 
 
Building 4, 720 Cailun Road  
 
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China 201203 
 
 
Analysis Plan Version 
Version Draft 1.0 
 
 
Effective Date 
10 October 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 or its subsidiaries. 
 






 
 
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TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................11 
2. 
STUDY DETAILS .....................................................................................................12 
2.1. 
Study Objectives .........................................................................................................12 
2.1.1. 
Primary Objective .......................................................................................................12 
2.1.2. 
Secondary Objective(s) ...............................................................................................12 
2.2. 
Study Design ...............................................................................................................13 
2.2.1. 
Brief Description ........................................................................................................13 
2.3. 
Determination of Sample Size ....................................................................................14 
3. 
ANALYSIS SETS ......................................................................................................17 
3.1. 
Definition of Analysis Sets .........................................................................................17 
3.1.1. 
All Enrolled Set ..........................................................................................................17 
3.1.2. 
Safety Analysis Set .....................................................................................................17 
3.1.3. 
Pharmacokinetic (PK) Analysis Set............................................................................17 
3.1.4. 
Pharmacodynamic (PD) ECG Analysis Set ................................................................17 
3.1.5. 
Efficacy Analysis Set ..................................................................................................17 
3.2. 
Protocol Deviations ....................................................................................................17 
4. 
ENDPOINTS ..............................................................................................................18 
4.1. 
General Principles for Derived Data and Transformed Data ......................................18 
4.1.1. 
Reference Start Date and End Date and Study Day ...................................................18 
4.1.1.1. 
First Dose Date ...........................................................................................................18 
4.1.1.2. 
Last Dose Date ............................................................................................................18 
4.1.1.3. 
Date of Last Known Alive ..........................................................................................18 
4.1.1.4. 
Date of Death ..............................................................................................................19 
4.1.1.5. 
Study Day ...................................................................................................................19 
4.1.2. 
Baseline and Change from Baseline ...........................................................................19 
4.1.3. 
Treatment Period ........................................................................................................19 


 
 
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4.2. 
Exposure Endpoints ....................................................................................................20 
4.3. 
Safety Endpoints .........................................................................................................21 
4.3.1. 
Adverse Events (AEs) .................................................................................................21 
4.3.2. 
Laboratory ...................................................................................................................22 
4.3.3. 
ECG ............................................................................................................................23 
4.3.4. 
Vital Signs ..................................................................................................................24 
4.3.5. 
ECOG Performance Status .........................................................................................25 
4.3.6. 
Echocardiogram (ECHO) ...........................................................................................25 
4.3.7. 
Physical Examination .................................................................................................25 
4.4. 
Efficacy Endpoints ......................................................................................................26 
4.4.1. 
Primary Endpoint ........................................................................................................26 
4.4.2. 
Secondary Endpoints ..................................................................................................26 
4.4.2.1. 
Objective Response Rate ............................................................................................26 
4.4.2.2. 
Time to Response .......................................................................................................27 
4.4.2.3. 
Duration of Response .................................................................................................28 
4.4.2.4. 
Progression Free Survival ...........................................................................................28 
4.4.2.5. 
Overall Survival ..........................................................................................................29 
4.5. 
Other Endpoints ..........................................................................................................30 
4.5.1. 
Pharmacokinetic Endpoint ..........................................................................................30 
4.5.1.1. 
Handling of Missing Plasma Concentration Data ......................................................30 
4.5.1.2. 
Handling of Below the Lower Limit of Quantification (BLQ) Data ..........................30 
4.5.1.3. 
Handling of the Difference between the Scheduled (nominal time) and the 
Actual Sampling Time (actual time) ...........................................................................30 
5. 
ANALYSIS METHOD ..............................................................................................31 
5.1. 
General Principles .......................................................................................................31 
5.1.1. 
General Methodology .................................................................................................31 
5.1.2. 
Handling Missing Data ...............................................................................................31 
5.1.2.1. 
Adverse Events and Start/End Date ............................................................................32 
5.1.2.2. 
Concomitant Medication/Procedure/Surgery Start/End Date .....................................33 
5.1.3. 
Visit Windowing .........................................................................................................33 
5.1.4. 
Adjustment for Covariates ..........................................................................................35 


 
 
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5.2. 
Analysis Methods .......................................................................................................35 
5.2.1. 
Patient Disposition ......................................................................................................35 
5.2.2. 
Protocol Deviation ......................................................................................................35 
5.2.3. 
Demographic and Other Baseline Characteristics ......................................................35 
5.2.4. 
Disease Characteristics ...............................................................................................36 
5.2.5. 
Medical History ..........................................................................................................36 
5.2.6. 
Prior Anti-Cancer Therapy .........................................................................................37 
5.2.6.1. 
Prior Anti-Cancer Medication ....................................................................................37 
5.2.6.2. 
Prior Anti-Cancer Radiotherapy .................................................................................37 
5.2.6.3. 
Prior Anti-Cancer Procedure or Surgery ....................................................................37 
5.2.7. 
Prior and Concomitant Medications ...........................................................................38 
5.2.8. 
Concomitant Procedure ..............................................................................................38 
5.2.9. 
Exposure of Study Treatment .....................................................................................38 
5.2.10. 
Safety Analyses ..........................................................................................................39 
5.2.10.1. 
Adverse Events ...........................................................................................................39 
5.2.10.2. 
Death ...........................................................................................................................41 
5.2.10.3. 
Laboratory Evaluations ...............................................................................................41 
5.2.10.4. 
ECG ............................................................................................................................42 
5.2.10.5. 
Vital Signs ..................................................................................................................42 
5.2.10.6. 
Performance Status .....................................................................................................42 
5.2.10.7. 
Echocardiogram ..........................................................................................................43 
5.2.10.8. 
Physical Examination .................................................................................................43 
5.2.11. 
Efficacy Analyses .......................................................................................................43 
5.2.11.1. 
Primary Efficacy Analyses .........................................................................................43 
5.2.11.2. 
Sensitivity Analysis for Primary Efficacy Endpoint ..................................................43 
5.2.11.3. 
Multiplicity Control ....................................................................................................43 
5.2.11.4. 
Secondary Efficacy Analyses .....................................................................................43 
5.2.11.5. 
Exploratory Efficacy Analyses ...................................................................................44 
5.3. 
Other Analyses ............................................................................................................44 
5.3.1. 
Listing and Presentation of Individual PK Data .........................................................44 


 
 
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5.3.2. 
Summary of PK Concentration Data ..........................................................................44 
5.3.3. 
Pharmacodynamic (Electrocardiogram) Analysiss .....................................................45 
5.3.4. 
Corrected QT Intervals ...............................................................................................45 
5.3.5. 
Heart Rate, QRS, and PR Intervals .............................................................................46 
6. 
PLANNED ANALYSIS .............................................................................................47 
6.1. 
Independent Data Monitoring Committee ..................................................................47 
6.2. 
Planned Interim Analysis ............................................................................................47 
6.3. 
Final Analysis .............................................................................................................47 
7. 
CHANGE FROM THE PROTOCOL ........................................................................48 
REFERENCE .................................................................................................................................49 
APPENDIX 1 .................................................................................................................................50 
APPENDIX 2 .................................................................................................................................54 
APPENDIX 3 .................................................................................................................................55 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Description 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ADaM 
Analysis Data Model 
ALP 
Alanine phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration-time curve 
BCRP 
Breast cancer resistance protein 
BMI 
Body mass index 
BLQ 
Below the lower limit of quantification 
BOR 
Best Overall Response 
CI 
Confidence interval 
CFB 
Change from baseline 
COVID-19 
Coronavirus 2019 
CTMS 
Clinical trial management system 
CR 
Complete response 
CS 
Clinically significant 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
CV 
Coefficient of variation 
CRO 
Clinical research organization 
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Event 
CxDy 
Cycle x Day y 
DBL 
Database lock 
DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DILI 
Drug-induced liver injury  
DoR 
Duration of response 
eCRF 
Electronic case report form 
ECHO 
Echocardiogram 
ECG 
Electrocardiogram 


 
 
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ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EOC 
End of cycle 
EOT 
End of treatment  
HR 
Hazard ratio 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
ITT 
Intent-to-treat 
LLQ 
Lower limit of quantification 
LS 
Least-square 
MCFB 
Mean change from baseline 
MedDRA 
Medical Dictionary for Regulatory activities 
MUGA 
Multigated acquisition  
NA 
Not applicable 
NCI 
National cancer institute 
NCS 
Not clinically significant 
NE 
Not evaluable 
NET 
Neroendocrine tumors 
ORR 
Objective response rate 
OS 
Overall survival 
P-gp  
P-glycoprotein 
PD  
Progressive disease 
PE 
Physical examination 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PR 
PR Interval (ECG Parameter) 
PS 
Performance status 
PT 
Preferred term 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QTcB 
QT correction Bazett formula 
QTcF 
QT correction Fridericia formula 
QRS 
A combination of the Q wave, R wave and S wave 


 
 
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RBC 
Red blood cells 
RD 
Relative dose 
RDI 
Relative dose intensity  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SD 
Stable disease 
StdDev 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
TLFs 
Tables, listings and figures 
TOC 
Table of contents 
TPR 
Time point response 
TTD 
Time to deterioration 
TTR 
Time to response 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantification 
WHODD 
World Health Organization Drug Dictionary  


 
 
H U T C H M E D Li mit e d 
St u d y Pr ot o c ol: 2 0 2 0- 0 1 2- 0 0 E U 1 
 
S A P V er si o n Dr aft 1. 0 
 
 
 
C O N FI D E N TI A L 
Pa ge 1 1 
Date: 1 0 O C T O B E R 2 0 2 4 
 
 
 
 
1.  I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) descri bes t he pla n ne d statistical a nal yses  a n d data prese ntati o ns 
f or st u d y 2 0 2 0- 0 1 2- 0 0 E U 1. T he S A P is base d o n t he Pr ot oc ol A me n d me nt 6, date d 0 1 Dece m ber 
2 0 2 3.  Wit h t his a me n d me nt, t he st u d y was ter mi n ate d base d u p o n t he strategic re-e val u ati o n of 
t he cli nical de vel o p me nt pr o gra m f or s ur ufati ni b i n E ur o pe a n d t he U nite d States. T his c ha n ge was 
n ot base d o n a n y c o ncer n f or patie nt safet y or ef ficac y relati ve t o s ur ufati ni b treat me nt.  
 
 
 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) f or t he st u d y is t o  e ns ure t hat t he data listi n gs, 
s u m mar y ta bles a n d fi g ur es t hat are t o b e pro d uce d, a n d t he statistical met h o d ol o gies t hat are 
use d, are c o m plete a n d a p pr o pria te t o all o w vali d c o ncl usi o ns re gar di n g t he st u d y o bjecti ves.  
T he S A P a d heres t o t he pr o per r e g ulat or y g ui deli n es a n d m ost re ce nt I nter n ati o nal C o u ncil f or 
Har m o nisati o n g ui deli nes (I C H) ( E 3, E 6, E 9). All decisi o ns re gar di n g t he fi nal a nal yses, as 
defi ne d i n t his S A P d oc u me nt, will be ma de pri or t o l oc ki n g t he data base; a n y de viati o ns fr o m 
t hese g ui deli nes will be d oc u me nte d i n t he cli nical st u d y re p ort ( C S R). 
T he a nal yses relate d t o p har m ac o ki netics ( P K) e n d p oi nts f or c o h ort D will be descri be d i n a 
se parat e a nal ysis pla n. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


 
 
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2. STUDY DETAILS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
x To evaluate the anti-tumour activity of surufatinib in patients with low- to intermediate-
grade (Grade 1 or Grade 2), well differentiated Neroendocrine tumors (NET). 
2.1.2. 
Secondary Objective(s) 
x To characterize the PK of surufatinib in patients with NET. 
x To evaluate the effect of surufatinib on cardiac repolarisation, as detected by changes in 
electrocardiogram (ECG) corrected QT interval (QTc), and the potential relationship with 
surufatinib plasma concentrations. 
x To further characterize the anti-tumour activity of surufatinib in patients with NET. 
x Cohort D only: To evaluate the effects of repeat dosing of surufatinib on the single-dose 
PK of CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) 
substrates in patients with NET. 
x To evaluate the safety and tolerability of surufatinib in patients with NET. 
Details of the study objectives and correspondent endpoints is provided in Table 1. 
 
Table 1 
Objectives and Corresponding Endpoints 
Tier 
Objectives 
Endpoints 
Primary 
To evaluate the anti-tumour activity of surufatinib 
in patients with low- to intermediate-grade (Grade 1 
or Grade 2), well differentiated NET. 
Disease Control Rate at 6 months 
Secondary 
 
To characterize the PK of surufatinib in patients 
with NET. 
Observed plasma concentrations, estimated 
population PK, and exposure parameters of 
surufatinib. 
To evaluate the effect of surufatinib on cardiac 
repolarisation, as detected by changes in ECG QTc, 
and the potential relationship with surufatinib 
plasma concentrations. 
QTc 
and 
plasma 
concentrations 
of 
surufatinib at specified time points. 
To further characterize the anti-tumour activity of 
surufatinib in patients with NET. 
Additional efficacy endpoints 
o 
Overall Response Rate (ORR) 
o 
Time to Response (TTR) 
o 
Duration of Response (DoR) 
o 
Progression Free Survival (PFS) 
Cohort D only: To evaluate the effects of repeat 
dosing of surufatinib on the single-dose PK of 
Cohort D only: Exposure parameters of 
CYP3A4, P-gp, and BCRP substrates 
 


 
 
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Tier 
Objectives 
Endpoints 
CYP3A4, P-gp, and BCRP) substrates in patients 
with NET. 
 
To evaluate the safety and tolerability of surufatinib 
in patients with NET. 
Safety assessments include: 
o 
Frequency and severity of adverse 
events (AEs) 
o 
Physical examination findings 
o 
Vital signs 
o 
Laboratory tests 
o 
ECG 
o 
Echocardiograms/Multigated 
Acquistion (MUGA) 
Exploratory 
None 
Efficacy endpoint 
o 
Overall Survival (OS) 
 
2.2. 
Study Design 
2.2.1. 
Brief Description 
This study is a Phase 2, open-label, multicentre study of surufatinib in patients with low- to 
intermediate-grade (Grade 1 or Grade 2), well-differentiated NETs. The study will enroll 4 cohorts 
of varying NETs, as follows: 
 
x Cohort A – NET of lung origin 
x Cohort B – NET of small bowel origin 
x Cohort C – NET of non-small bowel, non-pancreas, and non-lung origin 
x Cohort D – NET of any origin (Drug-drug interaction [DDI] substudy) 
All patients will be treated with a dose of oral surufatinib 300 mg QD in treatment cycles of 
28 days starting on Cycle 1 Day 1. All patients will undergo continuous safety monitoring and 
tumour assessment on a routine basis. Patients enrolled to Cohorts A, B, and C only will undergo 
electrocardiogram (ECG) monitoring via Holter monitor on day 1 and day 15 (+1 week) of the 
first cycle of treatment. The goal will be to obtain complete Holter monitoring data for 
approximately 40 patients. The number of subjects undergoing Holterassessments may be 
increased to ensure full, usable data is available. Patients will continue to receive surufatinib 
treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, lost to 
follow-up, the patient is no longer receiving clinical benefit in the opinion of the investigator, the 
start of subsequent anticancer therapy, or the sponsor ends the study. 
DDI Substudy (Cohort D): Patients with NETs of any origin. 
Approximately 16 additional patients with NET of any origin will be enrolled to Cohort D for the 
DDI substudy. The primary objective of this cohort is to investigate the potential DDI between 


 
 
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surufatinib and a drug cocktail containing selective probes of CYP3A4 (midazolam), P-gp 
(fexofenadine), and BCRP (rosuvastatin) substrates. Treatment cycles for Cohort D are outlined 
in Table 2. The DDI drug cocktail will be given on Day -2 during the pretreatment phase, and 
assessment of PK profiles of the probe substrates will be conducted at baseline on Days -2 and -1 
(ie, during the 48-hour period before starting treatment with surufatinib) and after repeated dosing 
with surufatinib at a dose of 300 mg QD for at least 14 days (surufatinib steady state on Cycle 1 
Day 15 [+1 week]). Patients enrolled to this cohort will not have to undergo Holter monitoring. 
For this DDI cohort, the most critical question will be answered with the completion of Cycle 1 
Day 17. Therefore, once all patients in this cohort have completed the required study procedures 
up to Cycle 1 Day 17, a data cutoff is planned to evaluate the short-term safety and the PK profile. 
An interim PK report for Cohort D will be written on the basis of this data cutoff date. 
Table 2 
Cohort D Treatment Overview  
Phase 
Cycle Day 
Dose Regimen 
Pretreatment 
D -2 
A single dose of drug cocktail consisting of the following: 
x midazolam 2.5 mg 
x fexofenadine 30 mg 
x rosuvastatin 10 mg 
Treatment 
C1D1 to C1D14 
Surufatinib 300 mg QD 
Treatment 
C1D15 (+1 week) 
A single dose of surufatinib 300 mg and a single dose of 
drug cocktail consisting of the following: 
x midazolam 2.5 mg 
x fexofenadine 30 mg 
x rosuvastatin 10 mg 
Treatment 
C1D16 and beyond 
Surufatinib 300 mg QD 
 
2.3. 
Determination of Sample Size 
Taking into account study feasibility, given that these tumours are relatively rare, it is planned to 
enroll approximately 20 patients each in Cohorts A and C and approximately 35 patients in Chort 
B. Twenty patients in Cohorts A and C and 35 patients in Cohort B can provide adequate precision 
for the estimate of DCR at a specific time point. 
Table 3A shows the range of DCR and the corresponding 95% confidence interval (CIs) for a 
sample size of 20 patients. Table 3B shows the range of DCR and the corresponding 95% CIs for 
a sample size of 35 patients. 
 


 
 
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Table 3A 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for N 
= 20 Patients 
Number of Cases 
Estimated DCR 
95% CI Lower Limit 
95% CI Upper Limit 
0 
0 
0.00 
0.17 
5 
0.25 
0.09 
0.49 
10 
0.50 
0.27 
0.73 
12 
0.60 
0.36 
0.80 
14 
0.70 
0.46 
0.88 
16 
0.80 
0.56 
0.94 
18 
0.90 
0.68 
0.99 
20 
1.0 
0.83 
1.0 
CI=confidence interval; DCR=disease control rate.  
95% Clopper-Pearson Interval for binomial distribution. 
 
Table 3B 
Estimated Disease Control Rate and 2-Sided 95% Confidence Intervals for N 
= 35 Patients 
Number of Cases 
Estimated DCR 
95% CI Lower Limit 
95% CI Upper Limit 
0 
0.00 
0.00 
0.10 
5 
0.14 
0.05 
0.30 
10 
0.29 
0.15 
0.46 
15 
0.43 
0.26 
0.61 
20 
0.57 
0.39 
0.74 
25 
0.71 
0.54 
0.85 
30 
0.86 
0.70 
0.95 
35 
1.00 
0.90 
1.00 
CI=confidence interval; DCR=disease control rate.  
95% Clopper-Pearson Interval for binomial distribution. 
 
Cohort D: Previously published clinical data indicate that the intrapatient coefficient of variation 
(CV) ranges from approximately 16% to 22% for area under the plasma concentration-time curve 
from time 0 to infinity (AUC0-) with respect to the probe drugs to be investigated in the study. 
Assuming an intrapatient CV of 22% among the probe drugs for AUC0-, a sample size of 14 
patients would be sufficient for the point estimate of the geometric mean ratio of AUC0- of test 
versus reference to fall within 87% and 115% of the true value with 90% confidence. Assuming a 


 
 
H U T C H M E D Li mit e d 
St u d y Pr ot o c ol: 2 0 2 0- 0 1 2- 0 0 E U 1 
 
S A P V er si o n Dr aft 1. 0 
 
 
 
C O N FI D E N TI A L 
Pa ge 1 6 
Date: 1 0 O C T O B E R 2 0 2 4 
 
 
 
 
1 5 %  dr o p o ut  r ate,  a p pr o xi matel y  1 6  patie nts  will  be  e nr olle d  t o  e ns ure  a  mi ni m u m  of  
1 4 c o m pleters. 
 
 
 T he ter mi nati o n of t his st u d y is base d u p o n t he 
strate gic re-e v al uati o n of t he cli nical de vel o p me nt pr o gra m f or s ur ufati ni b i n E ur o pe a n d t he 
U nite d States. T his c ha n ge is n ot base d o n a n y c o n cer n f or patie nt safet y or efficac y relati ve t o 
s ur ufati ni b treat me nt. 
 
C CI


 
 
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3. ANALYSIS SETS 
3.1. 
Definition of Analysis Sets  
3.1.1. 
All Enrolled Set 
All enrolled set includes all patients who signed informed consent form (ICF).   
3.1.2. 
Safety Analysis Set 
This set includes all patients who have received at least 1 dose of surufatinib. Patients in this set 
will be analyzed according to the actual dose initially received. This will be the analysis set for all 
safety evaluations. PFS will also be analyzed based on this population.   
3.1.3. 
Pharmacokinetic (PK) Analysis Set 
This population includes all patients who received at least 1 dose of surufatinib and have at least 
1 PK sample obtained and analyzed. 
x PK Population: All patients who received at least 1 dose of the study drug and have at 
least 1 measurable plasma concentration data point for at least 1 PK analyte without 
protocol violations or events with potential to affect the PK concentration. 
x PK Evaluable Population: All patients who received at least 1 dose of the study drug and 
have sufficient concentration data to derive at least 1 PK parameter. 
The PK population is used for tabulation of surufatinib concentrations from PK plasma samples. 
3.1.4. 
Pharmacodynamic (PD) ECG Analysis Set 
This population includes all patients who received at least 1 dose of study drug and have baseline 
and at least 1 post-dose ECG measurement.  
Patients who had reduced dosage, prolonged dose interruption of >2 days in cycle 1, any dose 
interruption within 7 days before cycle 1 day 15 (+1 week), or were discontinued from the study 
prior to the completion of ECG data collection (cycle 1 day 15 [+1 week]) will be excluded. 
3.1.5. 
Efficacy Analysis Set 
This population includes all patients who received at least 1 dose of surufatinib and had at least 1 
post-baseline tumor assessment unless death occurs before first-post-baseline assessment. 
All efficacy endpoints will be analyzed based on this analysis set except PFS, which will be 
analyzed based on the safety analysis set. 
 
3.2. 
Protocol Deviations  
Protocol deviations are recorded in the clinical trial management system (CTMS) as outlined in 
the protocol deviation and non-compliance management plan. All major and minor protocol 


 
 
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deviations including protocol deviations related to COVID-19 will be reviewed and confirmed 
during data review meeting prior to database lock. 
Data analyses will be based on the analysis sets defined above.  
4. ENDPOINTS 
4.1. 
General Principles for Derived Data and Transformed Data 
4.1.1. 
Reference Start Date and End Date and Study Day 
4.1.1.1. 
First Dose Date 
Reference start date is defined as the first date when a non-zero dose of any study drug 
(whichever occurs first) was administrated (first administration/dose date). Day 1 is the day of 
the first dose of study treatment in Cycle 1.  
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. 
 
4.1.1.2. 
Last Dose Date 
Last dose date is defined as the date of the last dose of study treatment received.   
For patients on treatment at the time of analysis prior to database lock, the last dose date is the date 
of the most recent study visit date in the database. 
4.1.1.3. 
Date of Last Known Alive 
The date of last known alive is defined as the last alive date of contact from the end of study page 
on the eCRF. For patients ongoing at time of analysis, the date of last known alive is the date of 
the most recent study visit date in the database. 
More specifically, the last known alive date will be derived for subjects not known to have died 
at the analysis cut-off date using the latest date (including complete and partial date with Month 
and Year information) among the following data: 
x 
All assessment dates (e.g. laboratory, vital signs assessments, ECG, ECOG, performance 
status assessment, tumor assessment dates etc.). 
x 
Medication dates including study medication, concomitant medications, anticancer 
therapies administered after study treatment discontinuation. 
x 
Adverse events start and end date, and the date of adverse event becoming serious. 
x 
Date latest known alive collected during the survival follow-up. 


 
 
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x 
Randomization date.   
 
After sorting properly for all those available dates, if the last last known alive date is a partial 
date with Month and Year information, day will be imputed as 15, unless this is after the cut off 
date in which case the cut off date will be used as last alive date. 
 
4.1.1.4. 
Date of Death 
Date of death is defined as the date of death from the Death Detail page on the eCRF.  Date of 
death is cross-checked with AEs where outcome is ‘Fatal’, if applicable. In rare case, if year and 
month of death date are known but the day is unknown, day will be imputed as 15. For example, 
if a patient is reported to die on Dec2017, the death date will be imputed as 15 Dec2017 (this is 
assuming there is no evidence patient was alive on the 15th based on date last known alive or 
most recent study visit date). 
4.1.1.5. 
Study Day 
The study day is determined relative to the date of the first dose of study treatment.  The day of 
the first dose of study treatment is defined as study day 1.  The day prior to the first dose of study 
treatment is study day -1.  There is no study day 0. 
For events that occur before the first dose of study treatment:  
study day = date of the event – first dose date;  
For events that occur on or after the first dose of study treatment:  
study day = date of the event – first dose date + 1. 
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, 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. 


 
 
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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. 
 
4.2. 
Exposure Endpoints 
Drug exposure, including number of cycles received, total duration of exposure, cumulative dose 
received (mg), dose intensity, and relative dose intensity of surufatinib will be calculated as per 
algorithms included in Table 4.  
Table 4 
Extent of Exposure Parameters 
Parameter 
Definition  
Duration of Exposure (days) 
Last dose date of study treatment from the last cycle – first 
dose date of study drug + 1. 
Number of Days with Recorded 
Dose  
Sum of days with recorded doses 
Number of Cycles Treatment 
Received 
Patients are considered to have started a cycle if they have 
received at least one dose of any study treatment. 
Number of Cycles Treatment 
Received Categories 
1, 2, 3, 4, 5, 6 and > 6 
Cumulative Dose (mg) 
Sum of doses administered in all cycles. The total dose 
administered in each cycle is defined as: the sum of 
(number of 300 mg capsules taken) where number of 
capsules taken = total capsules dispensed – total capsules 
returned. 
Dose Intensity (mg/day) 
Cumulative Dose (mg) / Duration of Exposure (day). 
Relative Dose Intensity (%) 
100 * [Dose Intensity (mg/day) / (300 × 28/28 (mg/day))]   
 
Drug accountability data will be used to calculate the total dose administered (mg) for each cycle 
for surufatinib.  The number of capsules taken for each dose level will be calculated as total 
capsules dispensed – total capsules returned in a cycle.  The total dose administered (mg) in a 
cycle will be the sum of 50 mg capsules taken. 
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).  
Dosing interruption: number of patients with any dosing interruption and reasons for dosing 
LQWHUUXSWLRQ DQG FDWHJRUL]HG IUHTXHQF\ RI GRVLQJ LQWHUUXSWLRQV     
Dose reduction: number of patients with any dose reduction and reasons for dose reduction, and 
categorized frequency of dose reduction (0, 1, 2, 3).  
 


 
 
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4.3. 
Safety Endpoints  
Safety endpoints include adverse events, serious adverse events, adverse events of special interest, 
laboratory results and abnormalities, physical examination findings, vital signs, ECG, 
Echocardiograms/MUGA and incidence of patients experiencing dose modifications (including 
dose reductions and dose delays) and/or dose discontinuation of study drug (and reason for 
discontinuation). 
4.3.1. 
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 treatment emergent adverse event (TEAE): 
 
1)  If the onset date is on after the start of study treatment 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.  
Other AE variables include treatment-related AEs, AEs leading to study drug modifications (i.e. 
dose interruption, dose reduction, or study drug withdrawal), AEs leading to study 
discontinuation, AEs leading to death, and SAEs.  
An AE is considered treatment-related in the summaries if it is assessed as related to study drug 
by the investigator 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.   
 
COVID-19 related AEs will be identified based on recorded verbation term and/or coded preferred 
terms. 
For AEs which are not on-going, duration of AE (days) is defined as AE end date – AE start date 
+1; for on-going AEs, the end date will be listed as ‘Ongoing’ and the duration of AE (days) will 
EH DSSUR[LPDWHG DV µ GDWH RI ODVW YLVLW – AE start date +1’. 
 
 
 
 


 
 
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AEs of Special Interest (AESI)  
AEs of special interest (AESI) will be identified based on the searching strategy listed in 
Appendix 2. AESIs will be extracted from MedDRA 27.0 by referring to the standardized 
queries in the table.  The SMQ code only consider a ‘narrow’ scope, i.e. category A terms.   
AESIs for surufatinib include drug related hepatic disorder, hypertension, haemorrhage, and acute 
renal failure. 
 
4.3.2. 
Laboratory 
Blood and urine samples for the determination of hematology, clinical chemistry, coagulation, 
thyroid function, lipid panel and urinalysis laboratory variables described in Table 5 will be 
measured. 
Table 5 
Laboratory Assessment 
Laboratory Category 
Parameters 
Hematology 
Complete blood count, including Red Blood Cell Count (RBC), haemoglobin, 
haematocrit, white blood cell count with differential and platelet count. 
Coagulation Assay 
PT/INR and aPTT. 
Blood Chemistry 
Blood urea nitrogen, creatinine, sodium, potassium, chloride, bicarbonate, calcium, 
magnesium, phosphate, 
glucose, 
total 
bilirubin, direct 
bilirubin, 
Alanine 
aminotransferase (ALT), Aspartate transaminase (AST), alkaline phosphatase, lactic 
dehydrogenase, amylase, total protein, albumin, and uric acid 
Thyroid Function 
Thyroid-stimulating hormone, free triiodothyronine, free thyroxine 
Lipid Panel  
Total cholesterol and triglycerides.  
Urinalysis 
pH, glucose, protein, and blood. 
 
Change from baseline in laboratory test results to each assessment will be calculated.  
The non-protocol specified tests (if any reported) and urinalysis results 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. 




 
 
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Twelve-lead ECGs will be performed according to the time points in Table 2 for Cohorts A, B, 
and C and Table 3 for Cohort D of the study protocol. The QTcF will be closely monitored.  
In addition, a continuous 12-lead Holter monitor will be used for corrected QT interval (QTc) 
evaluation during cycle 1 in patients enrolled across Cohorts A, B, and C. The goal will be to 
enroll and assign patients to Holter monitoring until approximately 40 patients have adequate 
ECG measurements at baseline, cycle 1 day 1, and cycle 1 day 15. The results will be sent for 
central reading (see below in Continuous 12-Lead Holter Monitor for QTc Evaluation for 
details).  
4.3.4. 
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 7.  
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 7 
Potentially Clinically Significant Criteria for Vital Signs 
Variable 
Criterion value   
Weight (kg) 
Percentage increase from baseline of 
ޒ 5%  
  – < 10%  
  - < 20%  
  
Percentage decrease from baseline of 
ޒ 5%  
  – < 10%  
  - < 20%  
  
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) 
 


 
 
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4.3.5. 
ECOG Performance Status 
Eastern cooperative oncology group (ECOG) performance status (PS) scores will be evaluated 
by the same Investigator throughout the study.  Details on the ECOG assessment and grading 
scale are available in following Table 8. 
Table 8 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Activity Level 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or chair 
5 
Death 
 
 
4.3.6. 
Echocardiogram (ECHO) 
ECHOs will be performed at Screening, every 12 weeks thereafter and at unscheduled visits.  
Assessment parameters include left ventricular ejection fraction (%) and overall interpretation of 
cardiac function. MULTIGATED ACQUISITION (MUGAs) are permitted if ECHOs cannot be 
performed.   
4.3.7. 
Physical Examination 
A comprehensive physical examination (PE) will be performed 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 are to be reported as AEs (post-baseline) or 
medical history (screening). 
 


 
 
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4.4. 
Efficacy Endpoints 
4.4.1. 
Primary Endpoint 
The primary endpoint of the study is Disease Control Rate (DCR) at 6 months. DCR is defined as 
the proportion of patients achieving a best overall response of confirmed CR, PR, or SD, per 
RECIST v1.1, as determined by the Investigator.  
4.4.2. 
Secondary Endpoints 
4.4.2.1. 
Objective Response Rate  
ORR is defined as the proportion of patients with a best overall response (BOR) of complete 
response (CR) or PR per RECIST Version 1.1. Both confirmed and unconfirmed responses will 
be evaluated. To be assigned a status of confirmed PR or CR, changes in tumor measurements 
must be confirmed by repeat assessments performed at least 4 weeks after the criteria for response 
are first met. 
 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.  
BOR will be determined using time point responses (TPRs) up until the last evaluable TPR prior 
to or on the date of (i) disease progression as defined by RECIST Version 1.1 Eisenhauer et al., 
2009) or death; or (ii) withdrawal of consent; whichever is earlier. 
The timing of an overall TPR will always be derived based on scan dates not response assessment 
dates. For a scheduled tumor scan assessment, it is expected that there may be a variation for the 
actual timing of scans among target, non-target, and new lesions. In assigning a date for the overall 
response assessment at a visit, the earliest date collected at that visit will be used. Within a grouped 
timepoint, if there are multiple assessments on different dates for the same target lesions, the last 
assessment will be used. A patient’s BOR will be determined based on Table 9.   
There are two ways of assigning BOR for a patient when the minimum interval for confirmation 
of CR and PR is not satisfied or if there are no confirmatory scans for CR and PR: 


 
 
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x Adding two more response categories as: unconfirmed CR, unconfirmed PR; 
x Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, 
Confirmed PR, SD, PD, or Not Evaluable (NE)) will be summarized.  
Table 9 
Best Overall Response When Confirmation of CR and PR are Required, also 
Includes Unconfirmed CR and PR 
 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time 
Point 
Best Overall Response* 
for ORR 
Best Overall 
Response for 
ORR UNCONFIRMED 
CR 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
Unconfirmed CR 
CR 
SD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
Unconfirmed CR 
CR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
Unconfirmed CR 
CR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise NE 
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
Unconfirmed PR 
PR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
Unconfirmed PR 
PR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise NE 
Unconfirmed PR 
NE 
NE 
NE 
NE 
CR=complete response; NE=inevaluable; PD=progressive disease; PR=partial response, SD=stable disease. 
1. 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
2. 
* A best overall response of SD can only be made after the subject is on study for a minimum of 49 days (counted from 
Cycle 1 Day 1).  If the subject is on study for less than 49 days, any tumor assessment indicating stable disease before 
this time period will have a best response of NE unless PD is identified.  
 
 
4.4.2.2. 
Time to Response 
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), 


 
 
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according to RECIST v1.1.  It will be calculated for patients whose BOR is either CR or PR (ie, 
responders). 
 
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 will 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 as the response date for confirmed responder. 
 
4.4.2.3. 
Duration of Response 
DoR is defined as the time (months) from the first time that the objective response reaches CR or 
PR, whichever comes first, until the occurrence of PD or death (if the death of the patient occurs 
before recording PD). Only those patients with confirmed responses of CR or PR will be included 
in calculating DOR. Censoring will follow the rules outlined for PFS in Table 10. DoR is calculated 
as (date of death or PD [or last assessment if censored] – date of first occurrence of confirmed CR 
or PR + 1)/30.4375.  Duration of response based on unconfirmed responses will also be 
summarized.  
4.4.2.4. 
Progression Free Survival  
PFS is defined as the time (months) from the start of study drug until the first objective disease 
progression as defined by RECIST v1.1, or death, whichever comes first.  More specifically, PFS 
will be determined using all the assessment data up to 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; whichever is earlier. Patients without report of PD or death from any cause at the time of 
analysis are censored as described in Table 10 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: 
1. Date of progression is determined based on the earliest of the dates of the component that 
triggered the progression. 
2. When censoring a patient for PFS, the patient is censored at the latest of the dates 
contributing to a particular overall visit assessment. 
 


 
 
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Table 10 
Censoring Rules for PFS 
Rule  
Situation 
Date of Progression or Censoring 
Outcome 
1 
PD documented between scheduled 
radiological assessment visits 
Date 
of 
first 
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 
first 
documented 
disease 
progression 
Event 
4 
No 
baseline 
nor 
post-baseline 
radiological assessments available 
Date of first dose  
Censored 
5 
No death nor PD by the time of data cut-
off for final analysis 
Date 
of 
last 
adequate 
radiological 
assessment 
Censored 
6 
Drops out before end of study 
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 126 days (=2* (8 weeks *7+ 7 
days)) since previous evaluable RECIST 1.1 or baseline assessment if there is no post baseline 
tumor assessment. 
 
4.4.2.5. 
Overall Survival 
OS is defined as the time (months) from 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. 
Patients with no event during the study will be censored at the date last known to be alive.  


 
 
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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: 
x All assessment dates (e.g. laboratory, vital signs assessments, ECG, ECOG, performance 
status assessment, tumor assessment dates etc.). 
 
x Medication dates including study medication, concomitant medications, anticancer 
therapies administered after study treatment discontinuation. 
 
x Adverse events start and end date. 
 
4.5. 
Other Endpoints  
4.5.1. 
Pharmacokinetic Endpoint 
The PK endpoint to be covered in this SAP includes surufatinib plasma concentrations in 
individual patients from Cohorts A, B and C primarily. In each cycle, PK samples will be collected 
as per Table 3 of the study protocol. Plasma concentrations of surufatinib for individual patients 
in Cohort D, transferred after the cut-off date of 18-May-2023 (see Section 6.2), will be listed but 
not summarized.  
4.5.1.1. 
Handling of Missing Plasma Concentration Data 
Missing concentration data for all patients who are administered scheduled study treatments is 
considered as non-informative missing and is not imputed. No concentration estimates are 
provided for missing sample values. 
4.5.1.2. 
Handling of Below the Lower Limit of Quantification (BLQ) Data 
For PK concentration summary, the following rules apply: 
x For predose samples on C1D1, PK concentrations below the BLQ are set to zero; 
x For samples at all other timepoints, BLQ values will be set to 0.5*lower limit of 
quantitation (LLOQ; 1.00 ng/mL). 
4.5.1.3. 
Handling of the Difference between the Scheduled (nominal time) and the 
Actual Sampling Time (actual time) 
For all sampling times, the actual sampling times relative to dosing are calculated as the difference 
between the actual clock time of sampling and the actual clock time of dosing.  The actual post-
dose sampling times relative to dosing expressed in hours and rounded off to two decimal digits 
are used, except for pre-dose samples occurring prior to dosing, which are reported as zero (0.00), 
regardless of the time difference.  Scheduled sampling times are listed but will not be summarized.  
If the actual time of sampling is missing, it will be reported as NR (not recorded) in the listing, the 
nominal time is used for summary statistics. 


 
 
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5. ANALYSIS METHOD 
5.1. 
General Principles  
5.1.1. 
General Methodology 
In general, all efficacy, safety and PK variables 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 variables will be analyzed using Kaplan-Meier method and summarized with median, 
25% and 75% percentiles with their corresponding 95% confidence intervals (CIs) which are 
calculated using log-log transformation based on the method by 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).  
For continuous data, unless otherwise specified, the mean, median, Q1, and Q3 will be presented 
with 1 more significant digits than the original values, and standard deviation and standard error 
(SE) 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 1 decimal place. Percentages will be reported with 1 decimal point; if the 
count is 0, no percentage will be presented. Value of percentage less than 1% will be presented as 
³´ 9DOXH RI SHUFHQWDJH OHVV WKDQ  EXW   ZLOO EH SUHVHQWHG DV ³!´ $Q\
rounding will be done after all calculations are made. 
5.1.2. 
Handling Missing Data 
Missing data is assumed to be missing at random.  Category ‘Missing’ is displayed for qualitative 
assessments, where applicable. 
There is no imputation of missing data for the analysis purpose, unless otherwise stated. 
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 for the method of imputation of missing AE onset 
and stop date and for the method of imputation of missing concomitant onset and stop dates. 
However, the imputed dates will not be shown in listings. 


 
 
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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 and 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; 
 
If the AE onset date is partially 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 
(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 use 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”. 


 
 
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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. 
5.1.3. 
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. 2. During Cycle 1, the visit window will be ±1 day (unless 
otherwise noted). From Cycle 2 onward, the visit window will be ±3 days (unless otherwise noted). 
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 patients 
listings.  
For windowed visits during the treatment cycles, if more than 1 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 treatment 
completion visit, 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 end of treatment visit will be "last dose date of last cycle to last 
dose date of last cycle + 37 days". 




 
 
 
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5.1.4. 
Adjustment for Covariates 
Not Applicable.   
5.2. 
Analysis Methods  
5.2.1. 
Patient Disposition 
The following summaries will be presented by cohort and overall to reflect the patient disposition: 
 Number of patients who signed the informed consent  
 Number and percentage of screen failures  
 Reason for screen failure 
 Number and percentage of patients who do not receive study treatment  
 Number and percentage of patients who received study treatment  
 Number and percentage of patients still on treatment at the time of analysis data cutoff  
 Reason for treatment discontinuation 
 Number and percentage of patients who discontinue the study 
 Reason for study discontinuation 
For patients screened but not enrolled and for the reasons for not being enrolled the denominator 
used to calculate the percentage will be the number of screened patients. For all other calculations 
the denominator will be the number of patients enrolled. 
A separate table will be presented to show the patients included in each analysis set and proper 
reasons for exclusion from an analysis set. 
5.2.2. 
Protocol Deviation 
Protocol deviations will be summarized descriptively as number and percentage of patients with 
at least 1 major protocol deviation and patients with at least 1 major protocol deviation related to 
COVID-19 for each cohort and overall in the Safety population. A patient may have multiple major 
and/or minor deviations and will be counted once per major and/or minor deviation. 
A listing of protocol deviations, including COVID-19-related protocol deviations will be 
provided. 
5.2.3. 
Demographic and Other Baseline Characteristics 
The following parameters will be summarized descriptively for each cohort and overall for the 
Safety analysis set. 
x Age at Screening (years) 
x Sex (Female, Male); If female, Child Bearing Potential status. 
x Race (American Indian or Alaskan Native, Asian, Black or African American, Native 


 
 
 
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Hawaiian or Other Pacific Islander, White, Not Reported, Unknown, and Other). 
x Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown)  
x Baseline Height (cm) 
x Baseline Weight (kg) 
x Baseline BMI (kg/m2): calculated as Weight at Baseline (kg)/ [Height at Baseline (m)]2 
x Baseline ECOG Performance Status: 0, 1 
Age (years) at screening is calculated by site personnel from the ICF date and recorded on eCRF. 
Demographic data and baseline characteristics, informed consent data, and inclusion/exclusion 
criteria will be listed by patient. 
5.2.4. 
Disease Characteristics  
History of cancer of the safety analysis will be summarized descriptively for each cohort for the 
following: 
x Time (months) since first diagnosis of cancer (calculated as date of first dose of treatment 
– date of first diagnosis of cancer + 1)/30.4375   
x Stage of cancer at first diagnosis (stage I, stage II, stage III, stage IV) 
x Grading of cancer at first diagnosis (Grade I, Grade II, Grade III) 
x Time (months) since date of diagnosis of locally advanced or metastatic disease (calculated 
as date of first dose of treatment – date of diagnosis of locally advanced or metastatic 
disease + 1)/30.4375   
x NET functional status 
x Anatomical location of primary tumor  
5.2.5. 
Medical History  
Conditions/diseases from medical history can either be ongoing prior to study entry or have 
stopped prior to 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 cohort and overall using 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 overall 
column and PT within each SOC. If the frequencies tie, an alphabetic order will be applied.  


 
 
 
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5.2.6. 
Prior Anti-Cancer Therapy 
Prior anti-cancer therapy, including mediation, radiotherapy, and procedure or surgery, will be 
summarized descriptively by cohort and overall for the safety analysis set. 
5.2.6.1. 
Prior Anti-Cancer Medication 
Prior anti-cancer medications are defined as those taken by the patient prior to the administration 
of study drug.   
Prior 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 overall column and PT within each ATC. If the frequencies tie, 
an alphabetic order will be applied.  
All prior anti-cancer medications will be presented in patient listing. 
5.2.6.2. 
Prior Anti-Cancer Radiotherapy 
Prior anti-cancer radiotherapy is defined as those taken by the patient prior to the administration 
of study drug.  
The number and percentage of patients with at least one prior anti-cancer radiotherapy will be 
summarized.  
All prior anti-cancer radiotherapy will be presented in patient listing.  
 
5.2.6.3. 
Prior 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.   
Prior 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 overall column and 
PT within each SOC. If the frequencies tie, an alphabetic order will be applied.  


 
 
 
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All anti-cancer procedure or surgery will be presented in a patient listing. 
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 overall 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 
The following summary for dose exposure will be summarized for each cohort:  
o Duration of exposure for surufatinib.  
o Number of days with recorded dose (actual duration of exposure) 
o Number of surufatinib treatment cycles received.  


 
 
 
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o Number and percentage of patients with 1, 2, 3, 4, 5, 6 , >6 cycles received 
o Cumulative dose for surufatinib. 
o Dose intensity of surufatinib. 
o Relative dose intensity of surufatinib.  
The following summary for dose adjustment will be summarized for each cohort: 
o Number and percentage of patients with any dose modification (including both drug 
interruption and dose reduction). 
o Frequency of dose modification: 0, 1, 2, 3, 4, 5, 6, > 6. 
o Drug interrupted (number and percentage of patients experienced drug interruption 
and reasons for drug interruption; frequency of drug interruptions). 
o Drug withdrawn (number and percentage of patients experienced drug withdrawn 
and reasons for drug withdrawn). 
o Dose reduced (Number of patients with any dose reduction and reasons for dose 
reduction; and frequency of dose reduction:    ), also the dose reduction 
category will be summarized (from 300mg QD to 250mg QD, from 250mg QD to 
200mg QD, from 200mg QD to 200mg on reduced schedule). 
Study treatment accountability, study treatment administration and extent of exposure will be 
listed by patient and visit. 
5.2.10. 
Safety Analyses 
Safety data during the treatment period will be evaluated and reported by cohort. 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 last dose. 
5.2.10.1. 
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: 


 
 
 
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Group 
Summary Scope 
All TEAEs 
 &7&$( *UDGH  $(V  
 Treatment-related AEs   
 AEs Leading to Dose Reduction 
 AEs Leading to Dose Interruption  
 AEs Leading to Treatment Discontinuation  
 Tteatment-related AEs Leading to Dose Reduction  
 Treatment-related AEs Leading to Dose Interruption 
 Treatment-related AEs Leading to Treatment 
Discontinuation 
 AEs Leading to Death 
Serious TEAEs 
 &7&$( *UDGH  6$(V 
 Treatment-related SAEs 
 SAEs Leading to Dose Reduction  
 SAEs Leading to Dose Interruption  
 SAEs Leading to Treatment Discontinuation  
 Treatment-related SAEs Leading to Dose Reduction  
 Treatment-related SAEs Leading to Dose Interruption 
 Treatment-related SAEs Leading to Treatment 
Discontinuation  
 SAEs Leading to Death 
Treatment-Emergent AESIs 
 
 &7&$( *UDGH  $(6,V  
 Treatment-related AESIs 
 AESIs Leading to Dose Reduction  
 AESIs Leading to Dose Interruption  
 AESIs Leading to Treatment Discontinuation  
 Treatment-related AESIs Leading to Dose Reduction  
 Treatment-related AESIs Leading to Dose Interruption  
 Treatment-related AESIs Leading to Treatment 
Discontinuation  
 AESIs Leading to Death   
 
COVID-19-related TEAEs    &7&$( *UDGH   
SAEs &7&$( *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 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. 


 
 
 
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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. 
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, AEs leading to death, AEs leading to dose 
reduction, AEs leading to dose interruption, and AEs leading to study drug discontinuation will 
be provided. 
5.2.10.2. 
Death 
Number of deaths, primary cause of death and whether autopsy was performed will be summarized 
descriptively for each cohort.  Deaths occurring during the treatment period will also be tabulated.  
Date of death will be provided in patient list in which the on-treatment death will be flagged. 
5.2.10.3. 
Laboratory Evaluations 
Summary tables for hematology, blood chemistry, coagulation, thyroid function, lipid panel and 
urinalysis (pH only) laboratory variables include descriptive statistics for result values and change 
from baseline for all continuous variables by visit and cohort.   
Toxicities for clinical labs will be characterized according to CTCAE and the frequency and 
percentage of patients with each CTCAE grade for each visit during the treatment period will be 
summarized. Any occurrence of toxicity grade 3 or grade 4 during the overall treatment period 
will be summarized. Shift in toxicity 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.  For some specific parameters with CTCAE grading in both high and low 
direction (e.g., calcium, glucose, magnesium, potassium, sodium), CTCAE in high and low 
directions will be presented separately, i.e. hyper for higher values of concern and hypo for lower 
values of concern.  
Qualitative assessments of urinalysis parameters are summarized for all patients using the number 
of patients with results of negative, trace, or positive. 
Summary of clinical significance (Abnormal not clinically significant [NCS] and Abnormal 
Clinically significant [CS]) is also provided by visit and treatment group. Shift from baseline to 
the worst post-baseline investigators’ assessment (i.e. normal, NCS, and CS for quantitative 
measurements and categorical measurements). 
All laboratory results (including hematology, blood chemistry, blood chemistry – thyroid function, 
urinalysis, coagulation, pregnancy test data) in SI units are presented in data listings.  Tests are 
listed in alphabetical order within their respective panels (hematology, blood chemistry, urinalysis, 
and coagulation). 


 
 
 
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A summary table and listing will also be provided for treatment-emergent liver injury by each 
cohort based on the pre-specified thresholds below: 
1. Potential Drug-Induced Liver Injury (DILI): AST and/or ALT > 3x ULN and total bilirubin 
> 2x ULN 
2. Hy's Law criteria: AST and/or ALT > 3x ULN and total bilirubin > 2x ULN and ALP < 2x 
ULN 
Listings of all laboratory data with normal reference ranges, and CTCAE grades (when possible) 
will be provided.  
5.2.10.4. 
ECG 
Descriptive statistics will be presented for each ECG parameter for the observed values and change 
from baseline to post baseline.  
The criteria for potentially clinically significant findings are defined in table 6. The frequency and 
percentage of patients with any potentially clinically significant findings during the induction 
treatment period will be presented. The supportive data will be provided in patient data listings.  
The minimum, and maximum, and their corresponding change from baseline ECG parameter 
values will be summarized descriptively overall treatment period for each cohort. 
Single 12-lead ECG interpretations by investigator data are listed by patient and visit. 
5.2.10.5. 
Vital Signs 
For vital sign parameters (Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, 
Temperature and Respiratory Rate) 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 (Table 7 Section 3.5.4) during the overall treatment period will be presented. A listing of 
all vital sign data will be provided.  
The minimum, maximum, and their corresponding change from baseline vital sign values will be 
summarized descriptively overall treatment period for each cohort. 
A listing of vital sign data will be provided. 
5.2.10.6. 
Performance Status 
The frequency and percentage of patients for each ECOG score level will be summarized by each 
visit and by maximum post-baseline score during the treatment period. Shift in grade from baseline 
to the maximum post-baseline score will be summarized.  


 
 
 
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A listing of ECOG score for all patients will be provided. 
5.2.10.7. 
Echocardiogram 
Descriptive statistics for Echocardiogram/MUGA will be summarized by visit. A by-patient 
listing of Echocardiogram/MUGA values at each time point will be generated. 
ECHO/MUGA data is listed by patient and visit. 
5.2.10.8. 
Physical Examination 
A listing of physical examination data for all patients will be provided. 
 
5.2.11. 
Efficacy Analyses 
5.2.11.1. 
Primary Efficacy Analyses 
The primary endpoint of DCR at 6 months is defined as the proportion of patients at 6 months 
whose best overall response from baseline is either a CR, PR, or SD per RECIST Version 1.1. To 
be assigned a status of PR or CR, changes in tumour measurements must be confirmed by repeat 
assessments performed at least 4 weeks after the criteria for response are first met. The estimated 
DCR and the corresponding 95% CIs based on the Clopper-Pearson method will be provided for 
each cohort.  
Tumor evaluation data will be presented in listings. 
5.2.11.2. 
Sensitivity Analysis for Primary Efficacy Endpoint 
Not Applicable. 
5.2.11.3. 
Multiplicity Control  
Not applicable. 
5.2.11.4. 
Secondary Efficacy Analyses 
The estimate for ORR and the corresponding 95% CIs based on the Clopper-Pearson method will 
be provided for each cohort.  Both confirmed and unconfirmed ORR will be presented. 
For time to event endpoints (TTR, DoR, and PFS), the median, 25th and 75th percentile of time-
to-event will be estimated using Kaplan-Meier method with their corresponding 95% CI. 
Additionally, estimates will be provided for the survival probability along with their 95% CIs 
which are calculated using log-log transformation based on the method by Brookmeyer and 
Crowley (1982) at selected landmarks, for example, at 3, 6, 9, 12, and 18 months. The Kaplan-
Meier plots will be produced.  The duration of follow-up for PFS will be calculated descriptively 
using the Kaplan-Meier method, while using different censoring rule which reverses censoring 


 
 
 
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indicator instead, i.e. patients who have event will be censored at the date of event. Patients who 
are censored will assigned as “event”.  
5.2.11.5. 
Exploratory Efficacy Analyses 
The estimate for OS and the corresponding 95% CIs based on the Clopper-Pearson method will be 
provided for each cohort.   
The median, 25th and 75th percentile of OS will be estimated using Kaplan-Meier method with 
their corresponding 95% CI. Additionally, estimates will be provided for the survival probability 
along with their 95% CIs which are calculated using log-log transformation based on the method 
by Brookmeyer and Crowley (1982) at selected landmarks, for example, at 3, 6, 9, 12, and 18 
months. The Kaplan-Meier plots will be produced.   
5.3. 
Other Analyses 
Planned PK analyses for Cohort D will be presented in a separate analysis plan. The following 
sections describe the summary results and listings to be generated as part of this SAP. 
5.3.1. 
Listing and Presentation of Individual PK Data 
PK data will be presented by cohort, patient, cycle and day (for instance, C1D1, C1D21, C2D1, 
etc.), and time point.  
1. Concentration data are presented to the same decimal place and in original units as reported by 
the bioanalytical lab, e.g., ng/mL;  
2. Listing of PK sampling times including nominal and actual time elapsed from dose with the 
deviation from the nominal time; 
3. Concentration data of surufatinib for individual patients in Cohort D, transferred after the cut-
off date of 18-May-2023, will be listed.  
5.3.2. 
Summary of PK Concentration Data  
The observed concentrations are summarized descriptively at each scheduled timepoint and dose 
level. Summaries are presented by cohort (A, B and C only), cycle and day (for instance, C1D1, 
C1D21, C2D1, etc.) and time point using descriptive statistics.  
If the time deviation is greater than ± 20% from nominal time, the PK concentration value is 
excluded from the summary descriptives.  
PK plasma concentration data at each scheduled timepoint and dose level is presented using the 
following descriptive statistics.  
x n  
x arithmetic mean and standard deviation (SD)  


 
 
 
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x geometic mean and geometric (CV)% 
x coefficient of variation (CV)%  
x median  
x minimum and maximum  
x number and percent of patient with BLQ  
 
The conventions presented in Table 12 below are used for the presentation of the descriptive 
statistics of plasma concentrations.  
Table 12 
PK Concentration Data Reporting Precision 
Variable  
Summarized with:  
Minimum, Maximum 
3 significant digits  
Mean (arithmetic), Median  
3 significant digits  
StdDev  
3 significant digits  
CV%  
1 decimal point  
 
5.3.3. 
Pharmacodynamic (Electrocardiogram) Analysiss 
Patients who 1) receive at least 1 dose of study drug and 2) have baseline and at least 1 postdose 
ECG measurement will be evaluable for pharmacodynamic (ECG) evaluation. Patients who had 
reduced dosage, prolonged dose interruption of >2 days in cycle 1, any dose interruption within 7 
days before cycle 1 day 15 (+1 week), or were discontinued from the study prior to the 
completion of ECG data collection (cycle 1 day 15 [+1 week]) will be excluded. For each of the 
ECG parameters, the average values from the 3 readings of a triplicate ECG set will be used in 
the analysis. 
For all ECG parameters, the baseline will be defined as the mean values of the triplicate ECG 
measurements taken at predose on cycle 1 day 1. 
 
5.3.4. 
Corrected QT Intervals  
The terminology QTc is used in this section as a general notation for QTc using any of the 
specified methods.  
 
The QT interval data will be corrected for heart rate using 2 correction methods (Fridericia – 
QTcF and Bazett – QTcB). For each QTc correction method, the relationship between QTc and 
RR interval at baseline will be evaluated graphically by plotting the logarithm of baseline QTc 
values against the logarithm of corresponding RR intervals. Fridericia will be used as the 


 
 
 
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primary correction method for statistical analysis. If the correlation between QTc and RR 
intervals remains significant using the Fridericia correction method, an alternative correction 
method may be considered for statistical analysis in addition to QTcF.  
 
For the statistical analysis based on the primary correction method (QTcF), the mean changes 
IURP EDVHOLQH ǻ47F DW HDFK WLPH SRLQW ZLOO EH VXPPDUL]HG PHDQ VWDQGDUG GHYLDWLRQ PHGLDQ
and range, and 2-sided 90% CI). Mean values for the difference and 2-sided 90% CI for mean 
difference will be calculated at each time point. Additionally figures for the change from 
baseline, over time, will be presented for QTcB and QTcF. 
 
In addition, QTc will be categorized based on International Council for Harmonisation (ICH) 
E14 guidelines. Tables will present the number and percentage of patients meeting or exceeding 
the following categories:  
 
• 
QTc prolongation: 
í $EVROXWH YDOXHV ! WR  PVHF  
í $EVROXWH YDOXHV ! WR  PVHF  
í Absolute values >500 msec  
 
•  
QTc change from baseline:  
í ,QFUHDVH IURP EDVHOLQH ! WR  PVHF  
í Increase from baseline >60 msec  
 
5.3.5. 
Heart Rate, QRS, and PR Intervals  
For each treatment and time point of measurement, heart rate, QRS interval, and PR interval, as 
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summarized using descriptive statistics. The number and percentage of patients with heart rate 
>100 bpm will be tabulated for each time point. The number and percentage of patients with QRS 
>110 msec will be tabulated for each time point. The number and percentage of patients with PR 
>200 msec will be tabulated for each time point. 


 
 
 
H U T C H M E D Li mit e d 
St u d y Pr ot o c ol: 2 0 2 0- 0 1 2- 0 0 E U 1  
 
S A P V er si o n Dr aft 1. 0  
 
C O N FI D E N TI A L  
Pa ge 4 7 
 Date: 1 0 O C T O B E R 2 0 2 4 
 
 
 
 
 
6.  P L A N N E D A N A L Y SI S  
6. 1.  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
N ot A p plica ble. 
6. 2.  
Pl a n ne d I nteri m A n al ysis 
F or C o h ort D o nl y, o nce t he last patie nt e nr olle d t o t his c o h ort has c o m plete d t he re q uire d st u d y 
pr oce d ur es u p t o C ycle 1 Da y 1 7, a n i nteri m a n al ysis  is pla n ne d t o e val uate t he s h ort-ter m safet y 
a n d t he P K pr ofile. 
 
 
6. 3.  
Fi n al A n al ysis 
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 c o m pleti o n of eac h c o h ort, 
a n d t he fi nal a n al ysis of t he st u d y will be c o n d ucte d at t he ti me of a n al ysis of t he last c o h ort. All 
st u d y data c ollecte d u p t hr o u g h t he ti me of t he fi nal a nal ysis will be s u m marize d. 
C CI


 
 
 
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7. CHANGE FROM THE PROTOCOL 
Overal survival has been added as an exploratory endpoint. 
Proteinuria and thyroid dysfunction have been removed from the AESI section 3.5.1 of this SAP 
since they are already considered fully characterized and there are no new or additional 
mitigation activities.  
This is a change from the planned analysis specified in section 8.4 of the study protocol. 
 
 


 
 
 
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REFERENCE 
1 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. 
 
2 Brookmeyer R., and Crowley J. (1982). A confidence interval for the median survival time. 
Biometrics, 29-41 
 
3 Haberer 2014 Haberer LJ, McSherry I, Cargill A, McCarthy L. Effects of vercirnon on the   
activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 
transporters using probe substrates. Eur J Clin Pharmacol. 2014;70(1):37-45 
 
4 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Guidance for 
Industry. Food and Drug Administration December 2018  
 
5 Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0, November 27, 
2017