Clinical trial NCT02549937
Conditions: Tumors
Keywords: biliary pancreatic neuroendocrine carcinoid PNET EP-NET extrapancreatic sarcoma soft tissue sarcoma STS BTC
Sponsor: Hutchmed
Start date: 2015-11-01; Completion date: 2023-06-02
Enrollment: 130 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Primary Objective Dose Escalation:

To evaluate the safety and tolerability of surufatinib in patients with advanced solid tumors and to determine the maximum tolerable dose (MTD) or recommended phase II dose (RP2D).

Primary Objective Dose Expansion:

To evaluate the anticancer activity of surufatinib in patients with advanced Biliary Tract Cancer (BTC), patients with advanced pancreatic neuroendocrine tumors (pNETs), patients with locally advanced, unresectable, metastatic extra-pancreatic neuroendocrine tumors (EP-NETs), and patients with soft tissue sarcomas (STS) treated at a dose of 300 mg QD.

Secondary Objective:

To evaluate the pharmacokinetic profile of multiple dose surufatinib in patients with advanced solid tumors and to evaluate the anti cancer activity of surufatinib in patients with advanced solid tumors.

Detailed description:
The study is an open-label, dose escalation and expansion clinical trial of surufatinib orally once daily (QD) in patients with advanced solid tumors.

The study consists of two phases:

Dose escalation phase - A 3+3 design will be used for this portion of the study.

* Approximately 15 to 35 evaluable patients will be enrolled. The actual number of patients depends on the Dose-limiting toxicity (DLT) situation as well as the RP2D dose level reached in this trial.
* The trial will approximately evaluate five surufatinib dose levels at 50,100, 200, 300 and 400 mg/day.

Expansion phase:

Approximately 115 patients will be enrolled into one of four open-label treatment arms during this phase: at least 30 patients with advanced BTC that has progressed on standard ﬁrst-line chemotherapy will be assigned to Arm A, at least 15 patients with advanced pNET that has progressed on either everolimus, sunitinib, or both will be assigned to Arm B, at least 15 patients with advanced EP-NET that has progressed on everolimus will be assigned to Arm C, and at least 45 patients with Soft Tissue Sarcoma will be assigned to Arm D. Subjects enrolled in this phase are to be evaluated for the safety, tolerability and pharmacokinetic (PK) characteristics to confirm the selected surufatinib dose.

Subjects will receive surufatinib daily treatment continuously with every 28-day treatment cycle until disease progression, death, or intolerable toxicity at the investigator's discretion for a favorable benefit to risk balance.

Arms: arm 1: Escalation cohort at 50 mg/day arm 2: Escalation cohort at 100 mg/day arm 3: Escalation cohort at 200 mg/day arm 4: Escalation cohort at 300 mg/day arm 5: Escalation cohort at 400 mg/day arm 6: Subjects will receive RP2D surufatinib daily treatment continuously with every 28-day treatment cycle. Four expansion cohorts will enroll BTC, pNET, EP-NET, and STS patients, respectively.
Interventions: intervention 1: surufatinib
Intervention descriptions: intervention 1: orally once daily (QD) in patients with advanced solid tumor.

Protocol documents:
Prot_000.pdf: 
Cli nic al St u d y Pr ot oc ol 2 0 1 5 -0 1 2 -0 0 U S 1  
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Clinical Study Protocol 2015-012-00US1 
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CONFIDENTIAL 
 
 
STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical Practice 
(GCP) as outlined by International Conference on Harmonisation (ICH) E6(R2), and all applicable 
local and national regulatory requirements.  Enrollment at any clinical study site may not begin 
prior to that site receiving approval from the ethics committee of record for the protocol and all 
materials provided to potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment.  Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The principal investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 


Cli nic al St u d y Pr ot oc ol 2 0 1 5 -0 1 2 -0 0 U S 1  
S ur uf ati ni b   
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H utc his o n M e di P h ar m a  
 
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C O N FI D E N TI A L  
 
 
S P O N S O R’ S A P P R O V A L  
Title  
A M ulti -Ce nter,  O pe n -La bel, Cli nical Trial t o E val uate t he Safet y, T olera bilit y, a n d 
P har mac o ki netics of S ur ufati ni b ( H M P L -0 1 2), Pre vi o usl y N a me d S ulfati ni b i n 
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N a me : [last na me, first na me] 
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Clinical Study Protocol 2015-012-00US1 
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INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study 2015-012-00US1 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and GCP as outlined 
by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those participants 
• To maintain records of each subject’s participation and all data required by the protocol 
 
Name: 
Title:  
Institution:  
 
 
 
Signature: 
Date:   
 
 
 


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DOCUMENT HISTORY 
Edition 
Amendment 
Date 
1.0 
Original 
15 Jan 2015 
1.1 
1 
15 Mar 2015 
1.2 
2 
17 Jun 2015 
1.3 
3 
31 Oct 2016 
1.4 
4 
16 Dec 2016 
2.0 
5 
8 Dec 2017 
3.0 
6 
30 May 2018 
4.0 
7 
25 Jan 2019 
5.0 
8 
4 Sep 2019 
5.1 
9 
27 Sep 2019 
6.0 
10 
28 Feb 2020 
 


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PROTOCOL AMENDMENT HISTORY 
Amendment 11 
Amendment Rationale 
This 2015-012-00US1 Amendment 11 replaces 2015-012-00US1 Amendment 10.  This 
amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The primary purpose of Amendment 11 is to correct text that was erroneously introduced and to 
update the protocol to match sponsor-approved format and language for clinical study protocols 
and to revise the protocol to comply with ICH E6(R2) guidance.  The changes made in this 
amendment are described in the table below.  Editorial and formatting changes are not included 
in this summary.  Previous amendments are detailed below in this section. 
Section 
Description of Changes 
Rationale for Change 
First page 
Revised Confidentiality Statement 
Align with updated sponsor-
approved template 
Statement of Compliance 
(section added) 
Added Statement of Compliance 
To add missing information for 
International Conference on 
Harmonisation (ICH) E6(R2) 
compliance 
Sponsor’s Approval 
Revised Sponsor’s Approval page 
Align with sponsor’s approved 
template 
Investigator’s Agreement 
Added Investigator’s Agreement page 
Align with sponsor’s approved 
template 
Document History 
Relocated and revised Document 
History to show each protocol 
amendment  
To align with sponsor’s approved 
template language and for 
compliance with ICH E6(R2) 
language 
Section 1 - Synopsis 
Updated Synopsis format and content 
To align with sponsor’s approved 
template language and for 
compliance with ICH E6(R2)  
Section 2.3 - Clinical 
Experience 
Updated information in the 
Background 
Align with sponsor’s approved 
template 
Section 4.2.3 - Secondary 
Objectives 
Added an efficacy objective to the 
Expansion Phase Secondary Objectives 
To add a secondary objective for 
efficacy correct a previous 
oversight and align with existing 
efficacy endpoints in the Expansion 
Phase 
Section 4.2.4 - Secondary 
Endpoints 
Changed order of Expansion Phase 
Secondary Endpoints  
To align with the order of the 
Secondary Endpoints in the 
Expansion Phase 
Section 4.2.5 - Exploratory 
Objectives 
Revised Exploratory Objectives in the 
Expansion Phase from evaluation of 
anticancer activity to evaluation of 
overall survival 
Clarification 
Section 4.2.6 - Exploratory 
Endpoints 
Revised text to state that efficacy 
would be evaluated in all 3 disease 
Clarification 


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Section 
Description of Changes 
Rationale for Change 
cohorts to ‘the biliary tract cancer 
(BTC), pancreatic neuroendocrine 
tumor , and extrapancreatic 
neuroendocrine tumor disease cohorts’ 
Section 5.1.1.2 - Definition of 
DLT Evaluable Patients 
Corrected definition of dose-limiting 
toxicity (DLT)-evaluable patients as an 
individual who has not received any 
preventive treatment during the DLT 
period 
Correction of error 
Section 5.1.2 - Dose Expansion 
Phase 
Removed text on Safety Review 
Committee (SRC) for the Dose 
Expansion Phase 
Text is redundant with Section 5.4 
Section 5.3 - Investigational Site 
Revised and updated maximum number 
of study sites to 15 sites 
Consistency with the informed 
consent form  
Section 5.4 - Safety Review 
Committee 
Revised text describing the SRC for the 
Dose Expansion Phase 
Clarification 
Section 7.1.6 - Dose and 
Administration 
Specified that for patients in the 
European Union, only 50 mg 
formulation capsules will be available 
Clarification 
Section 7.1.7 - Important Safety 
Risks 
Removed table of important identified 
risks and referred to the current 
Investigator’s Brochure 
Remove outdated information 
Section 10.1 - Determination of 
Sample Size (moved section) 
Moved section on sample size 
determination to beginning of 
Statistical Analysis section 
Align with sponsor’s clinical study 
protocol template 
Section 10.2 - Analysis 
Populations 
Clarified that efficacy endpoints, 
progression-free survival and overall 
survival for the BTC and soft tissue 
sarcoma cohorts will be analyzed using 
the Safety Analysis Set. 
Clarification 
Section 10.3 - Statistics and 
Analysis Method (revised 
header) 
Revised text in the Statistics and 
Analysis Method 
Revised header for align with 
sponsor’s protocol template.  
Revised text for improved clarity. 
Section 10.4 - Safety Analysis 
Specified that SRC decisions for the 
Dose Expansion cohorts will be based 
on clinical data presented to SRC 
members 
Clarification 
Section 10.6 - Tumor 
Assessment 
Specified that efficacy data from 
patients enrolled in the expansion phase 
at the recommended phase 2 dose will 
be presented by disease cohort 
Clarification 
Section 10.6.2 - Secondary 
Efficacy Endpoints 
Section 10.6.3 - Exploratory 
Endpoints 
Revised text on analysis of efficacy 
endpoints 
Clarification 
Section 11 - Ethics 
Section 12 - Oversight 
Revised Sections 11, 12, and 13, 
including all subsections 
Updated to align with sponsor’s 
approved template language and for 


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Section 
Description of Changes 
Rationale for Change 
Section 13 - Publication Policy 
compliance with ICH E6(R2) 
language 
Section 16 - Appendices 
(section added) 
Appendix 1 
Study 
Flowcharts (formerly Appendix 
A) 
Appendix 2 
ECOG 
Performance Status (formerly 
Appendix B) 
Appendix 3 
Response 
Evaluation Criteria in Solid 
Tumors Version 1.1 (formerly 
Appendix C) 
Appendix 4 
Guidelines for 
Interaction between Surufatinib 
and Concomitant Medication 
(formerly Appendix D) 
Appendix 5 
Guideline to 
Interpreting the Causality 
Question (formerly Appendix E) 
Appendix 6 
Prohibited 
Concomitant Medications That 
Have a Known Risk of QT 
Prolongation and/or Torsades 
DES Pointes (TDP) (formerly 
Appendix F) 
Appendix 7 
Clinical 
Evaluation of Possible Drug-
Induced Liver Injury (DILI) 
(formerly Appendix G) 
Appendix 8 
Conversion of 
Urinalysis Results Table 
(formerly Appendix H) 
Added level 1 section for appendices.  
Revised appendix numbering 
Align with sponsor’s clinical study 
protocol template 
 
 


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Protocol Amendment 10 (Version 6.0, 28 Feb 2020) 
Amendment Rationale  
The primary objective of this amendment is to include a section to highlight the benefit and risk 
assessment of surufatinib, allow the inclusion of Synovial Sarcoma patients, and to update the 
Investigator Brochure version referenced, along with supporting data. 
 
Section Number 
Description of Changes 
2.3 Benefit and Risk Assessment 
(new section) 
Section added as it was not included in previous version. 
5.1 Inclusion Criteria 
Addition of Synovial Sarcoma subtype in the STS arm (Arm 
D), along with applicable language throughout protocol.  
4.2 Sample Size 
Addition of 10 patients to Arm D 
3 Study Objectives and Endpoints 
Reorganized such that all endpoint subcategories (ie, safety 
endpoint, efficacy endpoint, pharmacokinetic endpoint) are 
grouped together under secondary endpoints.  This is to 
comply with endpoint categories defined in clinical trial 
registries. 
6.1.7  Important Safety Risks 
Table 5 
Table and risk language updated to align with current version 
of surufatinib Investigator Brochure (v9). 
6.1.4 
Clarified that room temperature for drug storage is between 
10℃ to 30℃ protected from light and moisture. 
9  Statistical Analysis 
Added that final analysis for each cohort will occur once the 
last patient had been followed for sufficient time for the 
analysis of primary endpoint. 
Appendix H new section 
Inclusion of a urinalysis conversion table for reference 
Throughout the document 
Editorial revisions were made for clarity and consistency. 
 


Clinical Study Protocol 2015-012-00US1 
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Protocol Amendment 9 (Version 5.1, 27 Sep 2019) 
Amendment Rationale  
The reason for this amendment is to update language in Table 9 of this protocol for clarity and 
consistency. 
 
Section Number 
 
Section Title 
Description of Changes 
6.2.2 
Table 9 Dose 
Modification for 
Proteinuria 
Clarifying language added to footnote a for 24-hour urine 
collection, as well as updated language to align with dose 
modification guidelines for grade 2 and 3 proteinuria. 
 


Clinical Study Protocol 2015-012-00US1 
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Protocol Amendment 8 (Version 5.0, 4 Sep 2019) 
Amendment Rationale  
The reasons for this amendment primarily concern: the addition of a sarcoma cohort and 
subtypes eligible for enrollment as well as the addition of the progression free survival rate at 4 
months as a primary endpoint during the dose expansion phase of the study, in the sarcoma 
cohort; and, to update the schedule of events to reflect overall survival follow up and to change 
tumor assessment timelines.  


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Section Number 
 
Section Title 
 
Description of Changes 
 
2.0 
Study Rationale 
Background information and rationale for sarcoma added 
3.2.2 
Primary Endpoints 
PFS rate at 4 months in the sarcoma cohort added 
3.2.3 
Secondary Objectives 
Added PK of patients with sarcoma as secondary objective 
3.2.4 
Secondary Endpoints 
Clarified secondary endpoints for anti-tumor efficacy would 
include: ORR, DCR, DoR, and percentage change in tumor 
size. 
3.2.5 
Exploratory Objectives 
Added to evaluate the anticancer activity of surufatinib in 
patients with advanced BTC and sarcoma 
3.2.6 
Exploratory Endpoints 
Added OS as an exploratory endpoint. 
3.2 
Dose Expansion Phase 
Removed duplicative language. 
4.4 
Safety Review 
Committee 
Added language clarifying the role of the Safety Review 
Committee during dose expansion. 
4.8 
End of Treatment 
(Individual Patient) 
Added additional guidance to clarify the end of study 
treatment for individual patients. 
9.6 
Sample Size 
Updated number of patients to be enrolled 
4.5 
Patient Discontinuation 
Added language clarifying that patients who discontinue 
protocol therapy for reasons other than progression should 
continue to under protocol defined tumor assessments per 
Appendix A until disease progression, start of new therapy, 
or withdrawal of consent. 
4.6 
Overall Survival 
Follow-up 
Added language for OS follow up. 
5.0 
Patient Selection 
Removed duplicative language 
5.1 
Inclusion Criteria 
Item #4, added sarcoma cohort and subtypes eligible for 
enrollment. 
7.3.3 
Study Completion/Early 
Termination Visit 
Added clarifying language regarding follow up for OS visit. 
8.1.2 
Adverse Events of 
Special Interest 
Added specific language to address how AEs of special 
interest should be defined and characterized. 


Clinical Study Protocol 2015-012-00US1 
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CONFIDENTIAL 
 
 
9.0 
Statistical Analysis 
Statistical analysis section revised to match primary and 
secondary objectives of study during dose escalation and 
dose expansion. Updated sample size requirements for the 
study and added specific requirements for Arm D (STS 
cohort). Updated primary and secondary efficacy endpoints. 
Added OS as an exploratory endpoint. 
10.0 
Ethics 
Updated the language pertaining to the ethical 
considerations in the study according to the new guidelines 
in ICH E6 (R2). 
Appendix A 
Study flowchart 
Updated to reflect OS follow up and to change tumor 
assessment timelines. 
 
Protocol Amendment 7 (Version 4.0, 25 Jan 2019) 
Amendment Rationale 
The reasons for this amendment primarily concern: an increase in the number of patients to be 
enrolled in Arm A (advanced biliary tract cancer [BTC]) from 15 to 30 in the dose expansion 
phase; the addition of a third group of patients (Arm C, n=15 patients with advanced 
extrapancreatic neuroendocrine tumors [epNETs]) to the dose expansion phase and to report the 
change in the international nonproprietary name (INN) from sulfatinib to surufatinib (see 
Summary of Changes below). 


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Section Number 
 
Section Title 
Description of Changes 
Not applicable 
Title page and 
throughout the 
protocol 
Changed the INN from sulfatinib to surufatinib. This 
information was published by the World Health Organization 
(WHO) on 31 October 2018 [1]. 
Synopsis, Section 1.3 
Clinical Experience 
Updated clinical experience per IB edition 8.0. 
Synopsis. Section 1.4 
Study Rationale 
Added text describing mechanism of action of surufatinib. 
Fifteen (15) additional patients, for a total of 30 patients, with 
advanced BTC to be enrolled in Arm A (BTC) of the 
Expansion Phase, based on encouraging preliminary results 
from the present trial. 
Synopsis, 
Section 3.1.1 
Dose Escalation 
Phase 
Added that the MTD/RP2D was declared as 300 mg QD 
during Cohort 7 of the dose escalation phase on 30 November 
2018.  
Synopsis, Section 1.4, 
Section 4.1, and 
Section 4.2 
Study Rationale 
Inclusion Criteria 
Exclusion Criteria 
Added a third arm (Arm C; patients with advanced 
extrapancreatic neuroendocrine tumors [epNETs]) to the dose 
expansion phase.  Added the inclusion and exclusion criteria 
for patients in Arm C. Removed the upper age limit on 
inclusion criteria. 
Synopsis and Section 2 
Study Objectives and 
Endpoints 
Consolidated the primary and secondary objectives and 
endpoints of the dose escalation and dose expansion phases 
under a single heading. 
Synopsis and Section 
3.2 
Sample Size 
Updated the total sample size in the dose escalation and dose 
expansion phases. 
Section 5.1.3 
Packaging and Drug 
Labeling 
Specified that the investigational drug is packaged in white 
HDPE bottle with 50 capsules per bottle (old formulation, 
PD-012-023) or 30 capsules per bottle (new formulation, PD-
012-042). Deleted expiry date from specifications for 
investigational drug label. 
Section 5.3.1 
Concomitant 
Therapies 
Added permitted concomitant medication (somatostatin 
analogues) for patients with functioning advanced pNETs 
(Arm B) or functioning advanced epNET (Arm C) and time 
frame for discontinuation of SSAs by patients with functioning 
pNETs or epNETs.  Specified INR range for patients taking 
Coumadin or warfarin-like drugs.  
Section 6.2.1 and Study 
Flowchart 
Tumor Assessment 
Clarified scans required at baseline 


Clinical Study Protocol 2015-012-00US1 
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Section Number 
 
Section Title 
Description of Changes 
Section 6.2.2 and Study 
Flowchart 
 
Exploratory 
Assessment of 
Circulating Tumor 
Markers 
Added Section 6.2.2 to specify the circulating tumor markers 
to be assessed, updated Study Flowchart to show the schedule 
of assessments of circulating tumor markers. 
Section 7.1.2 
Dose Limiting 
Toxicities 
Specified timeframe and procedures for reporting of DLTs. 
Section 8 
Statistical Methods 
Organized Section 8 to align it with the corresponding section 
of 2015-013-00US1. 
Section 8.1 
General 
Methodology and 
Study Endpoints 
Specified the primary efficacy endpoint for patients with 
advanced epNETs; specified that tumor markers are 
exploratory endpoints. 
Section 8.4 
Tumor Assessment 
Specified the analysis population for primary efficacy 
endpoints and defined the Response Evaluable Population.  
Specified the primary efficacy endpoint for patients with 
advanced epNETs 
Described the exploratory analysis of tumor marker data 
8.5 
Determination of 
Sample Size 
Specified that a cohort of at least 15 patients with advanced 
epNET will be added to the study (as Arm C of the dose 
expansion phase).  
Specified the definition of an evaluable patient. 
14 
References 
Added citations supporting discussion of surufatinib 
mechanism of action in Section 1.4. 
Appendix A 
Study Flowchart 
Added column for C1D16, pre-dose PK sample, and provided 
a copy of the PK sampling schedule sampling times. 
Added copy of Table 12 (PK Sampling Times) at the end of 
the study flowchart. 
 
 
Corrected spelling and/or grammatical errors in the document 
as needed. 
 
 
 
 


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CONFIDENTIAL 
 
 
Protocol Amendment 6 (Version 3.0, 30 May 2018):  
Summary of Changes: Protocol Amendment 6 (Version 3.030 May 2018) 
Specified initial dose of study drug in dose expansion phase as 300 mg QD. Per SRC review of data for patients 
treated with 300 mg QD, specified option of escalation to 400 mg QD for patients in dose expansion phase with 
decrease in tumor size but not enough to achieve CR or PR and no SAE or any AE ≥Grade 3 after 3 cycles on 300 
mg QD. 
Added 6 more patients in 400 mg cohort in the dose escalation phase 
Specified the study population, the target number of patients to be enrolled in the dose escalation and expansion 
phases, and the number of sites needed to enroll the patients in a timely fashion 
Specified planned enrollment of approximately 65-70 patients.  
Specified the study population, the target number of patients to be enrolled in the dose escalation and expansion 
phases, and the number of sites needed to enroll the patients in a timely fashion 
Updated the number of investigational sites. 
Stipulated that the term “tumor assessment” would be used throughout the protocol; that tumors would be 
assessed according to RECIST V. 1.1 at Screening, Cycle 2 Day 1 (C2D1), and every 8 (±1) weeks thereafter.   
Specified dose adjustment for impaired liver function. 
Specified tumor markers to be assessed: CEA and CA 19-9 for patients with BTC (Arm A) and chromogranin-A 
for patients with pNET (Arm B). 
Changed PK sampling times on C1D1, C1D15 and C2D1 post-dose 12 hours (± 60 minutes)” to post-dose 6 
hours (± 60 minutes)” 
Added chemistry panel and urinalysis to study flowchart C1D8 and C1D22 for safety monitoring. 
Added study visit windows: Day 8 (D8), D15, D22 of Cycle 1 and D1, D15 of Cycle2 (±1d); Cycle 3 and 
onwards: D1 (±3 day) and then every 4 weeks. 
Added the dose modification guideline to Section 5.2.2. Specified dose modification guideline for proteinuria and 
for Grade 3 liver function impairment.  
 
 
 
 
 


Clinical Study Protocol 2015-012-00US1 
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CONFIDENTIAL 
 
 
Protocol Amendment 5 (Version 2.0, 8 December 2017): Summary of Changes: Protocol Amendment 5 
(Version 2.0, 8 December 2017) 
Specified study population, target number of patients to be enrolled in the dose expansion phase and the number 
of sites needed 
Specified the number of patients to be enrolled in the two arms (BTC and pNET) of the dose expansion phase, 
increased the number of study sites, and increased the total planned enrollment 
Specified the criteria for end of treatment (treatment completion and early discontinuation) 
Clearly described the objectives of the dose escalation phase and the dose expansion phase 
Defined the efficacy endpoints of the dose expansion phase 
Provided the rationale for the study drug dose to be used in the dose expansion phase 
Reinstated “4 weeks” as the washout period for any previous anticancer therapies prior to study drug 
Added relevant new clinical data on the safety and efficacy of surufatinib 
Provided the rationale for the sample size determination and describe the statistical analyses for patients in the 
dose expansion phase 
Added to the Section 1.2.1 Nonclinical Pharmacology: CSF-1R is another target of surufatinib from preclinical 
data 
 
Protocol Amendment 4 (Version 1.4, 16 Dec 2016): 
Summary of Changes: Protocol Amendment 4 (Version 1.4, 16 December 2016) 
Excluded patients over 75 years of age from the study population 
Exempted from the DLT definition: Grade 3 hypertension which could be well managed and downgraded within 
3 days  
Changed exclusion criterion for anticancer medication taken prior to study drug from 4 weeks to 4 weeks or 5 
half-lives, whichever is shorter 
  


Cli nic al St u d y Pr ot oc ol 2 0 1 5 -0 1 2 -0 0 U S 1  
S ur uf ati ni b   
A me n d me nt 1 1  
 
 
H utc his o n M e di P h ar m a  
 
P a ge 1 8  
 
C O N FI D E N TI A L  
 
 
Pr ot oc ol A me n d me nt 3  ( Versi o n 1. 3, 3 1 Oct 2 0 1 6): 
S u m m ar y of C h a n ges: Pr ot oc ol A me n d me nt 3 ( Versi o n 1. 3, 3 1 Oct 2 0 1 6)  
I ntr o d uce d ne w f or m ulati o n of s ur ufati ni b P D-0 1 2 -0 4 2 (re placi n g f or m ulati o n N o. P D -0 1 2 -0 2 3) f or  d ose 
escalati o n a n d re mai n der of trial. Starti n g d ose of 3 0 0 m g wit h f or m ulati o n P D -0 1 2 -0 4 2 is acce pta ble if safet y 
pr ofile of f or m ulati o n P D -0 1 2 -0 2 3 was acce pta ble (i n d ose escalati o n p hase). Pr o vi de d details of q ualit y of dr u g 
s u bsta nce ( A PI) a n d dr u g pr o d uct (ca ps ule) of f or m ulati o n P D-0 1 2 -0 4 2.  
Clarifie d t hat c o nc o mita nt use of gastr o d u o de nal m uc osal pr otecti ve a ge nts, s uc h as s ucralfate, are all o we d i n 
c ycle 1 of d ose escalati o n p hase.  
A d de d cl ose m o nit ori n g of c o nc o mita nt a d mi nistrati o n of s ur ufati ni b wit h C Y P 3 A s u bstrat es d ue t o ris k of 
dr u g -dr u g i nteracti o n  
U p date d t he l o n g -ter m st ora ge sta bilit y data f or P K plas ma s a m ples: -2 0 C f or 3 1 7 da ys a n d at -8 0° C f or 7 1 6 
da ys.  
 
Pr ot oc ol A me n d me nt 2  (Versi o n 1. 2, 1 7 J u ne 2 0 1 5):  
S u m m ar y of C h a n ges : Pr ot oc ol A me n d me nt 2 ( Versi o n 1. 2, 1 7 J u ne 2 0 1 5) 
A d de d M T D a n d R P 2 D t o pri mar y o bj ecti ves  
A d de d gl o mer ular filtrati o n rate ( G F R) t o e xcl usi o n criteri o n 5. A d d creati ni ne cleara nce per C oc kcr oft -Ga ult per 
ser u m creati ni ne le vel. 
Defi niti o n of D L T: e xcl u de na usea/ v o miti n g, diarr hea, c o nsti pati o n or electr ol yte i m bala nc e if d o w n gra de d t o 
less t ha n gra d e 3 wit hi n 3 da ys; d elete d “te n de nc y of” bef or e “ blee di n g”. A d de d t o D L T defi niti o n: a n y life-
t hreate ni n g c o m plicati o n or a b n or malit y n ot c o vere d i n t he N CI C T C A E v 4. 0 3.  
Defi ne d M T D as t he ma xi m u m d ose at w hic h n o m ore t ha n 1 of 6 patie nts i n a si n gle d ose gr o u p e x perie nces 
D L T i n C ycle 1 ( Da ys 1 -2 8)  
Re vise d t he d ose a d mi nistrati o n ti me fr o m bef ore brea kfast t o after brea kfast per t he res ults of f o o d effect  st u d y 
 
A d de d m ore details o n car diac m o nit ori n g (sc he d ule of ultras o nic car di o gra m or M U G A a n d 1 2 -lea d 
electr ocar di o gra m assess me nts).  
A d de d “c ha n ges  i n E C G/ec h o car di o gra m res ults” i nt o safet y a nal ysis. 
 
Pr ot oc ol A me n d me nt 1 ( V ersi o n 1. 1, 1 5 M arc h 2 0 1 5):  
C CI


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Summary of Changes: Protocol Amendment 1 (Version 1.1, 15 March 2015) 
Specified planned enrollment of 21-36 patients, doses in dose escalation phase (50,100, 200, 300, and 400 
mg/day) and revised duration of study to 18 months. Specified that this is a dose escalation trial with a dose 
expansion phase to confirm the MTD or the RP2D. The MTD or RP2D will be confirmed in the dose 
expansion phase. 
Defined inclusion criteria. Added QTc interval prolongation to exclusion criteria. 
Added to definition of DLT (any Grade 4 non-hematologic toxicity; Grade 4 thrombocytopenia or ≥Grade 3 
thrombocytopenia associated with tendency of bleeding); dose interruption for > 14 days due to toxicity 
Modified flowchart to show initial steps 
Added to the list of excluded therapies (acid-reducing agents)  
Specified ECG time points.  Specified PK sample collection time points. 
 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 2 
SPONSOR’S APPROVAL ............................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................. 4 
DOCUMENT HISTORY............................................................................................................... 5 
PROTOCOL AMENDMENT HISTORY ..................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................. 20 
LIST OF TABLES ....................................................................................................................... 24 
LIST OF APPENDICES .............................................................................................................. 25 
LIST OF ABBREVIATIONS ...................................................................................................... 26 
1 
SYNOPSIS ....................................................................................................................... 30 
2 
BACKGROUND ............................................................................................................. 34 
2.1 
Physical, Chemical and Pharmaceutical Properties of Surufatinib ............................... 34 
2.2 
Summary of Nonclinical Studies .................................................................................. 34 
2.2.1 
Nonclinical Pharmacology ......................................................................................... 34 
2.2.2 
Nonclinical Pharmacokinetics ................................................................................... 35 
2.2.3 
Nonclinical Toxicology ............................................................................................. 36 
2.2.3.1 
Safety Pharmacology .............................................................................................. 36 
2.2.3.2 
General Toxicology ................................................................................................ 36 
2.2.3.3 
Reproductive and Development Toxicology .......................................................... 37 
2.2.3.4 
Genetic toxicology .................................................................................................. 37 
2.3 
Clinical Experience ....................................................................................................... 37 
3 
STUDY RATIONALE .................................................................................................... 39 
3.1 
Mechanism of Action .................................................................................................... 39 
3.2 
Unmet Medical Need .................................................................................................... 40 
3.3 
Benefit and Risk Assessment ........................................................................................ 43 
4 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 45 
4.1 
Dose Escalation Phase .................................................................................................. 45 
4.1.1 
Primary Objective ...................................................................................................... 45 
4.1.2 
Primary Endpoint ....................................................................................................... 45 
4.1.3 
Secondary Objectives................................................................................................. 45 
4.1.4 
Secondary Endpoints ................................................................................................. 46 


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4.2 
Dose Expansion Phase .................................................................................................. 46 
4.2.1 
Primary Objective ...................................................................................................... 46 
4.2.2 
Primary Endpoints ..................................................................................................... 46 
4.2.3 
Secondary Objectives................................................................................................. 46 
4.2.4 
Secondary Endpoints ................................................................................................. 47 
4.2.5 
Exploratory Objectives .............................................................................................. 47 
4.2.6 
Exploratory Endpoints ............................................................................................... 47 
5 
INVESTIGATIONAL PLAN .......................................................................................... 48 
5.1 
Description of the Study ............................................................................................... 48 
5.1.1 
Dose Escalation Phase ............................................................................................... 48 
5.1.1.1 
Dose-Limiting Toxicity Assessment Window ........................................................ 49 
5.1.1.2 
Definition of DLT Evaluable Patients .................................................................... 49 
5.1.1.3 
Definition of a Dose-Limiting Toxicity (DLT) ...................................................... 50 
5.1.1.4 
Definition of Maximum Tolerated Dose (MTD) .................................................... 50 
5.1.2 
Dose Expansion Phase ............................................................................................... 50 
5.2 
Sample Size ................................................................................................................... 51 
5.3 
Investigational Site........................................................................................................ 51 
5.4 
Safety Review Committee ............................................................................................ 51 
5.5 
Patient Discontinuation ................................................................................................. 51 
5.6 
Overall Survival Follow Up .......................................................................................... 52 
5.7 
Study Discontinuation ................................................................................................... 52 
5.8 
End of Treatment (Individual Patient) .......................................................................... 53 
5.8.1 
End of Study .............................................................................................................. 53 
5.8.2 
Study Completion Date .............................................................................................. 53 
6 
PATIENT SELECTION .................................................................................................. 54 
6.1 
Inclusion Criteria .......................................................................................................... 54 
6.2 
Exclusion Criteria ......................................................................................................... 55 
7 
STUDY TREAMENT ..................................................................................................... 58 
7.1 
Investigational Product ................................................................................................. 58 
7.1.1 
Investigational Product Supply .................................................................................. 58 
7.1.2 
Drug Formulation and Specification .......................................................................... 58 
7.1.3 
Packaging and Drug Labeling .................................................................................... 58 


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7.1.4 
Drug Storage .............................................................................................................. 58 
7.1.5 
Drug Accountability................................................................................................... 58 
7.1.6 
Dose and Administration ........................................................................................... 59 
7.1.7 
Important Safety Risks ............................................................................................... 59 
7.1.8 
Important Potential Risks ........................................................................................... 59 
7.2 
Dose Modification ........................................................................................................ 59 
7.2.1 
General Dose Adjustment Note ................................................................................. 59 
7.2.2 
Dose Modification Guidance ..................................................................................... 60 
7.2.3 
Dose Modification for Important Identified Risks..................................................... 61 
7.3 
Concomitant and Excluded Therapies .......................................................................... 63 
7.3.1 
Concomitant Therapies .............................................................................................. 63 
7.3.2 
Excluded Therapies .................................................................................................... 64 
7.3.3 
Drug-Drug Interactions .............................................................................................. 65 
8 
STUDY ASSESSMENTS AND METHODS ................................................................. 66 
8.1 
Safety Assessments ....................................................................................................... 66 
8.1.1 
Vital Signs Assessment .............................................................................................. 66 
8.1.2 
Physical Examination................................................................................................. 66 
8.1.3 
Laboratory Test Evaluations ...................................................................................... 66 
8.1.4 
Cardiac Monitoring .................................................................................................... 67 
8.2 
Efficacy Assessments.................................................................................................... 67 
8.2.1 
Tumor Assessment ..................................................................................................... 67 
8.2.2 
Assessment of Tumor Markers .................................................................................. 68 
8.3 
Study Visits and Assessments ....................................................................................... 68 
8.3.1 
Screening and Pretreatment Assessment ................................................................... 68 
8.3.2 
Assessments during Treatment Phase ........................................................................ 68 
8.3.3 
Study Completion/Early Termination Visit ............................................................... 68 
8.4 
Assay Methods .............................................................................................................. 69 
8.4.1 
Bioanalysis Assay Methods ....................................................................................... 69 
8.4.2 
Pharmacokinetic Samples Handling and Shipment ................................................... 69 
9 
SAFETY MONITORING ................................................................................................ 71 
9.1 
Definitions..................................................................................................................... 71 
9.1.1 
Adverse Events and Serious Adverse Events ............................................................ 71 


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9.1.2 
Adverse Events of Special Interest ............................................................................ 71 
9.2 
Reporting of Dose-Limiting Toxicity ........................................................................... 72 
9.3 
Adverse Events Reporting Period ................................................................................. 72 
9.4 
Eliciting Adverse Events............................................................................................... 72 
9.5 
Assessment of Severity ................................................................................................. 72 
9.6 
Causality of Adverse Events ......................................................................................... 73 
9.7 
Documenting Adverse Events....................................................................................... 73 
9.8 
Diagnosis vs Symptom and Signs ................................................................................. 73 
9.9 
Adverse Event Occurring Secondary to Other Events .................................................. 73 
9.10 
Persistent or Recurrent Adverse Events ........................................................................ 74 
9.11 
Abnormal Laboratory Values ....................................................................................... 74 
9.12 
Death ............................................................................................................................. 74 
9.13 
Previously Existing Medical Condition ........................................................................ 74 
9.14 
Hospitalization, Prolonged Hospitalization, or Surgery ............................................... 75 
9.15 
Pregnancy ...................................................................................................................... 75 
9.16 
Liver Function Abnormality ......................................................................................... 75 
9.17 
Worsening of Solid Tumor ........................................................................................... 76 
9.18 
Expedited Reporting Requirements for Serious Adverse Events ................................. 76 
9.18.1 
Reporting Requirements for Serious Adverse Events ............................................... 76 
9.19 
Adverse Event Follow-Up Duration ............................................................................. 76 
9.20 
Post-Study Adverse Events ........................................................................................... 76 
10 
STATISTICAL ANALYSIS ........................................................................................... 77 
10.1 
Determination of Sample Size ...................................................................................... 77 
10.2 
Analysis Populations ..................................................................................................... 78 
10.3 
Statistics and Analysis Method ..................................................................................... 79 
10.4 
Safety Analysis ............................................................................................................. 79 
10.5 
Pharmacokinetic Analysis ............................................................................................. 80 
10.6 
Tumor Assessment ........................................................................................................ 81 
10.6.1 
Primary Efficacy Endpoints ....................................................................................... 81 
10.6.2 
Secondary Efficacy Endpoints ................................................................................... 81 
10.6.3 
Exploratory Endpoints ............................................................................................... 82 
11 
ETHICS............................................................................................................................ 83 


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11.1 
Good Clinical Practice .................................................................................................. 83 
11.2 
Ethics Review ............................................................................................................... 83 
11.3 
Patient Informed Consent ............................................................................................. 83 
11.4 
Data Privacy .................................................................................................................. 84 
11.5 
Disclosure ..................................................................................................................... 84 
11.6 
Data Quality Assurance ................................................................................................ 85 
11.7 
Biological Specimens and Data .................................................................................... 85 
12 
OVERSIGHT ................................................................................................................... 86 
12.1 
Independent Monitoring................................................................................................ 86 
12.2 
Quality Control and Assurance ..................................................................................... 86 
12.2.1 
Monitoring ................................................................................................................. 86 
12.2.2 
Audits ......................................................................................................................... 86 
12.2.3 
Records ...................................................................................................................... 87 
12.2.3.1 
Data Capture and Management ............................................................................... 87 
12.2.3.2 
Source Data Documentation ................................................................................... 87 
12.2.3.3 
Records Retention ................................................................................................... 88 
12.3 
Study Termination or Study Site Closure ..................................................................... 88 
Investigator’s Decision ................................................................................................................ 88 
Sponsor’s Decision ...................................................................................................................... 88 
13 
PUBLICATION POLICY ............................................................................................... 89 
14 
FINANCING AND INSURANCE .................................................................................. 90 
15 
REFERENCES ................................................................................................................ 91 
16 
APPENDICES ................................................................................................................. 94 
 
LIST OF TABLES 
Table 1 
Distribution of Neuroendocrine Tumors by Primary Site.................................... 40 
Table 2 
FDA-Approved Drugs for the Treatment of Neuroendocrine Tumors (NETs) ... 41 
Table 3 
Flowchart of Dose Escalation .............................................................................. 49 
Table 4 
Drug Formulation and Strength ........................................................................... 58 
Table 5 
Dose Modification Sequence by Starting Dose ................................................... 60 
Table 6 
Dose Modification for Hematologic and Non-Hematologic Toxicities .............. 61 
Table 7 
Dose Modification for Hypertension ................................................................... 61 


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Table 8 
Dose Modification for Proteinuria ....................................................................... 62 
Table 9 
Dose Modification for Liver Function Impairment ............................................. 62 
Table 10 
Dose Modification for Hemorrhage ..................................................................... 63 
Table 11 
Pharmacokinetic Sampling Time Points .............................................................. 70 
Table 12 
Schedule of Events ............................................................................................... 95 
 
LIST OF APPENDICES 
Appendix 1 
Study Flowcharts ................................................................................................. 95 
Appendix 2 
ECOG Performance Status .................................................................................. 99 
Appendix 3 
Response Evaluation Criteria in Solid Tumors Version 1.1 .............................. 100 
Appendix 4 
Guidelines for Interaction between Surufatinib and Concomitant Medication . 111 
Appendix 5 
Guideline to Interpreting the Causality Question .............................................. 114 
Appendix 6 
Prohibited Concomitant Medications That Have a Known Risk of QT 
Prolongation and/or Torsades DES Pointes (TDP) ............................................ 115 
Appendix 7 
Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) .................. 117 
Appendix 8 
Conversion of Urinalysis Results Table ............................................................ 119 
 
 


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LIST OF ABBREVIATIONS 
Abbreviations 
Definition 
AE 
Adverse event 
ALT 
Alanine amino transaminase  
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransaminase  
BRCP 
Breast cancer receptor protein 
BTC  
Biliary tract cancer  
CA 19-9 
Carbohydrate antigen 19-9 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CgA 
Chromogranin A 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration 
CR 
Complete response 
CRF  
Case report form 
CRO 
Contract research organization 
CSF1R 
Colony stimulating factor 1 receptor 
CT 
Computed tomography 
CTC 
Common toxicity criteria  
CTC AE 
Common terminology criteria for adverse events 
DCR 
Disease control rate 
DILI 
Drug-induced liver inquiry 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
DVT 
Deep vein thrombosis 
EAS 
Efficacy analysis set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EC 
Ethics Committee 
epNET 
Extrapancreatic neuroendocrine tumor 
FGFR1 
Fibroblast growth factor receptor 1 


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Abbreviations 
Definition 
G1 
Grade 1 (refers to BTC, pNETs, and epNETs) 
G2 
Grade 2 (refers to BTC, pNETs, and epNETs) 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal  
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HUVEC(s) 
Human umbilical vein epithelial cells 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
INN 
International nonproprietary name 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
KDR 
Kinase domain insert receptor 
Kinact/KI 
Rate constant describing the efficiency of covalent 
bond formation resulting from the potency (KI) of the 
first reversible binding event and the maximum 
potential rate (Kinact) of inactivation [2]).  
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase 
MRI 
Magnetic resonance imaging 
MRT 
Median residence time 
MTD 
Maximum tolerated dose 
NET 
Neuroendocrine Tumors  
NCI 
National Cancer Institute 
NSCLC 
Non - Small Cell Lung Cancer 
NSE 
Neuron-specific enolase 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progression of disease 
PE 
Pulmonary embolism 


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Abbreviations 
Definition 
PECAM-1 
platelet and endothelial cell adhesion molecule 
PFS 
Progression-free survival 
P-gp 
p-glycoprotein 
PK 
Pharmacokinetics 
PKAS 
Pharmacokinetics analysis set 
pNET 
Pancreatic neuroendocrine tumor 
PR 
Partial response 
PR 
Partial response 
PRES 
posterior reversible encephalopathy syndrome 
PT 
Preferred term (MedDRA) 
PVNS 
Pigmented villonodular synovitis 
RAS 
a small GTPase involved in signal transduction 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
QD 
Once daily 
QTc 
QT interval 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SD 
Stable disease 
SOC 
System organ class (MedDRA) 
SRC 
Safety review committee 
SSA(s) 
Somatostatin analogue(s) 
STS 
Soft tissue sarcoma 
Surufatinib 
International 
nonproprietary 
name 
assigned 
to 
sulfatinib by the World Health Organization [1] 
t1/2 
Half-life 
TAM(s) 
Tumor-associated macrophage(s) 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach maximum concentration 
TTR 
Time to response 
TSH 
Thyroid stimulating hormone 
UPS 
Undifferentiated pleomorphic sarcoma 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
VIP 
Vasoactive intestinal peptide  


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Abbreviations 
Definition 
WHO 
World Health Organization 






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Brief Summary: 
The purpose of this study is to evaluate the safety and tolerability of surufatinib and to confirm the safety 
and efficacy results of clinical studies performed in China in a Western patient population.  Accordingly, 
this is an open-label trial of surufatinib, which consists of 2 phases: a dose escalation phase in patients 
with advanced solid tumors of any type, and a dose expansion phase in patients with advanced BTC (Arm 
A), advanced pNETs (Arm B), advanced epNETs (Arm C), or STSs (Arm D).Study details are outlined 
below. 
Condition/Disease 
Dose escalation phase will enroll patients with advanced solid 
tumors of any type. 
Dose expansion phase will enroll patients with advanced BTC 
(Arm A), advanced pNETs (Arm B), advanced epNETs (Arm 
C), and STSs (Arm D). 
Study Duration 
Study duration for patients in the dose escalation is up to 
approximately 1 year and 2 months, including: 
• Screening period of up to 28 days 
• Treatment period until disease progression, death, end of 
study, or early discontinuation as specified in the protocol, 
or up to 1 year 
• Dose Completion visit at 30 (±7) days after the last dose of 
study drug 
Study duration for patients in the dose expansion consists of: 
• Screening period of up to 28 days 
• Treatment period until disease progression, death, end of 
study, or early discontinuation as specified in the protocol 
• Dose Completion visit at 30 (±7) days after the last dose of 
study drug 
Treatment Duration 
Treatment duration is: 
• Up to 1 year for patients in the dose escalation phase 
• Approximately 16 weeks for Arm A 
• Approximately 11 months for Arms B and C 
• Approximately 4 months for Arm D 
Health Measurement/ Observation 
The dose escalation phase will evaluate the safety and 
tolerability of surufatinib in patients with advanced solid 
tumors of any type and determine the MTD and/or RP2D by 
evaluating the incidence of DLT.  
The expansion phase evaluates the anticancer activity of 
surufatinib at the RP2D determined in the dose escalation phase 
as determined from the PFS.   
Visit Frequency 
All enrolled patients undergo screening, which may be up to 28 
days prior to the first dose of study drug.   
Each treatment cycle is 28 days.  Patients are assessed at day 
1, day 8 (±1), day 15 (±1), and day 22 (±1) in cycle 1, day 1 
and day 15 (±1) in cycle 2, and then day 1 (±3) of cycle 3 and 
all subsequent treatment cycles.  Tumor assessments are 
conducted according to RECIST Version 1.1 criteria at 
screening, cycle 2 day 1 and every 8 (±1) weeks thereafter.   
After receiving the last dose of study drug, patients undergo a 
Treatment Completion visit at 30 (±7 days) after receiving the 
last dose of surufatinib. 
The safety of all enrolled patients will be closely monitored 
from the time of the initial dose of investigational treatment 
until 30 days after the last treatment dose.   


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Number of Participants 
In the dose escalation phase, approximately 35 patients will be 
enrolled. 
In the dose expansion phase, approximately 115 patients will be 
enrolled into the 4 open-label treatment arms: at least 
30 patients with advanced BTC that have progressed on 
standard ﬁrst-line chemotherapy will be assigned to Arm A, at 
least 15 patients with advanced pNET that have progressed on 
either everolimus, sunitinib, or both will be assigned to Arm B, 
and at least 15 patients with advanced epNETs that have 
progressed on everolimus will be assigned to Arm C, and at 
least 55 patients with STS will be assigned to Arm D. 
Intervention Groups and Duration 
In the dose escalation phase, patients are observed for toxicity 
at each dose level.  The DLT assessment window is the 28 
days in the first cycle (Day 1 to Day 28).  Patients who 
complete the DLT observation window and are deemed, in the 
Investigator’s judgment, to have benefited from surufatinib 
treatment could be permitted, at the Investigator’s discretion, to 
continue with surufatinib treatment until disease progression, 
death, intolerable toxicity, pregnancy, or loss of benefit from 
the study drug.  Patients with acceptable toxicity and ongoing 
clinical benefit were to be permitted to receive surufatinib for 
up to 1 year.  
In the dose expansion phase, patients receive treatment until 
disease progression, death, end of study, or early 
discontinuation as specified in the protocol. 
Patients in both the dose escalation and dose expansion 
portions undergo a Treatment Completion visit at 30 days (±7) 
after receiving the last dose of surufatinib.   
Data Monitoring/Other Committee 
Safety monitoring and evaluation for dose escalation will be 
carried out by the Safety Review Committee (SRC) upon 
completion of the DLT observation period of each cohort in 
dose escalation.  The SRC is chaired by the Sponsor’s Clinical 
Program Leader of the surufatinib program, and members will 
include the principal investigators (PIs), the Sponsor’s PK 
scientist, medical monitor, safety scientist, and the contract 
research organization’s medical monitor. 
For the dose expansion phase of the trial, a separate, specific 
SRC will be established to ensure the safety of all patients 
treated with study drug in the STS cohort (STS-SCR).  
Review of available safety laboratories, adverse events, and any 
other pertinent data available will be reviewed after the first 4 
patients in each sarcoma cohort have completed at least 1 cycle 
of treatment. 
 


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2 
BACKGROUND 
2.1 
Physical, Chemical and Pharmaceutical Properties of Surufatinib 
• International nonproprietary name (INN): Surufatinib, previously named 
Sulfatinib [1].  
• Lab Code：HMPL-012  
• Chemical name：N-(2-(dimethylamino)ethyl)-1-(3-(4-(2-methyl-1H-indol-5-
yloxy)pyrimidin-2-ylamino)phenyl)methanesulfonamide 
• Molecular formula：C24H28N6O3S 
• Molecular weight：480.58 g/mol 
• Surufatinib is a study drug formulated as odorless, white or off-white powder in 
capsules, with strength of 50 mg or 200 mg per capsule. 
• The active ingredient is insoluble in water, and slightly soluble in methyl alcohol 
or ethyl alcohol. 
• The melting point of the active ingredient is 162to170°C. 
2.2 
Summary of Nonclinical Studies 
2.2.1 
Nonclinical Pharmacology 
Surufatinib is an anti-angiogenesis agent.  It selectively targets tyrosine kinases involved 
in vascular formation, mainly on the vascular endothelial growth factor receptor family 
(VEGFR1, 2, and 3), fibroblast growth factor receptor 1 (FGFR1) and colony stimulating 
factor 1 receptor (CSF1R). In the [32p-ATP] incorporation assay, the IC50s of surufatinib 
on VEGFR1, 2, 3 (also known as Flt1, KDR, and Flt4) were found to be 2 nM, 24 nM, and 
1 nM, respectively. The IC50s of the kinase activity of FGFR1, 2, 3 were determined as 15 
nM, 236 nM and 181 nM, respectively. The IC50 for CSF1R (FMS) was 4 nM. 
Consistent with its biochemical activity on inhibiting KDR kinase, surufatinib 
demonstrated strong activity in inhibiting VEGF stimulated phosphorylation of KDR in the 
HEK293-KDR engineered cell line, with an IC50 of 2 nM.  In addition, the activation of 
KDR downstream signaling cascade pathways, including the PI3K/AKT pathway, 
RAS/RAF/MEK/ERK pathway, and p38 were also inhibited dose-dependently.  
Furthermore, in functional assays using HUVECs (human umbilical vein endothelial cells), 
surufatinib demonstrated inhibition of VEGF-dependent cell proliferation with an IC50 of 
16 nM and HUVEC tube formation with an inhibition of 75% at 0.3 M.  In the rat aortic 
ring model, surufatinib inhibited vessel outgrowths of rat aortic rings in a dose-dependent 
manner with an IC50 of 192 nM.  
Surufatinib was evaluated for cytotoxicity in 11 human tumor cell lines and 3 normal human 
cell lines.  Surufatinib showed a weak effect on cell survival with IC50≥5 µM, which was 
about 300-fold less potent than the IC50 of surufatinib in a VEGF- dependent anti-
proliferation assay in HUVEC (16 nM), consistent with its good kinase selectivity.  
The inhibitory effect of surufatinib on the phosphorylation of KDR, angiogenesis and tumor 
growth were evaluated in vivo.  The results indicated that upon stimulation with VEGF 
(i.v., 0.5 g/mouse), KDR phosphorylation (p-KDR) in the mouse lung tissue was 
significantly induced.  Surufatinib orally dosed at 20 and 40 mg/kg completely inhibited 
VEGF-stimulated KDR phosphorylation for 4 hours and at 80 mg/kg for 8 hours, suggesting 


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a dose dependent inhibition. In this experiment, the drug exposure was determined.  For 
instance, at 4 hr after oral administration of 20 mg/kg of surufatinib, the drug concentration 
in plasma reached 181 ng/mL (AUC for 20 mg/kg was 2720 ng∙h/mL).  These data 
provided pharmacokinetic (PK)/PD correlation and the effective concentration for complete 
p-KDR inhibition (EC100=181 ng/mL) useful to guide clinical dose selection. 
Surufatinib was further evaluated for anti-tumor activity and demonstrated high potency on 
inhibiting tumor growth in multiple human tumor xenografts, such as gastric cancer BGC-
823, non-small cell lung cancer (NSCLC) NCI-H460, human renal cell carcinoma Caki-1 
and colon cancer HT-29.  Surufatinib was orally dosed at 20, 40, and 80 mg/kg twice daily 
and there appeared to be good dose response in these studies.  Among the four models, 
gastric cancer BGC-823 showed the highest sensitivity to surufatinib.  The tumor growth 
inhibition (TGI) achieved 68%, 90% and 103% at 20, 40 and 80 mg/kg, respectively.  
The anti-angiogenesis effect of surufatinib in the anti-tumor efficacy studies was 
investigated by detecting the changes of endothelial cell marker CD31 (PECAM-1) in 
tumor tissue by immunohistochemistry (IHC) technology.  Surufatinib significantly 
decreased the vascular vessel density (CD31) significantly in both NCI-H460 and Caki-1 
xenografts.  A clear dose-dependent inhibition of surufatinib on angiogenesis in Caki-1 
xenograft tumor tissue was observed.  The level of CD31 inhibition appeared to correlate 
with the tumor growth inhibition. 
The plasma and tumor concentrations of surufatinib were analyzed in BGC-823 tumor 
bearing mice at the end of the efficacy study after last dosing.  AUC increased with the 
increase of dose from 20 to 80 mg/kg. The minimum efficacious dose was 20 mg/kg twice 
daily (TGI ≥58%, P<0.05) in BGC-823 model (TGI=68%), and the corresponding 
minimum efficacious exposure, AUC0-24h, in plasma was 4712 ng∙h/mL.  Surufatinib 
given orally at 80 mg/kg twice daily resulted in tumor regression with an AUC0-24h of 16444 
ng∙h/mL.  PK/PD analysis indicated that at this dose complete p-KDR inhibition was 
maintained for more than 16 hours/day. 
2.2.2 
Nonclinical Pharmacokinetics 
After a single intravenous dose of 10mg/kg surufatinib in rats, the plasma elimination half-
life of surufatinib was measured as 2.8 hours, and plasma clearance and apparent volume 
of distribution were 3.53 L/h/kg and 13.1 L/kg, respectively.  Following dosing via oral 
gavage at low, medium and high dose levels, the mean value of time to reach maximum 
concentration was 3.0~4.2 hours.  The oral bioavailability was observed to be dose 
dependent.  At the dose level of 10 mg/kg, the bioavailability was just 9.9%. When the 
dose was increased to 40 mg/ml or above, the bioavailability exceeded 50%.  The low 
bioavailability observed at the low dose level might be associated with the efflux by P-
glycoprotein in intestinal epithelial cells. 
After a single intravenous dose of 5 mg/kg in dogs, the plasma elimination half-life was 3.3 
hours, and plasma clearance and apparent volume of distribution were 3.94 L/h/kg and 18.5 
L/kg, respectively.  Following a single oral dose of 5, 10 and 20 mg/kg, the mean value of 
time to reach maximum concentration was 3.5~4.5 hours.  In the dose range of 5~20 
mg/kg, surufatinib exposure (Cmax and AUC0-t) increased dose-proportionally.  Feeding 
had no obvious effect on the extent and speed of surufatinib absorption.  At the oral dose 
level of 10 mg/kg, the absolute bioavailability was 30.5%. 


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After administration via oral gavage in rats, surufatinib was distributed widely in various 
tissues mainly including lung, liver, spleen, adrenal gland, kidney, pancreas and stomach 
wall.  The lowest drug concentration was observed in brain, indicating poor brain blood 
penetration. At 24 hours post-dose, concentrations in most tissues reduced to 10% or lower 
than the peak concentrations. 
The results of [14C]-surufatinib excretion study revealed that surufatinib was mostly 
excreted via faeces (approximately 80% of the dose, including 40% for bile excretion), and 
a small amount was excreted via urine (approximately 10% of the dose). 
In-vitro liver microsomal metabolic stability assays in various species showed high liver 
extraction of surufatinib.  The clearance of surufatinib in liver microsomes was higher in 
male rats than in female rats.  No significant gender difference was observed in other 
species.  In an in-vitro liver microsomes incubation study, phase 1 enzymes mediating the 
metabolism of surufatinib included CYP3A4/5 (dehydrogenation, N-demethylation), 
CYP2C8 (dehydrogenation, N-demethylation), CYP2E1 (mono-oxidization), and FMO. 
Surufatinib showed weak reversible inhibition against CYP2D6 and CYP3A4/5 with the 
IC50 of 13 µM and 14 µM, respectively.  Time-dependent inhibition study of CYP3A4/5 
indicated the potential with a kinact [2] of 0.73 min-1 and KI [2] of 163 µM. The results of 
CYP1A2 and CYP3A4 induction assay in primary human hepatocytes revealed that 
surufatinib did not significantly induce CYP1A2 at a concentration of 10 µM or CYP3A4 
at a concentration of 2 µM.  In an in-vitro permeability and efflux transportation assay 
using Caco-2 cells, it was found that surufatinib might be a substrate of P-gp.  
The protein binding rates of surufatinib were found to be 93~96% in plasma of various 
species, indicating a moderate to high extent of protein binding in plasma. 
2.2.3 
Nonclinical Toxicology  
2.2.3.1 
Safety Pharmacology 
The effect of surufatinib on hERG tail currents was evaluated in CHO cells using a patch 
clamp technique.  The effect on the cardiovascular system was evaluated in anesthetized 
Beagle dogs and no adverse effects were found at the doses evaluated.  No adverse effect 
was observed on behaviors in mice and respiratory system in anesthetized dogs. 
2.2.3.2 
General Toxicology 
In single dose toxicity studies in rat and dog, no deaths were found up to the highest dose 
tested at 2000 mg/kg, suggesting good tolerability following single oral dosing.  Repeated 
dose toxicity studies were carried out for surufatinib in rat (1-month, 3-months and 6-
months) and dog (1-, 3-, and 9-months), respectively.  The NOAEL (No-observed-
adverse-effect-level) of surufatinib in 28-day repeated dose toxicity was 20 and 6 mg/kg in 
rats and dogs, respectively.  The toxicokinetic results indicated that the exposures of 
surufatinib in rats at the NOAEL dose were higher than the exposures at the efficacious 
dose in mice (40 mg/kg/day).  According to the results of toxicity studies, the digestive 
system (GI, liver), lymphatic system (thymus, spleen, and lymph nodes), kidney, 
hemapoietic system, reproductive system, endocrine system and skeletal muscle were 
considered to be the target organs.  The toxic responses were found to be completely or 
nearly completely recovered after a 28-day recovery phase. 


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The key findings included kidney changes at high doses (60 mg/kg or higher) in rats in the 
28-day study.  At lower doses, with extended duration of treatment, changes in lymphatic 
system were found in the rats.  In addition, injury to teeth was a consistent finding possibly 
related to the target inhibition.  In the dog, findings in the GI tract were noted in all 3 
repeated dose studies.  Changes in the lymphatic system were also present in the 9-month 
study.  Taken together, it is worthwhile to note that at high doses surufatinib might cause 
kidney and GI toxicities.  In addition, with extended dosing at lower/tolerated doses, the 
lymphatic system might be affected.  Therefore, during initial dose escalation phase in 
humans, attention should be paid to kidney and GI side effects.  Adverse effects related to 
lymphatic system should also be monitored for long term use of surufatinib.  Most adverse 
events (AEs) may be reduced or resolved by discontinuation of surufatinib treatment. 
2.2.3.3 
Reproductive and Development Toxicology 
In fertility and early embryonic development to implantation study, the NOAEL of 
surufatinib was 15 mg/kg for parental male rats, and 10 mg/kg for parental female rats.  
The NOAEL for fertility and early embryonic development in male and female rats was 
found to be 45 mg/kg and 10 mg/kg, respectively.  In the embryo-fetal development study, 
the NOAEL for maternal effects and the embryo-fetotoxic dose was found to be 5 and 3 
mg/kg in rats, respectively.  In rabbits, the NOAEL of surufatinib for maternal effects and 
embryo-fetotoxic effects was found to be 48mg/kg and 24 mg/kg, respectively.  
2.2.3.4 
Genetic toxicology 
No potential genetic toxicity was found in the bacterial reverse mutation test, the 
chromosome aberration test in Chinese Hamster Lung Cell, or the micronucleus test in 
mice. 
2.3 
Clinical Experience 
As of 11 February 2020, the safety database includes 717 patients (714 in monotherapy and 
3 in combination therapy) and 60 healthy patients who received surufatinib as monotherapy 
or combination therapy in completed or ongoing studies.  
Of 714 patients who received at least 1 dose of monotherapy of surufatinib, 693 (97.1%) 
reported treatment-emergent adverse events (TEAEs) and 675 (94.5%) reported treatment-
related TEAEs.  Treatment-related TEAEs reported in ≥20% of patients included 
proteinuria, hypertension, diarrhea, blood bilirubin increased, blood thyroid stimulating 
hormone increased, aspartate aminotransferase (AST) increased, and hypertriglyceridemia.  
A total of 476 (66.7%) 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 ≥1%) were gastrointestinal hemorrhage, intestinal obstruction, hepatic function 
abnormal, proteinuria, pneumonia, acute kidney injury, jaundice cholestatic, abdominal 
pain, and anemia.  The reported fatal SAEs that were considered related to study drug (9 
patients) included hypovolemic shock, diarrhea, gastrointestinal hemorrhage, disseminated 
intravascular coagulation and hepatic encephalopathy, liver injury, cerebral hemorrhage, 
and death.  A total of 113 (15.8%) patients reported TEAEs leading to drug 
discontinuation.  The TEAEs leading to drug discontinuation reported in ≥1% of patients 
included proteinuria (2.0%) and hepatic function abnormal (1.1%). 


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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).  The SANET-ep study met its primary endpoint at the planned interim analysis, with 
significantly improved progression-free survival (PFS) in surufatinib treated patients 
compared with placebo-treated patients (median PFS of 9.2 months in surufatinib treated 
patients versus 3.8 months in placebo-treated patients; hazard ratio [HR] 0.334; p<0.0001).  
Similarly, surufatinib-treated patients in the SANET-p study showed a statistically 
significant improvement in PFS compared with placebo-treated patients (median PFS of 
10.9 months in surufatinib-treated patients versus 3.7 months in placebo-treated patients; 
HR 0.491; p=0.0011).  In addition to the primary PFS endpoint, SANET-ep and SANET-
p demonstrated meaningful improvements in other important efficacy measures such as 
overall response rate (ORR), disease control rate (DCR), duration of response (DoR), and 
time to response (TTR).  
Please refer to the surufatinib Investigator’s Brochure (IB) for additional details regarding 
clinical safety and efficacy in ongoing and completed studies of surufatinib. 


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3 
STUDY RATIONALE 
During the pathogenesis of cancer, tumors can secrete a variety of factors to stimulate the 
formation of tumor vasculatures in order to increase their supply of nutrients and oxygen.  
Such tumor vasculatures are often formed by rapid endothelial cell proliferation and packed 
coarsely, leading to increased permeability and tumor cell leakage into the circulation [3].  
Vascular endothelial cell growth factor (VEGF) and fibroblast cell growth factor (FGF) 
play key roles in tumor angiogenesis and have become two molecular targets of intense 
research for anti-angiogenesis therapies [4-5].  
Highly selective antibodies against VEGF or its receptor VEGFR have demonstrated 
significant clinical benefit and have been widely used for the treatment of certain cancers 
[6].  Small molecule drugs, including sunitinib and sorafenib, targeting the VEGF receptor 
(VEGFR) tyrosine kinase signaling pathway have also contributed significantly in treating 
cancer [7,8].  However, most of the early generation small molecule VEGFR tyrosine 
kinase inhibitors (TKIs) inhibit many kinases (multi-kinase inhibitors) in addition to 
VEGFR, resulting in “off-target” toxicities [9]. Improving kinase selectivity has become a 
key focus for newer generation TKIs.  
Surufatinib, discovered by Hutchison MediPharma International, primarily inhibits 
VEGFR, fibroblast growth factor receptor (FGFR), and CSF-1R, sparing many other 
kinases.  Preclinical safety evaluation results supported a good safety profile for 
surufatinib. 
3.1 
Mechanism of Action 
The primary action of surufatinib is anti-angiogenic, by inhibition of VEGFR 1, 2, and 3.  
As stated above, angiogenesis is a validated target in a variety of solid malignancies, 
through inhibition VEGF or VEGFR, and either by a monoclonal antibody or small 
molecule tyrosine kinase inhibitor.  Surufatinib also inhibits fibroblast growth factor 
receptor (FGFR) and colony stimulating factor-1 receptor (CSF-1R). 
Fibroblast growth factor receptor (FGFR) signaling plays important roles in tumor cell 
proliferation, angiogenesis, migration, and survival [10].  Inhibition of FGF and/or its 
receptor are therefore attractive targets in cancer therapy.  A recent finding is that 
approximately 10-16% of patients with intrahepatic cholangiocarcinoma, a type of BTC, 
have FGFR genetic aberrations; the most common of these are gene fusions of FGFR-2 
[11].  This raises the possibility that the FGFR is a potential target in the treatment of a 
subset of patients with BTC.  There is an intensive ongoing research effort to address this 
question. It is possible that surufatinib could have an anti-tumor effect through FGFR in 
patients with gene fusions or other genetic aberrations of FGFR-2. 
CSF-1 is produced by tumor cells and/or other cells in the tumor microenvironment to 
stimulate tumor associated macrophages (TAMs), which result in local suppression of the 
immune response to malignant tumor cells [12].  Drugs that inhibit CSF-1 or CSF-1R are 
currently under investigation.  The aim is to block the local immunosuppressive effect of 
TAMs that protects tumor cells.  Inhibition of CSF-1 signaling can change TAMs from an 
immunosuppressive to a pro-inflammatory state with tumoricidal activity [12]. Surufatinib 
may exert such an action on TAMs through inhibition of CSF-1R. 
The results of completed and ongoing clinical studies of surufatinib in China are reviewed 
in Section 2.3.  The most encouraging preliminary results are in patients with BTC, pNET, 
and epNET, and this is the rationale for including patients with these malignancies in the 


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expansion phase of this study.  Soft tissue sarcomas (STSs) have also been chosen as an 
expansion cohort based upon anti-tumor activity of multitargeted kinase inhibitors for the 
indication.  Information about these malignancies and how surufatinib, if approved, would 
fit into current practice guidelines, is discussed below. 
3.2 
Unmet Medical Need 
There is an unmet medical need for new, safe and effective therapy for patients with 
advanced BTC, advanced pNET, advanced epNET, and advanced STS. 
Biliary Tract Cancers (BTCs) include the following malignancies: gallbladder carcinoma, 
intrahepatic and extrahepatic cholangiocarcinoma, and cancer of the Ampulla of Vater.  
According to current NCCN practice guidelines [13], standard first-line therapy for locally 
advanced or metastatic BTC is cytotoxic chemotherapy with gemcitabine and cisplatin; for 
patients with microsatellite-instability high (MSI-H) tumors, immunotherapy with 
pembrolizumab is also indicated [13].  However, there is no established second-line 
therapy, so patients who have failed first-line therapy have an unmet medical need, and will 
be investigated in the expansion phase of the current study. 
Neuroendocrine Tumors (NETs): Neuroendocrine cells are widely distributed throughout 
the body, and neuroendocrine tumors arise from almost any part of the gastrointestinal tract, 
lungs, and other sites [14].  These tumors are broadly divided into well differentiated, 
relatively slow-growing tumors, and poorly differentiated, aggressively growing tumors 
termed neuroendocrine carcinomas. 
Table 1 
Distribution of Neuroendocrine Tumors by Primary Site 
Primary site 
Number 
Percent 
Lung                        20,948 
24.6 
Rectum                      14,938 
17.5 
Small intestine                10,519 
12.4 
Pancreas                     7,612 
8.9 
Stomach                     3,967 
4.7 
Appendix                    
3,341 
3.6 
Colon                       
2,989 
3.5 
Cecum                       2,206 
2.6 
Liver                        509 
0.6 
Thymus                      237 
0.3 
Other/ unknown               17,865 
21.0 
Total                        85,131 
100 
Source: Sackstein P, et al. Seminars Oncol. 2018 Aug; 45(4):249-258 [14] 
Well-differentiated tumors that arise from the digestive system or lungs have traditionally 
been called carcinoid tumors, but now are called gastrointestinal NETs or extrapancreatic 
(EP)-NETs.  Those that arise from the pancreas were traditionally called pancreatic islet 
cell tumors, but are now called pancreatic NETs, or pNETs.  Collectively, the well 
differentiated tumors are called Gastroenteropancreatic (GEP) NETs.  In considering the 
distribution of GEP-NETs by site of origin according to the Surveillance, Epidemiology, 
and End Results (SEER) database (Table 1), it is evident that pNETs comprise 
approximately 8.9% of all NETs [13]. 


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Functioning NETs: GEP-NETs can also be defined by their functional status.  
Functioning epNETs are characterized by the presence of clinical symptoms (carcinoid 
syndrome) due to excess secretion of a variety of substances by the tumor (polypeptides, 
biogenic amines, and prostaglandins).  The most common symptoms of carcinoid 
syndrome are flushing and diarrhea. Carcinoid syndrome is treated with somatostatin 
analogues (SSAs), octreotide and lanreotide, both of which are effective in relieving 
symptoms [16-19]. 
Functioning (hormone-secreting) pancreatic NETs are classified according to the 
predominant hormone they secrete and the resulting clinical syndrome (eg, insulinoma, 
gastrinoma, glucagonoma, VIPoma, somatostatinoma). 
Treatment of NETs: The names, routes of administration, and indications of FDA-
approved drugs for the treatment of patients with well-differentiated, low to intermediate 
grade NETs are summarized in Table 2.  The somatostatin analogues (SSAs) octreotide 
[17] and octreotide LAR [18] are approved for the symptomatic treatment of patients with 
functioning metastatic carcinoid tumors (diarrhea, flushing) and functioning VIPomas 
(profuse watery diarrhea).  The SSA lanreotide depot [19] is approved for the treatment of 
patients with unresectable, well- or moderately-differentiated, locally advanced or 
metastatic GEP-NETs to improve PFS. 
When there is disease progression (during treatment with SSAs, where applicable) in 
patients with pNETs, the oral kinase inhibitors everolimus [20] and sunitinib [21] are 
indicated to improve PFS.  Everolimus is also approved for the treatment of patients with 
progressing, well-differentiated, non-functioning, epNETs (carcinoid tumors) of GI tract or 
lung origin, to improve PFS [20], but is not approved for functioning carcinoid tumors. 
Patients with a clinically high disease burden are treated with cytotoxic chemotherapy [22].  
A recently 
approved 
option 
for 
patients 
with 
somatostatin 
receptor-positive 
gastroenteropancreatic (GEP-NETs) is Peptide Receptor Radioligand therapy (PRRT) with 
Lutathera® (177Lu-Dotatate) [23].  Current limitations of 177Lu-Dotatate include the 
complexity of its administration, lack of widespread availability, and uncertainty of its 
efficacy relative to more established therapies. 
Table 2 
FDA-Approved Drugs for the Treatment of Neuroendocrine 
Tumors (NETs) 
Drug Name 
Brand (INN) 
Route of 
administration 
Drug Type and FDA-Approved Indication 
Sandostatin® 
Injection 
(octreotide) 
s.c. injection 
Sandostatin Injection is a somatostatin analogue for the 
symptomatic treatment of patients with metastatic carcinoid 
tumors where it suppresses or inhibits the severe diarrhea and 
flushing episodes associated with the disease. (Symptomatic) 
treatment of profuse watery diarrhea associated with VIPomas. 
Sandostatin studies were not designed to show an effect on the 
size, rate of growth, or development of metastases. 
Sandostatin LAR 
Injection® 
(octreotide LAR) 
i.m. injection 
Sandostatin LAR is a somatostatin analogue indicated for 
treatment in patients who have responded to and tolerated 
Sandostatin Injection for severe diarrhea/flushing episodes 
associated with metastatic carcinoid tumors; and profuse 
watery diarrhea associated with VIPomas. The effect of 
Sandostatin Injection and Sandostatin LAR Depot on tumor 
size, rate of growth and development of metastases, has not 
been determined. 


Cli nic al St u d y P r ot o c ol 2 0 1 5 -0 1 2 -0 0 U S 1  
S ur uf ati ni b   
A me n d me nt 1 1  
 
 
H utc his o n M e di P h a r m a  
 
P a g e 4 2  
 
C O N FI D E N TI A L  
 
 
T a ble 2  
F D A -A p p r o ve d Dr u gs f or t he Tre at me nt of Ne u r oe n d ocri n e 
T u m ors ( N E Ts)  
Dr u g N a me 
B r a n d (I N N)  
R o ute of 
a d mi nist r ati o n  
Dr u g T y pe a n d F D A -A p pr o v e d I n dic ati o n  
S o mat uli ne 
De p ot I nj ecti o n ®  
( d e p ot la nr e oti d e) 
d ee p s. c. i nj ecti o n  
S o mat uli ne is a s o mat ostati n a nal o g ue i n dicate d f or t he 
tr eat me nt of p atie nts wit h u nr esecta ble, well -or m o d er atel y -
differ e ntiate d, l o call y a d va nce d or metastatic 
gastr o e nter o p a ncr eatic ne ur o e n d o cri ne t u m ors ( G E P -N E Ts) t o 
i m pr o ve pr o gr essi o n-fr ee s ur vi val. 
Afi nit or ®  
( e ver oli m us) 
or al  
Afi nit or is a ki nase i n hi bit or i n dicate d f or t he tr eat me nt of 
a d ults wit h pr o gr essi ve ne ur o e n d o cri ne t u m ors of p a ncr eatic 
ori gi n ( p N E T ) a n d a d ults wit h pr o gr essi ve, well-differ e ntiat e d, 
n o n -f u ncti o nal ne ur o-e n d o cri n e t u m ors ( N E T) of 
gastr oi ntesti nal ( GI) or l u n g ori gi n t hat ar e u nr esect a ble, 
l o call y a d va nce d or metastatic. Afi nit or is n ot i n dicate d f or t he 
tr eat me nt of p atie nts wit h f u ncti o nal car ci n oi d t u m ors. 
S ute nt ®  
(s u niti ni b) 
or al  
S ute nt is a ki nase i n hi bit or i n dicate d f or t he tr eat me nt of 
pr o gr essi ve, well -differ e ntiate d p a ncr eati c ne ur o e n d o cri ne 
t u m ors ( p N E T) i n p atie nts wit h u nr esecta ble l o call y a d va nce d 
or metastatic disease.  
L utat her a ( 1 7 7L u -
d otatate) 
i nj ecti o n®  
i. v. i nj ecti o n 
(r a di o acti ve)  
L utat her a is a r a di ola b ele d s o mat ostati n a nal o g i n dicate d f or 
t he tr eat me nt of s o mat ostati n r ec e pt or-p ositi ve gastr o e nter o -
p a ncr eatic ( G E P -N E Ts), i ncl u di n g f or e g ut, mi d g ut, a n d 
hi n d g ut ne ur o e n d o cri ne t u m ors i n a d ults.  
 
I n t he c urr e nt st u d y, pati e nts wit h N E Ts m ust ha ve u nr ese cta ble or m etastati c, w ell-
differe nti at e d, l o w -t o-i nt er me diate-gra d e ( G 1 -G 2) disease t hat h as pr o gr esse d o ver t h e 
1 2  m o nt hs pri or t o e nr oll m e nt.  P ati e nts wit h p N E T S m ust ha ve fail e d pri or t hera p y wi t h 
eit her e v er oli m us or s u niti ni b, a n d t h ose wit h e p N E T s m ust ha v e fail e d t her a p y wit h 
e ver oli m us.  P ati e nts m a y re cei ve S S As f or s y m pt o m ati c c o ntr ol of f u ncti o ni n g t u m ors if 
t he y h a ve b ee n o n a sta bl e d ose of t h e S S A f or at l east 2 m o nt hs pri or t o e nr oll me nt.  S S A 
t hera p y d uri n g t he st u d y is n ot per mitt e d i n pati e nts wit h n o n-f u ncti o ni n g N E Ts.  P ati e nts  
w h o ha ve rec ei ve d S S A t hera p y i n t h e a bs e n ce of s y m pt o ms, wit h t he i nt e nti o n of 
pr ol o n gi n g P F S, s h o ul d als o ha ve rec ei ve d tar gete d t hera p y (e v er oli m us or s u niti ni b) i n 
or der t o be eli gi bl e f or e nr oll m e nt.  Si nce disease pr o gressi o n is a r e q uire me nt f or 
e n r oll m e nt, b ot h t he S S A a n d t he tar gete d t her a p y m ust ha ve b ee n disc o nti n ue d at least 
4  wee ks bef ore t h e first d ose of st u d y dr u g.  
Preli mi nar y d ata fr o m t he o n g oi n g P has e 2  st u d y of s ur ufati ni b i n t he tre at me nt of pati e nts 
wit h a d va nce d B T C 
, a n d t he c o m pl ete d P hase 1 b/ 2 st u d y 
i n pati e nts wit h a d va nce d N E Ts ( b ot h p N E Ts a n d e p N E T s) i n C hi na are pr o misi n g.  
T hese data s u p p ort t he i ncl usi o n of pati e nts wit h a d va nce d B T C, a d va n c e d p N E Ts, a n d 
a d va nc e d e p N E T s i n t he e x pa nsi o n p hase of t he c urre nt st u d y.  
S oft tiss ue sarc o ma s ( S T Ss) are mali g n a nt t u m ors t hat arise i n mes o der mal tiss ues of t he 
e xtre miti es ( 5 0 %), tr u n k a n d retr o perit o ne u m ( 4 0 %), or he a d a n d nec k ( 1 0 %).  
I nter nati o nal i nci de nc e r ates ra n ge fr o m 1. 8 t o 5 cases per 1 0 0, 0 0 0 i n di vi d uals per ye ar 
[2 4 ].  I n t he year 2 0 1 9, t here w as a n esti mate d 1 2, 7 5 0 ne w cases a n d 5, 2 7 0 deat hs fr o m 
s oft tiss ue sarc o m a i n t he 
U nite d States ( U S) [2 5] .  S oft tiss ue sarc o m as ar e 
heter o ge n e o us, wit h m ore t ha n 1 0 0 differe nt s u bt y pes i de ntifie d b y t h e 
W orl d Healt h 
Or ga niz ati o n a n d ar e classifie d acc or di n g t o tiss ue of ori gi n [2 6 ].   
C CI
C CI


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For patients with incurable disease not amenable to locoregional therapies, first line 
systemic treatment consists of cytotoxic chemotherapy.  Doxorubicin has been considered 
the standard systemic therapy in the management of metastatic sarcomas for several years 
[27], [28].  Gemcitabine and docetaxel were found to have similar outcomes as 
doxorubicin alone [29].  Other drugs that may have clinical activity as single agents are 
ifosfamide, and paclitaxel (depending on histology) [30],[31],[32],[33]. 
Since 2012, three drugs have been approved for the treatment of soft tissue sarcomas after 
failure of a first-line chemotherapy: pazopanib for all soft tissue sarcomas except adipocytic 
subtypes, eribulin for liposarcoma, and trabectedin for leiomyosarcoma and liposarcoma 
[34],[35],[36],[37].  Despite new agents, treatment for advanced STS remain paliative 
only, and remains an unmet medical need.  
Pazopanib is a multitargeted, oral, small molecule inhibitor of several tyrosine kinases 
including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth 
factor receptor alpha and beta; and fibroblast growth factor receptor-1, and -3.  The phase 
3 randomized, double-blind PALETTE study (NCT00753688) from the European 
Organization for Research and Treatment of Cancer compared pazopanib to placebo in 369 
patients with different subtypes, excluding adipocytic sarcomas and gastrointestinal stromal 
tumors, after progression on a first-line anthracycline-based regimen [38].  The median 
PFS was 4.6 months for patients who received pazopanib versus 1.6 months for patients 
who received placebo.  Overall survival (OS) difference was not statistically significant at 
12.5 months for patients who received pazopanib versus 10.7 months for patients who 
received placebo (HR, 0.86; 95% confidence interval [CI], 0.67–1.1).  Overall response 
rate was 6% for patients who received pazopanib versus 0% for patients who received 
placebo.  The most common grade 3/4 toxicities associated with pazopanib were fatigue, 
hypertension, diarrhea, anorexia, and transient liver function tests abnormalities.  Based 
on the above data, pazopanib was approved by the U.S. Food and Drug Administration 
(FDA) in 2012 for the treatment of patients with soft tissue sarcomas, excluding adipocytic 
subtypes, who have received previous chemotherapy.  
Given the limited efficacy of currently available treatment options for patients with 
unresectable or metastatic soft tissue sarcomas, testing of new agents is warranted.  
This is a dose escalation and dose expansion study, which is conducted in a US patient 
population to confirm the safety and efficacy results of clinical studies performed in China.  
During the dose expansion portion of the study, 4 expansion cohorts have been added, Arm 
A (BTC cohort), Arm B (pNET cohort), Arm C (epNET cohort), and Arm D (STS).  
Preliminary data from the cohort of patients with advanced BTC in the Expansion Cohort 
of the present study have shown encouraging results.  In order to characterize further the 
safety and efficacy of surufatinib in this patient population, an additional 15 patients will 
be enrolled into Arm A (BTC ) of the expansion phase, for a total enrollment of at least 30 
patients.  Arm B (pNET) and Arm C (epNET) will enroll no less than 15 patients each.  
If needed, Arm B and Arm C could also enroll additional patients to characterize further 
the safety and efficacy of surufatinib in these patient populations.  Arm D (STS) will enroll 
approximately 55 patients. 
3.3 
Benefit and Risk Assessment 
Based on the available non-clinical and clinical data, identified risks of surufatinib include 
hepatic disorders, proteinuria, hypertension, myelosuppression, haemorrhage, and acute 
kidney injury.  Potential risks include infection, intestinal obstruction, myocardial 


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ischaemia, cardiac failure, thromboembolism, pancreatitis, GI perforation, and posterior 
reversible encephalopathy syndrome.  These are further described in the surufatinib IB. 
Appropriate exclusion criteria, monitoring, and dose modification guidance are included in 
the protocol to ensure the safety of patients enrolled in the clinical trial.  Patients are 
excluded if they have signs, symptoms, or history that may put them at risk in the context 
of the identified and potential risks of surufatinib including abnormal serum total bilirubin 
or ALT/AST or other signs of hepatic damage; urine protein ≥2+; uncontrolled 
hypertension; abnormal neutrophil count, platelet count, or haemoglobin level; signs of risk 
of haemorrhage; creatinine clearance <60 mL/min; conditions that could possibly result in 
gastrointestinal tract hemorrhage or perforation; clinically significant cardiovascular 
disease; history of thromboembolic events; and posterior reversible encephalopathy 
syndrome (PRES).  Patients with other disease, metabolic disorder, physical examination 
abnormality, abnormal laboratory result, or any other condition that investigators suspect 
may prohibit use of the investigational product, affect interpretation of study results, or put 
the patient at high risk are also excluded.  
Section 7.2.3 provides detailed guidance on dose modifications for important identified 
risks including hypertension, proteinuria, liver function and haemorrhage, and general 
dosing guidance to protect subjects are included in Section 7.2.2.  Thus, the identified and 
potential risks of treatment with surufatinib are appropriately mitigated by measures in the 
protocol.  
There remains an unmet need for patients with advanced BTC, NETs, and STS.  Evidence 
to date suggests that surufatinib may potentially be efficacious in the treatment of various 
cancers, including those to be included in the proposed trial.  Based on the preclinical 
toxicology data, the safety profile from clinical trials, the proposed safety management 
actions, the limited life expectancy of patients with advanced malignancies, the lack of 
effective alternative treatments and the scientific design of clinical trial protocol, and the 
overall benefit/risk assessment support the administration of surufatinib to patients with 
advanced cancer as an investigational treatment in this clinical trial. 


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4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Dose Escalation Phase 
4.1.1 
Primary Objective 
The primary objective of the dose escalation phase is to evaluate the safety and tolerability 
of surufatinib in patients with advanced solid tumors of any type and to determine the MTD 
and/or RP2D. 
4.1.2 
Primary Endpoint 
The incidence of DLTs in each cohort. 
DLT is defined as: 
⚫ Any Grade 4 non-hematologic toxicity; 
⚫ Any Grade 3 non-hematologic toxicity related to study drug except for 
nausea/vomiting, diarrhea, constipation, hypertension and electrolyte imbalances 
downgraded within 3 days with appropriate supportive treatment; 
⚫ Grade 4 neutropenia lasting >3 days; 
⚫ Grade 3 febrile neutropenia (absolute neutrophil count [ANC] <1.0 × 109/L with a 
single temperature of >38.3°C or a sustained temperature of ≥38°C for more than 
one hour;  
⚫ Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; 
⚫ Dose interruption for >14 days due to toxicity; 
⚫ Any life-threatening complication or abnormality not covered in the NCI CTCAE 
v. 4.03. 
− In the absence of clinical abnormality, repeat laboratory testing will be 
conducted to confirm significant laboratory findings prior to designation as a 
DLT. 
− The MTD is the highest dose at which no more than 1 of 6 patients developed 
DLT. If 2 or more of 6 patients developed DLT at a particular dose level, then 
that dose has exceeded the MTD. 
− In general, the safety and tolerability of surufatinib will be evaluated based on 
the AE data. Other safety parameters include physical examination, vital signs, 
laboratory test results (ie, hematology, chemistry panel, thyroid function, and 
urinalysis), 12-lead electrocardiogram, and echocardiogram.  
4.1.3 
Secondary Objectives 
• To evaluate the PK characteristics of multiple-dose surufatinib and to investigate the 
metabolite profile of surufatinib in the plasma of patients with solid tumors 


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• To evaluate the anticancer activity of surufatinib in patients with solid tumors 
according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
4.1.4 
Secondary Endpoints 
The secondary endpoints of the study include the primary PK parameters and the treatment 
outcomes (per RECIST Version 1.1) as described below. 
• Pharmacokinetic parameters, which include: 
− Maximum plasma concentration (Cmax) 
− Time to reach maximum concentration (Tmax) 
− Terminal half-life (t1/2) 
− Area under the concentration-time curve in a selected time interval (AUC0-t) 
− Area under the concentration-time curve in the time interval from 0 to infinity 
(AUC0˗) 
− Apparent clearance (CL/F) 
− Apparent volume of distribution (Vz/F) 
− Mean residence time (MRT) 
− Accumulation index based on AUC 
• ORR 
• DCR 
• DoR 
• PFS 
• Percentage change in tumor size from baseline according to RECIST Version 1.1 
4.2 
Dose Expansion Phase  
4.2.1 
Primary Objective 
To evaluate the anticancer activity of surufatinib at the recommended phase 2 dose (RP2D) 
from the dose escalation phase, in patients with advanced BTC, patients with advanced 
pNETs, patients with locally advanced, unresectable, metastatic epNETs, and patients with 
STS treated at a dose of 300 mg QD . 
NOTE: The MTD/RP2D of 300 mg QD was declared at the time Amendment 7 was 
written.  The RP2D in this trial is the same as the RP2D used in clinical trials in China. 
4.2.2 
Primary Endpoints 
The primary efficacy endpoints are: 
• PFS rate at 16 weeks in the BTC cohort (Arm A); 
• PFS rate at 11 months in the pNET cohort (Arm B); 
• PFS rate at 11 months in the epNET cohort (Arm C); 
• PFS rate at 4 months in the STS cohort (Arm D). 
4.2.3 
Secondary Objectives 
• To evaluate the PK profile of multiple dose surufatinib in patients with advanced 
BTC, patients with advanced pNET, patients with advanced epNET, and patients 
with advanced STS. 


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• To evaluate the safety of surufatinib in patients with advanced BTC, patients with 
advanced pNET, patients with advanced epNET, and patients with advanced STS. 
• To evaluate the anticancer activity of surufatinib in patients with advanced BTC, 
patients with advanced pNET, patients with advanced epNET, and patients with 
advanced STS. 
4.2.4 
Secondary Endpoints 
• Pharmacokinetic parameters, which include but are not limited to, Cmax, Tmax, first-
order rate constant Kel, AUC, t1/2, CL/F, Vz/F, accumulation ratio, and dose 
proportionality between AUC and dose and Cmax and dose 
• Safety, as assessed by: 
− The frequency and severity of adverse events  
− Physical examination findings 
− Vital signs 
− Laboratory test results (ie, hematology, chemistry panel, and urinalysis) 
− 12-lead electrocardiogram 
− Echocardiogram 
• Efficacy treatment outcomes, which consist of: 
− ORR 
− DCR 
− TTR 
− DoR 
− Percentage change in tumor size from baseline (per RECIST Version 1.1) 
4.2.5 
Exploratory Objectives 
• To assess selected tumor markers based on type of malignancy 
• To evaluate the OS in patients with advanced BTC and advanced STS 
4.2.6 
Exploratory Endpoints 
• Tumor markers may include, but are not be limited to, serum CEA and CA 19-9 
(patients with BTC) serum chromogranin A (CgA) and neuron-specific enolase 
(NSE) for patients with pNET and epNET; and VEGF for the BTC, pNET, and 
epNET disease cohorts.  Assessment of tumor markers will be performed within 
28 days prior to the start of treatment with study drug (C1D1) and at each tumor 
assessment visit.  
• Overall survival limited to patients enrolled to the BTC and STS cohorts only. 
 
 


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5 
INVESTIGATIONAL PLAN 
5.1 
Description of the Study 
This is an open-label trial of surufatinib taken orally once daily (QD), and it consists of 
two phases: a dose escalation phase in patients with advanced solid tumors of any type, and 
a dose expansion phase in patients with advanced BTC (Arm A), advanced pNETs (Arm B), 
advanced epNETs (Arm C), or STSs (Arm D). The two phases will be conducted as 
described below.  
5.1.1 
Dose Escalation Phase  
A 3+3 design will be used for this phase of the study. As of Amendment 7, a total of 35 
evaluable patients have been enrolled in the dose escalation phase and the MTD/RP2D has 
been declared at 300 mg QD. 
The trial was to evaluate 5 dose levels of surufatinib 50 mg, 100 mg, 200 mg, 300 mg and 
400 mg on a QD dosing schedule. 
A minimum of 3 patients were to be enrolled and observed for toxicity at each dose level.  
If the 3 patients initially enrolled in a dose cohort completed the DLT assessment window 
(Cycle 1, Days 1-28) without experiencing a DLT, another 3 patients were to be enrolled at 
the next higher dose level.  If 1 of the initial 3 patients enrolled at any dose level 
experienced a DLT during the DLT assessment window, additional patients were to be 
enrolled at that dose level for a minimum of 6 evaluable patients for the DLT evaluation.  
If 1 DLT was observed in 1 of the 6 evaluable patients at this dose level, dose escalation 
was to proceed to the next pre-defined dose level.  If 2 or more DLTs were observed in 
the 6 evaluable patients at a given dose level, the dose escalation was to be halted.  If this 
dose level was ≥50% higher than the previous dose level, an intermediate dose level was to 
be evaluated for toxicity in the same manner as described above.  If the dose level was 
<50% higher than the previous dose level, additional patients were to be enrolled at the 
previous dose level, if necessary, to form a dose cohort of minimum 6 evaluable patients.  
The MTD is the highest dose reached with no more than 1 DLT among 6 evaluable patients. 
Pharmacokinetic samples will be collected as specified in Table 12.  
Safety monitoring and evaluation for dose escalation will be carried out by the Safety 
Review Committee (SRC) upon completion of the DLT observation period of each cohort.  
Dose escalation decisions are based on safety and PK data from this ongoing trial, as well 
as consideration of safety and PK data at comparable drug exposures from patients in 
previously conducted clinical trials in China. 
If a patient meets any DLT non-evaluable criteria during the DLT assessment period, the 
patient will be replaced. 
Patients who complete the DLT observation window (Cycle 1, Day 1-28) and are deemed, 
in the investigator’s judgment, to have benefited from surufatinib treatment could be 
permitted, at the investigator’s discretion, to continue with surufatinib treatment until 
disease progression, death, intolerable toxicity, pregnancy, or loss of benefit from the study 
drug.  Patients with acceptable toxicity and ongoing clinical benefit were to be permitted 
to receive surufatinib for up to 1 year at the investigator’s discretion and with the sponsor’s 
agreement.  Intra-patient dose escalation to a higher dose that has been cleared (ie, no DLT 


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in 3 patients or 1 or less DLT in at least 6 patients) was to be allowed if the sponsor and 
investigator both agreed.  
Please see the flowchart for dose escalation in Table 3 and Section 7.2 for dose modification 
instructions. 
Table 3 
Flowchart of Dose Escalation 
Cohort 
Dose 
Patients 
DLTs/patients 
Dose Escalation Decision 
1 
50 mg QD 
3-6 
 
 
 
 
 
0/3 
Escalate to 100 mg QD 
 
 
 
1/3 
Enroll 3 additional patients 
 
 
 
1/3+0/3 
Escalate to 100 mg QD 
 
 
 
1/3+1/3 or 2/3 or 3/3 
Stop dose escalation  
2 (or 3, 4, 
etc.) 
100 mg QD or 
higher 
3-6 per cohort 
Follow the same rules as above 
An improved surufatinib formulation in 50 mg and 200 mg capsules (formulation No. PD-
012-042) was introduced while the dose escalation phase of the study was ongoing.  The 
improved surufatinib capsules have replaced the older surufatinib capsules (formulation 
No. PD-012-023), and will be used for the rest of the trial.  Improved formulation (PD-
012-042) showed improved consistency of production capability compared to the prior 
formulation (PD-012-023), including content uniformity with comparable quality 
attributes.  The dose escalation of the new surufatinib capsules will follow the same rules 
as described above.  
After considering the safety, tolerability, and PK data in the 300 mg QD (n=9) and initial 
400 mg QD (n=7) cohorts, the SRC members agreed to enroll another 6 patients in the 400 
mg QD cohort of the dose escalation phase.  A total of 13 patients were enrolled in 400 
mg QD dose escalation cohorts: Cohort 6 (n=4), Cohort 6+ (n=3), and Cohort 7 (n=6).  
However, the MTD and RP2D were declared at 300 mg QD on 30 November 2018, when 
2 of 6 DLT-evaluable patients reported DLTs in Cohort 7 (400 mg QD) of the dose 
escalation phase (see subheading d. below for additional information). 
5.1.1.1 
Dose-Limiting Toxicity Assessment Window 
The DLT assessment window is the 28 days in the first cycle (Days 1-28).  Any patient 
considered to be non-evaluable for DLT as defined below was to be replaced by an 
additional patient at that same dose level.  
5.1.1.2 
Definition of DLT Evaluable Patients 
A patient will be DLT evaluable if the patient: 
• Has not received any preventive treatment during the DLT period; AND 
• Has completed the first 28-day treatment cycle with complete safety evaluations 
and has received at least 75% of the assigned surufatinib dose;  
OR 
• Has a confirmed DLT during the first 28-day treatment cycle. 


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5.1.1.3 
Definition of a Dose-Limiting Toxicity (DLT) 
All AEs, including DLTs, are to be graded according to the NCI CTCAE, v. 4.03. A DLT 
is defined as one of the following toxicities occurring during the DLT assessment window 
(Cycle 1, Days 1-28) and determined by the investigator to have a reasonable possibility of 
being related to surufatinib. 
• Any Grade 4 non-hematological toxicity; 
• Any Grade 3 non-hematological toxicity except for nausea/vomiting, diarrhea, 
constipation, electrolyte imbalances, or transient hypertension downgraded within 
3 days with appropriate supportive treatment; 
• Grade 4 neutropenia lasting >7 days; 
• Grade 3 febrile neutropenia (absolute neutrophil count <1.0 × 109/L with a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for more than one 
hour; 
• Grade 4 thrombocytopenia or ≥Grade 3 thrombocytopenia associated with 
tendency to bleed;  
• Dose interruption or delay for >14 days due to toxicity;  
• Any life-threatening complication or abnormality not covered in the NCI CTCAE 
v. 4.03. 
In the absence of clinical abnormality, repeat laboratory testing will be conducted to 
confirm significant laboratory findings prior to designation as a DLT.  
5.1.1.4 
Definition of Maximum Tolerated Dose (MTD) 
The MTD is defined as the maximum dose at which no more than 1 out of 6 patients in a 
single dose group experiences a DLT in Cycle 1 (Days 1-28). 
5.1.2 
Dose Expansion Phase 
The expansion phase will evaluate the anti-cancer activity of surufatinib, and confirm the 
safety and tolerability of surufatinib at the RP2D determined at the end of the dose 
escalation phase. 
Under amendment 7 of this protocol, the MTD was declared when 2 of the 6 DLT evaluable 
patients in Cohort 7 (400 mg QD dose) of the dose escalation phase reported DLTs.  There 
was an ad hoc meeting of the SRC on 30 November 2018.  The SRC agreed with the 
declaration of 300 mg QD as the MTD of surufatinib in this trial and agreed that 300 mg 
QD is the RP2D going forward.  The minutes of this ad hoc SRC meeting were distributed 
to all investigative sites on the same day.  It was also agreed that patients who were already 
receiving 400 mg QD could remain on this dose, provided that 1) there was no major 
toxicity and 2) the affected patients gave informed consent not to reduce the dose to 300 
mg after discussion with the investigator.  However, no patients could have their dose 
escalated to 400 mg going forward, including all patients in the dose expansion phase. 
The safety of all enrolled patients will be closely monitored from the time of the initial dose 
of investigational treatment until 30 days after the last treatment 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 AEs will be graded in accordance with the NCI 
CTCAE v. 4.03.  Tumor assessments will be conducted according to RECIST Version 1.1 
criteria at screening, Cycle 2 Day 1 and every 8 (±1) weeks thereafter.  Confirmation of 


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CR and PR is required at no less than 4-week intervals between the date of initial 
response/progression and the confirmation assessment date. 
5.2 
Sample Size 
Approximately 95 to 150 patients will be enrolled in this two-phase study: 35 patients in 
the dose escalation phase and approximately 115 additional patients in the dose expansion 
phase.  The actual enrollment number may vary, depending on the number of dose levels 
evaluated and the number of DLTs observed in each cohort, as well as the potential need to 
further characterize individual cohorts in the dose expansion phase. 
As of Amendment 7, an additional 15 patients will be enrolled into Arm A (BTC) of the 
Expansion phase, for a total enrollment of at least 30 advanced BTC patients.  The reason 
for increasing enrollment into Arm A (advanced BTC) is that preliminary data from the 
ongoing patients in this cohort have shown encouraging results.  The additional patients 
will allow further characterization of the safety and efficacy of surufatinib in this patient 
population.  Arm B (pNET) and Arm C (epNET) will enroll at least 15 patients each.  If 
needed, Arm B and Arm C could enroll additional patients in order to characterize further 
the safety and efficacy of surufatinib in these patient populations. 
As of Amendment 8, approximately 45 additional patients with STS will be enrolled to Arm 
D. 
As of Amendment 10, an additional 10 patients will be added to the arm D (STS) for a total 
enrollment of 55 patients. 
5.3 
Investigational Site 
The study plans to enroll patients at approximately 8 to 15 sites. 
5.4 
Safety Review Committee 
Safety monitoring and evaluation for dose escalation will be carried out by the Safety 
Review Committee (SRC) upon completion of the DLT observation period of each cohort 
in dose escalation.  The SRC is chaired by the Sponsor’s Clinical Program Leader of the 
surufatinib program, and members will include the principal investigators (PIs), the 
Sponsor’s PK scientist, medical monitor, safety scientist, and the contract research 
organization’s (CRO’s) medical monitor.  Dose escalation decisions are based on safety 
and PK data from this ongoing trial, as well as consideration of safety and PK data at 
comparable drug exposures from patients in previously conducted clinical trials in China. 
For the dose expansion phase of the trial, a separate, specific SRC will be established to 
ensure the safety of all patients treated with study drug in the STS cohort (STS-SCR).  
Review of available safety laboratories, adverse events, and any other pertinent data 
available will be reviewed after the first 4 patients in each sarcoma cohort have completed 
at least 1 cycle of treatment.  The recommendations of the STS-SRC will be based on the 
members’ clinical assessment of the cumulative safety data provided for review.  The SRC 
will not be charged with the application of formal statistical stopping rules for safety. 
5.5 
Patient Discontinuation 
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The investigator has the right to discontinue a patient from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if he or she 
continues in the study and for reasons of non-compliance (eg, missed doses, visits) or 
pregnancy or if the investigator determines it is in the best interest of the patient.  
Any patient who discontinues treatment but does not withdraw informed consent should be 
encouraged to return to the study site for a treatment completion visit.  See Appendix 1 
for the assessments that are to be performed for patients who prematurely withdraw from 
the study during the treatment period.  The primary reason for discontinuation must be 
recorded on the appropriate CRF.  Patients discontinuing surufatinib for reasons other than 
progression of the underlying malignancy are to continue tumor assessments per 
Appendix 1, until documentation of disease progression, start of new anti-tumor therapy, 
or withdrawal of informed consent. 
5.6 
Overall Survival Follow Up 
Overall survival is defined as the time from the date of the first dose of study drug until the 
date of patient death (any cause).  Investigators and/or delegated site staff should follow 
patients enrolled to the BTC and STS expansion cohorts, who have signed informed consent 
under sponsor Amendment 8 (or later), until death or until the patient is lost to follow up.  
Follow up for OS will begin after the end of treatment (EOT) visit has been completed.  
Patients should be followed every 8 weeks (± 2 weeks) via telephone or in a manner that 
follows local site SOPs.  Site staff should attempt to contact a patient 3 times and consult 
with authorized family members for the status of the patient (when applicable) before 
considering a patient lost to follow up.  Data to be collected should include the date the 
patient was last known to be alive, the date of death, and the cause of death.  
Treatment completion of patients will occur if any of the following 3 criteria is met: 
1. Disease progression (according to RECIST Version 1.1), unless there is reasonable 
evidence of clinical benefit to justify continuation on the study drug. The 
continuation decision should be made by the investigators in consultation with the 
sponsor. The disease progression date is the date when radiological disease 
progression is first reported according to RECIST Version 1.1 criteria;  
2. Death;  
3. End of this study. 
Early discontinuation of study drug will occur if any of the following criteria is met: 
1. Patient withdrawal of informed consent;  
2. Intolerable toxicity;  
3. Poor patient compliance;  
4. Use of other antitumor treatment during the study;  
5. Pregnancy occurred during the study treatment period;  
6. Patient is lost to follow-up;  
7. Treatment discontinuation is in the best interest of the patient based on the 
assessment of the investigator and sponsor. 
5.7 
Study Discontinuation 
Hutchison MediPharma has the right to stop the study at any time.  The reasons for 
stopping the study may include, but are not limited to, the following: 


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• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• Patient enrollment is unsatisfactory. 
5.8 
End of Treatment (Individual Patient) 
5.8.1 
End of Study 
A subject is considered to have completed the study once he or she has completed the last 
visit or the last scheduled procedure as outlined in the Schedule of Events (Table 12). 
5.8.2 
Study Completion Date 
The study will be considered completed once the following has occurred:  
• The last subject has completed the last visit or last scheduled procedure. 


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6 
PATIENT SELECTION 
Patients with locally advanced or metastatic solid tumors for whom approved therapy either 
does not exist or has proven to be ineffective or intolerable are eligible to participate in the 
dose escalation phase of this study.  Patients will undergo a screening period of up to 
4-weeks, during which they will be assessed for compliance with the inclusion and 
exclusion criteria as outlined below. 
6.1 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet all of the following criteria: 
1. Fully understand the study and voluntarily sign the ICF; 
2. At least 18 years old;  
3. Dose escalation phase: Histologically or cytologically documented, locally 
advanced or metastatic solid malignancy of any type, that has progressed on 
available standard systemic therapy, and for which no effective therapy or 
standard of care exists;  
4. Dose expansion phase: Histologically or cytologically documented, locally 
advanced or metastatic BTC that has progressed on standard first line 
chemotherapy (Arm A), low-to-intermediate grade (G1 or G2), well-differentiated, 
unresectable or metastatic pNET that has progressed on everolimus, sunitinib, or 
both (Arm B), low-to-intermediate grade (G1 or G2), well-differentiated, 
unresectable or metastatic epNET that has progressed on everolimus (Arm C), and 
advanced STS (of the subtypes listed below) that has progressed on at least one 
line of standard therapy (if available) or refused standard frontline cytotoxic 
chemotherapy will be evaluated for enrollment; 
NET expansion patients must also meet the following criteria: 
a. Gastroenteropancreatic NETs (GEP-NETs) or NETs of origins other than 
the lung or thymus (including unknown origins), with a mitotic rate of ≤ 
20/10 high powered field (HPF) and/or a Ki-67 proliferative index of ≤ 
20%; if the mitotic rate and Ki-67 index indicated different grades, the 
higher grade is used to assign classification; or 
b. NETs of the lung or thymus with a mitotic rate of ≤10/10 HPF; 
STS subtype eligible to be enrolled: 
i. 
Leiomyosarcoma (LMS) 
ii. 
Undifferentiated pleomorphic sarcoma (UPS) 
iii. Epitheloid sarcoma  
iv. 
Angiosarcoma 
v. 
Pigmented villonodular synovitis (PVNS) 
vi. 
Synovial sarcoma (SS)  
5. Patients taking a somatostatin analogue (SSA) to control symptoms of functioning 
pNET or epNET will be permitted to enroll in the study provided that they have 
been on a stable SSA regimen for at least 2 months before enrollment and will 
continue on this regimen during the study; 
6. Patients taking SSAs in the absence of secretory symptoms must also have been 
treated with everolimus (pNET or epNET) or sunitinib (pNET) in order to be 
eligible for this study.  Since disease progression is a requirement for enrollment 


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in the dose expansion phase, in such cases both the targeted therapy (everolimus 
and sunitinib) and the SSA must be discontinued at least 4 weeks before the first 
dose of study drug.  
7. Patients must have measurable disease (according to RECIST Version 1.1); 
8. Patients must have radiological documentation of progression of disease in the last 
12 months prior to the initiation of study drug; 
9. ECOG performance status of 0 or 1; 
10. Expected survival of more than 12 weeks; 
11. For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement (by patient and partner) 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 hormonal contraception (combined 
estrogen/progestogen, or progestogen-only), associated with inhibition of 
ovulation together with another additional barrier method (e.g., diaphragm, always 
containing a spermicide), intrauterine device (IUD), intrauterine hormone-
releasing system (IUS), bilateral tubal ligation, vasectomized partner (on the 
understanding that this is the only one partner during the whole study duration), or 
sexual abstinence.  Oral contraception should always be combined with an 
additional contraceptive method (i.e., barrier method) because of a potential 
interaction with the study drug.  The same rules are valid for male patients 
involved in this clinical trial if they have a partner of childbearing potential.  
Male patients must always use a condom.  A woman 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). 
6.2 
Exclusion Criteria 
Patients will be excluded from the study, if any of the following criteria is met: 
1. Patients with high-grade (G3) neuroendocrine tumor, even if it is well 
differentiated; 
2. Absolute neutrophil count (ANC) of < 1.5 × 109/L, or platelet count of <100 × 
109/L, or hemoglobin <9 g/dL; 
3. Serum total bilirubin >1.5 times the upper limit of normal (× ULN); 
4. ALT or AST >1.5 × ULN without hepatic metastases or ALT or AST >3 × ULN 
with hepatic metastases; 
5. Serum potassium, calcium, or magnesium levels out of normal laboratory range, 
and clinically significant in the investigator’s judgment; 
6. Creatinine clearance <60 mL/min on the basis of either 24-hour urine collection or 
the glomerular filtration rate estimated by Cockcroft-Gault equation: 
[(140 − age)  (weight in kg) × 0.85 if female] ÷  
[72 × (serum creatinine in mg/dL)] 


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7. Urine protein ≥2+; patients discovered to have ≥1+ proteinuria on dipstick 
urinalysis at baseline should undergo a 24-hour urine collection and must 
demonstrate ≤1 g of protein in 24-hour urine;  
8. Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or 
diastolic blood pressure ≥90mmHg; 
9. International Normalized Ratio (INR) >1.5 or activated partial thromboplastin 
time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intending to 
receive anti-coagulants for therapeutic purposes; 
10. Risk of or active hemorrhage; history of: active gastric/duodenal ulcer or 
ulcerative colitis; active hemorrhage of an unresected gastrointestinal tumor; 
history of gastrointestinal perforation or fistulas; or any other condition that could 
possibly result in gastrointestinal tract hemorrhage or perforation within 6 months 
prior to first dose of study drug; 
11. History of severe hemorrhage from any other site (eg, hemoptysis or hematemesis) 
within 2 months prior to first dose of study drug; 
12. History of thromboembolic event (including deep vein thrombosis [DVT], 
pulmonary embolism [PE], stroke and/or transient ischemic attack [TIA]) within 6 
months prior to the first dose of study drug; 
13. Patients with squamous non-small cell lung cancer (NSCLC); 
14. 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, New York Heart Association Class 
III/IV congestive heart failure, ventricular arrhythmias requiring treatment or left 
ventricular ejection fraction (LVEF) <50%; 
15. Mean corrected QT interval by Fridericia’s formula (QTcF) >480 msec or any 
factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as hypokalemia, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age in a first-degree 
relative;  
16. Concomitant use of any medication known to cause QT prolongation or torsades 
de pointes (See the table in Appendix 6; see full list at http://www.qtdrugs.org/); 
17. Systemic anti-neoplastic therapies within 5 half-lives or 4 weeks (whichever is 
shorter) prior to the first dose of study drug, including chemotherapy, radical 
radiotherapy, hormonotherapy, biotherapy and immunotherapy; 
18. Administration of SSAs in the absence of secretory symptoms must be 
discontinued at least 4 weeks before the first dose of study drug; 
19. Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 
5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug; 
20. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the first 
dose of study drug; 
21. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first 
dose of study drug (3 weeks for St John’s Wort).  
22. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the 
first dose of study drug; 
23. Surgery or invasive procedure (ie, procedure that include a biopsy), or unhealed 
surgical incision, within 60 days prior to the first dose of study drug; 
24. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 
(except for alopecia); 
25. Known human immunodeficiency virus (HIV) infection; 


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26. Known clinically significant history of liver disease, including active viral or other 
hepatitis, current alcohol abuse, or cirrhosis. For patients with evidence of chronic 
hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on 
suppressive therapy, if indicated. Patients with a history of hepatitis C virus 
(HCV) infection must have been treated and cured. Patients with HCV infection 
who are currently on treatment are eligible if they have an undetectable HCV viral 
load; 
27. Evidence of ongoing or active infection requiring intravenous antibiotics; 
28. Women who are pregnant or lactating; 
29. Brain metastases and/or spinal cord compression untreated with surgery and/or 
radiotherapy, and without clinical imaging evidence of stable disease for 14 days 
or longer; patients requiring steroids within 4 weeks prior to start of study 
treatment will be excluded; 
30. Inability to take medication orally, dysphagia or an active gastric ulcer resulting 
from previous surgery or a severe gastrointestinal disease, or any other condition 
that investigators believe may affect absorption of the investigational product; 
31. Received investigational treatment in another clinical study within 4 weeks prior 
to the initiation of investigational treatment; 
32. Other disease, metabolic disorder, physical examination anomaly, abnormal 
laboratory result, or any other condition that investigators suspect may prohibit use 
of the investigational product (ie, hypersensitivity to excipients of the study drug), 
affect interpretation of study results, or put the patient at high risk. 


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7 
STUDY TREAMENT 
7.1 
Investigational Product 
7.1.1 
Investigational Product Supply 
Surufatinib will be supplied by Hutchison MediPharma Limited. 
7.1.2 
Drug Formulation and Specification 
Hutchison MediPharma Limited authorizes Shanghai STA Pharmaceutical Product Co., 
Ltd. (ie originally WuXi AppTec (Shanghai) Co., Ltd) to manufacture and package 
surufatinib capsules.  The technical guidance and quality assurance will be conducted by 
Hutchison MediPharma Limited. The drug information is provided in Table 4.  
Table 4 
Drug Formulation and Strength 
Formulation 
Strength 
Route of Administration 
Manufacturer 
Capsule 
50 mg 
Oral 
Shanghai STA Pharmaceutical Product Co., 
Ltd. 
Capsule 
200 mg 
Oral 
Shanghai STA Pharmaceutical Co., Ltd. 
 
7.1.3 
Packaging and Drug Labeling 
The investigational drug is packaged in white HDPE bottle with 50 capsules per bottle (old 
formulation, PD-012-023) or 30 capsules per bottle (new formulation, PD-012-042).  
The following information will appear on the label affixed to either the bottle or carton; 
additional information may be added as required: 
• Sponsor identification 
• Protocol number 
• Drug identification 
• Quantity of contents 
• Storage conditions 
• Dosing instructions 
• Route of administration 
• Blank spaces to write the patient’s identification number  
• Finishing lot # 
7.1.4 
Drug Storage 
Study drugs should be sealed and stored in a secure, limited access area between 10°C to 
30°C, protected from light and moisture.  Surufatinib capsule should not be used beyond 
expiration date provided by the manufacturer. 
The temperature log should be recorded and filed in the study binder. 
7.1.5 
Drug Accountability 
All study drug required for this study will be provided by Hutchison MediPharma.  The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation 
form indicating shipment content and condition.  Damaged supplies will be replaced. 


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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. 
Study drug will be either disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Hutchison MediPharma with the 
appropriate documentation, as determined by the study site.  If the study site chooses to 
destroy study drug, the method of destruction must be documented. 
7.1.6 
Dose and Administration 
If baseline (pre-dose) PK blood samples need to be collected on the days of PK sample 
collection, patients must take the investigational product after sampling.  
It is recommended that surufatinib be taken with 200 mL water within 1 hour after breakfast.  
The administration time should be accurately recorded on the day of PK sampling. 
For patients treated with surufatinib under new formulation, the minimum number of 
capsules will be administrated in combination of two strengths (50 mg and 200 mg), eg for 
300 mg QD dose, one 200 mg capsule and two 50 mg capsules will be administrated; for 
400 mg QD dose, two 200 mg capsules will be administrated, etc.  For patients enrolled 
in the European Union, only 50 mg capsules will be available.  
On the day of PK sampling, patients should avoid high-fat, high-calorie meals for the entire 
day.  No caffeine containing foods or drinks, no grapefruit or grapefruit juice, tobacco and 
tobacco containing products, or alcohol or recreational drugs will be allowed during the PK 
assessment period (Cycle 1).  
If patients miss a dose in the morning, a replacement dose can be taken before 10 pm on the 
same day.  Otherwise, the patient 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 in the CRF. 
7.1.7 
Important Safety Risks 
The important Identified Risks reported for patients who have received surufatinib may be 
found in the current version of the surufatinib IB. 
7.1.8 
Important Potential Risks 
The important potential risks of surufatinib include the following: infection, intestinal 
obstruction, gastrointestinal perforation, myocardial ischaemia, cardiac failure, venous 
thromboembolism, arterial thromboembolism, and pancreatitis.  One patient in the 2015-
012-00US1 trial experienced grade 3 PRES, which was deemed related to study drug and 
was considered resolved.  For more information, please see surufatinib IB. 
7.2 
Dose Modification 
7.2.1 
General Dose Adjustment Note 
The severity of AEs will be graded according to the NCI CTCAE v. 4.03.  Reasons for 
dose modifications or delays, the supportive measures taken, and the outcome will be 
documented in the patient's chart and recorded in the CRF. 
• For any concomitant conditions already apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if 


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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 one 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 interruption.  In addition, no dose reductions or interruptions 
will be required for anaemia (non-haemolytic) 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 drug.  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. 
7.2.2 
Dose Modification Guidance 
The dose modification sequence by starting dose is shown in Table 5.  A patient is 
normally allowed to have dose reductions no more than twice, e.g. dose reductions from 
300 mg QD to 250 mg QD and then 200 mg QD or from 400 mg QD to 300 mg QD and 
then 200 mg QD is allowed.  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. 
 
Table 5 
Dose Modification Sequence by Starting Dose 
Daily Starting Dose 
300 mg 
400 mg** 
-1 Dose 
250 mg 
300 mg 
-2 Dose 
200 mg 
200 mg 
-3 Dose* 
200 mg on reduced schedule* 
200 mg on reduced schedule* 
 
Off study drug 
Off study drug 
*Dosing schedule 200 mg QD, 3 weeks on/1 week off, every 28-day cycle. 
**No new patients will be enrolled at the 400 mg QD dose. 
Dose reduction guidelines for hematologic and non-hematologic toxicities other than 
hypertension, proteinuria, liver function impairment and hemorrhage are shown in Table 6.  
In principle, treatment should be held until 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 
Grade 3 non-haematologic toxicity that does not resolve to ≤Grade 1 within 3 weeks should 
permanently discontinue the study drug. 


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Table 6 
Dose Modification for Hematologic and Non-Hematologic Toxicities 
NCI CTCAE v4.03 Toxicity Grading 
Action 
Grade 1 or 2 
None 
Grade 3 or 4 
 
Expected manageable/reversible with dose 
reduction 
Holda 
Toxicity remains Grade 3 >7 days 
Discontinue treatment 
Toxicity lasts ≤7 days and resolves to 
≤Grade 1 
Reduce 1 dose level 
Reoccurrence of Grade 3 toxicity 
Reduce 1 dose level or discontinue treatmenta 
Reoccurrence of Grade 4 toxicity 
Discontinue treatment 
Not expected manageable/irreversible with 
dose reduction 
Discontinue treatment 
a 
Treatment should be withheld until toxicity recovers to ≤Grade 1. For patients who cannot recover 
within 21 days, the study drug should be discontinued permanently. 
7.2.3 
Dose Modification for Important Identified Risks  
Dose modifications for important identified risks are provided in Table 7 (hypertension), 
Table 8 (proteinuria), Table 9 (liver function impairment), and Table 10 (hemorrhage). 
Table 7 
Dose Modification for Hypertension 
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 1:  
prehypertension (systolic BP120-
139 mmHg or diastolic BP 80-89 
mmHg) 
None. 
None. 
Grade 2:  
Stage 1 hypertension (systolic 
BP140-159 mmHg or diastolic BP 
90-99 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 anti-hypertensive 
treatment guidelines for dose 
administration and modification and 
consult cardiologist if necessary.  
Grade 3:  
Stage 2 hypertension (Systolic 
pressure ≥ 160mmHg or diastolic 
pressure ≥ 100mmHg); medical 
intervention indicated; more than 
one drug or more intensive 
therapy than previously used 
indicated 
If BP >160/100mmHg lasts 
for >3 days after initiation of 
anti-hypertensive treatment or 
modification of current anti-
hypertensive treatment, 
surufatinib treatment should 
be held. If hypertension 
resolves to Grade 1 or baseline 
level within 21 days, sulfatinib 
treatment could be re-started 
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. 


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Table 7 
Dose Modification for Hypertension 
Grade and Definition 
Dose Modification 
Suggested Actions 
Grade 4:  
Life-threatening consequences 
(e.g., malignant hypertension, 
transient or permanent neurologic 
deficit, hypertensive crisis); 
urgent intervention indicated 
Discontinue surufatinib 
treatment. 
Emergent medical intervention. 
 
Table 8 
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 as planned schedule. 
Grade 2: 
2+or 3+ proteinuria; urinary 
protein 1.0 - 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 - 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 
resolves 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. 
a 
If urine dipstick reveals proteinuria 2+, 24-hour urine collection should be performed for determination 
of total protein within one week. The CTCAE grade recorded for proteinuria should be determined by 
the 24-hour urine collection, however the start date of the AE will be recorded as the first instant of 
proteinuria (i.e. urine dipstick). If surufatinib dose has been reduced to 200mg 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 1-week drug holiday and repeat for each treatment cycle, (i.e. 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 9 
Dose Modification for Liver Function Impairment 
Grade and 
Definitions 
Dose Adjustment 
Suggested Actions 
Grade 1: 
ALT >1-3  ULN or 
AST >1-3  ULN 
None. 
Follow up per planned 
schedule. Check total bilirubin.a 
Grade 2:  
ALT >3-5  ULN or 
AST >3-5  ULN 
Maintain the original dose, provide supportive 
care of complications of liver impairment, 
observation for 1 week, If the ALT and AST is 
Check total bilirubin.a Provide 
supportive care and increase the 
frequency of liver function 
monitor to 1-2 times a week. 


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Table 9 
Dose Modification for Liver Function Impairment 
Grade and 
Definitions 
Dose Adjustment 
Suggested Actions 
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. 
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.a 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.a Urgent 
medical intervention indicated. 
a 
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 7 for important additional information. 
 
Table 10 
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.  
7.3 
Concomitant and Excluded Therapies 
7.3.1 
Concomitant Therapies 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation and 
the termination visit. 
• Patients who use hormonal therapy with GnRH agonists for prostate cancer, oral 
contraceptives, hormone-replacement therapy, or other allowed maintenance 
therapy should continue their use.  
• Prophylactic use of anticoagulation for the maintenance of patency of permanent 
indwelling central venous access devices or for patients at high risk of venous 
thromboembolism is permitted during study treatment.  If patients are receiving 
low-dose anti-coagulation at study entry: 


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− Patients who are receiving warfarin or Coumadin-like products should have 
their INR monitored and maintained at the lower end of the therapeutic range 
(ie, close to 2.0 if the therapeutic range is 2.0 – 3.0). 
− 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 
drug.  If a patient suffers a venous thromboembolic event whilst still receiving 
study drug, it may still be possible for him or her to remain on study drug under 
adequate monitoring and dose modification.  
• Patients who have functioning pNETs or epNETs and have been on a stable dose 
of a somatostatin analogue (SSA) for a minimum of 2 months prior to the first 
dose of study drug for control of their secretory symptoms will be permitted to 
enroll in the dose expansion phase.   
• All supportive measures consistent with optimal patient care will be given 
throughout the study. 
• All concomitant medications should be reported to the investigator and recorded 
on the appropriate CRF. 
7.3.2 
Excluded Therapies 
Any therapy intended for the treatment of cancer (with the exceptions as noted above), 
whether currently marketed or experimental, is prohibited.  This includes, but is not 
limited to, the following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, 
or herbal therapy. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage 
colony-stimulating factors, platelet simulating factors or erythropoietin are not allowed 
during DLT observation period in the dose escalation phase.  
Concomitant use with acid-reducing agents (eg, proton pump inhibitors, histamine receptor 
antagonists, antacids) in Cycle 1 of the dose escalation phase should be avoid as those 
agents may interfere with reliable identification of the MTD and/or RP2D.  However, use 
of gastroduodenal mucosal protective agents, such as sucralfate, is allowed. 
Concomitant use of SSAs by patients with non-functioning pNETs or NETs is not 
permitted, and must have been discontinued at least 4 weeks before administration of the 
first dose of study drug. 
Concomitant use of medications that are known to cause QTcF prolongation, and/ or 
Torsades des Pointes.  See Appendix 6 for a table of current medications in this category, 
and also consult the current list at http://www.qtdrugs.org/, which is updated continuously, 
for the most complete information.   
Palliative radiation for symptom control is allowed provided it does not compromise tumor 
assessments of target lesions.  However, surufatinib treatment should be suspended during 
the radiation period and resumed at least 7 days after radiation only after meeting the 
following criteria: 
• Radiation related toxicities resolves to ≤ Grade 2; 
• No disease progression observed. 


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7.3.3 
Drug-Drug Interactions 
The in-vitro metabolism study in liver microsomes studies indicated that phase 1 metabolic 
enzymes for surufatinib included CYP3A4/5 (dehydrogenation, N-demethylation), 
CYP2C8 (dehydrogenation, N-demethylation), CYP2E1 (mono-oxidization) and FMO.  
Surufatinib showed weak and reversible inhibition against CYP2D6 and CYP3A4/5 with 
the IC50 of 13 µM and 14 µM, respectively.  Time-dependent inhibition study of 
CYP3A4/5 indicated the potential with a kinact of 0.73 min-1 and KI of 163 µM.  
Induction tests of CYP1A2 and CYP3A4 in primary human hepatocytes indicated that 
surufatinib had no obvious induction to CYP1A2 and CYP3A4 at 10 µM and 2 µM, 
respectively.  Caco-2 in-vitro permeability and efflux transportation tests indicated that 
surufatinib was a substrate of the P-gp efflux transporter. 
Although the overall risk of a drug interaction between surufatinib and other drugs is not 
significant, the use of surufatinib should be with caution when combined with certain drugs.  
Patients receiving a CYP3A4 strong inhibitor or inducer within 2 weeks (3 weeks for 
hyperforin perforatum) prior to receiving the study drug treatment should be excluded from 
the study.  CYP3A4 strong inhibitors or inducers should be avoided throughout the study.  
The list of CYP3A4 substrates, strong inhibitors or inducers is provided in Appendix 4.  If 
investigators consider necessary, CYP3A4 substrates, strong inhibitors or inducers can be 
used with close monitoring of potential drug- drug interaction. 
 
 


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8 
STUDY ASSESSMENTS AND METHODS 
8.1 
Safety Assessments 
8.1.1 
Vital Signs Assessment 
Vital signs will include measurements of body temperature, heart rate, respiratory rate, 
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 anti-hypertensive medications, with either a baseline history of 
hypertension or new onset of hypertension during the study, blood pressure should be 
monitored daily by the patient at home.  Affected patients will be provided with home 
blood pressure monitoring equipment, educated on how to measure blood pressure, take 
their own blood pressure daily at 3 hours (±2 hours) after the daily doses of anti-
hypertensive medication.  The patient will keep a record of home blood pressure readings 
in a Blood Pressure Diary, and bring this to each study visit. 
8.1.2 
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. 
At subsequent visits, a limited physical examination will be performed to assess changes 
from baseline abnormalities, any new abnormalities, and to evaluate patient-reported 
symptoms.  New or worsened abnormalities should be recorded as adverse events 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. 
8.1.3 
Laboratory Test Evaluations 
Samples for hematology, serum chemistry, urinalysis and pregnancy testing will be 
analyzed at the study site’s local laboratory. Laboratory assessments will include the 
following: 
Hematology: complete blood count [CBC], including red blood cell [RBC] count, 
hemoglobin, hematocrit, white blood cell [WBC] count with differential [neutrophils, 
eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet count), INR, 
PT and aPTT. 
Serum chemistry: blood urea nitrogen [BUN], creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, magnesium, phosphate, glucose, total bilirubin, direct bilirubin, ALT, 
AST, alkaline phosphatase, lactic dehydrogenase [LDH], amylase, total cholesterol, 
triglycerides, total protein, albumin, and uric acid. 
Serum pregnancy test at screening and within 30 days after treatment completion for all 
women of childbearing potential, including those who have had a tubal ligation.  In 


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addition, urine pregnancy tests will be performed on Day 1 of Cycle 2, and continue on Day 
1 at each 28-day cycle thereafter. 
Urinalysis (pH, glucose, protein, and blood); if there is ≥2+ protein on urinalysis, then a 24-
hour urine protein should be done within in one week.  For urinalysis results conversions, 
please refer to Appendix H 
Thyroid function: TSH, free T3, free T4； 
Stool blood test (as per the institutions standard practice); 
Plasma surufatinib concentrations (for PK evaluations) will be assessed using a validated 
assay. 
8.1.4 
Cardiac Monitoring 
Left ventricular ejection fraction (LVEF) assessed via echocardiogram or MUGA at 
Screening-Baseline and every 12 (± 1) weeks thereafter and at the end of study treatment.  
The modality of the cardiac function assessments must be consistent within a patient i.e. if 
echocardiogram is used for the screening assessment then echocardiogram should also be 
used for subsequent scans if required.  The patients should also be examined using the 
same machine and operator whenever possible. 
The 12-lead ECGs should be performed at screening, pre-dose and at 2 hours ± 15minutes 
post surufatinib dose on Days 1 and 15 in Cycle 1, on Day 1 of each cycle from Cycle 2 
and onward and at the end of study treatment.  The QTcF interval will be closely 
monitored (See Appendix 1).   
Test results will be reviewed by the investigator to determine patient eligibility at screening.  
Additional test and other cardiac monitoring will be provided as clinically indicated during 
the study. 
8.2 
Efficacy Assessments  
8.2.1 
Tumor Assessment 
All measurable lesions should be assessed and documented at screening and re-assessed at 
each subsequent tumor evaluation (see Appendix 1).  Response assessments will be 
performed by the investigator using physical examination and image-based evaluation. 
Screening assessments include CT scans with oral or IV contrast (unless contraindicated) 
of the chest, abdomen, and pelvis.  MRI scans are allowed if CT contrast is 
contraindicated.  Bone scans and CT scan of neck should also be performed if clinically 
indicated.  The same radiographic procedure used to define measurable or non-measurable 
lesions at baseline must be used throughout the study for each patient.  At the 
investigator’s discretion, CT scans may be repeated at any time if progressive disease is 
suspected.  
Disease status will be assessed using RECIST Version 1.1 (see Appendix 3).  At the 
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST Version 1.1 may be used.  Confirmation of CR and PR is required at no less than 
4-week intervals between the date of initial response/progression and the confirmation 
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8.2.2 
Assessment of Tumor Markers 
Tumor markers assessment will be performed at each tumor assessment visit.  Tumor 
markers may include, but are not be limited to, serum CEA and CA 19-9 (patients with 
BTC) serum chromogranin A (CgA) and neuron-specific enolase (NSE) for patients with 
pNET and epNET; and VEGF for all 3 disease cohorts.  Assessment of tumor markers will 
be performed within 28 days prior to the start of treatment with study drug (C1D1) and at 
each tumor assessment visit. 
8.3 
Study Visits and Assessments 
8.3.1 
Screening and Pretreatment Assessment 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or procedures.  Informed Consent Forms for patients 
who are not subsequently enrolled will be maintained at the study site.  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.  
Please see the Study Flowchart provided in Appendix 1 for the schedule of screening and 
pre-treatment assessments.  Screening and pre-treatment tests will be performed within 28 
days to the first dose day of study drug, unless otherwise specified.  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, urinalysis, and 
stool blood test results); such tests do not need to be repeated for screening. 
8.3.2 
Assessments during Treatment Phase 
All visits must occur within ± 3 days (± 1 day during the DLT observation window) from 
the scheduled date, unless otherwise noted (see Appendix 1).  All assessments will be 
performed on the day of the specified visit unless a time window is specified.  
Please see the Study Flowchart provided in Appendix 1 for the schedule of treatment period 
assessments. 
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. 
If during the DLT assessment window, 2 or more patients in a single cohort experience the 
same study drug-related Grade 3 toxicity that does not otherwise qualify as a DLT, the 
patients subsequently enrolled to this dose level and to the subsequent dose level will 
undergo increased monitoring during Cycle 1, as clinically indicated. 
8.3.3 
Study Completion/Early Termination Visit 
Patients who complete the study or discontinue study drug will be asked to return to the 
clinic at 30 ± 7 days after the last surufatinib administration for a follow-up visit.  Ongoing 
adverse events thought to be related to surufatinib will be followed until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new anti-
tumor treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, 
or when it has been determined that the study drug or participation is not the cause of the 
adverse event. 


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Subjects enrolled to the BTC and STS expansion cohorts, who have signed informed 
consent under sponsor Amendment 8 (or later), will enter into OS follow up at the 
completion of their Study Completion/Early Termination Visit. 
Please see the Study Flowchart provided in Appendix 1 for assessments to be performed at 
the study completion or early termination visit. 
8.4 
Assay Methods 
8.4.1 
Bioanalysis Assay Methods 
Concentrations of the surufatinib in plasma will be measured using a pre-validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) by a qualified central laboratory. 
All plasma samples from patients having received surufatinib will be analyzed. 
8.4.2 
Pharmacokinetic Samples Handling and Shipment 
Blood samples will be taken for pharmacokinetic evaluation by cannula or direct 
venipuncture at nominated time points.  See Table 11 for the sampling time points.  The 
exact time and dates of blood sampling are to be recorded in the CRFs. 
Blood sample (2.5 mL) for surufatinib pharmacokinetics will be collected into Sodium 
Heparinate vacutainers.  The tubes will be immediately inverted gently at least 5 times to 
mix the blood and then placed in ice bath prior to centrifugation.  The tubes will be 
centrifuged at approximately 1000g and 4°C for 10 min and then the plasma will be 
transferred into 2 clean prelabelled tubes immediately.  About 0.5mL plasma will be 
placed in each tube (Tube A and Tube B).  After tightly capping the tubes, the samples 
should be stored at -20°C or -80°C immediately.  The whole process of plasma collection 
should be completed within 2 hours of the blood sampling.  According to plasma stability 
results, surufatinib can be stored at -20°C for 317 days and at -80°C for 716 days.  It is 
recommended that the plasma samples are stored at -80°C for the long-term storage.  
Each sample will be identified by date of collection, study number, patient number and 
initials, and sample time point identifier (ie, 30 minutes, 1 hour, 4 hour etc.).  Tube B 
samples must be labeled as “duplicate”.  
All plasma samples will be shipped on dry ice to the central laboratory within 30 days of 
sample collection.  The dry ice should be sufficient to keep the samples frozen during the 
whole shipment period.  The samples of Tube B are shipped out after the prior batch of 
Tube A has been received safely by the central lab.  Tube A samples will be used for 
bioanalysis. Tube B samples will be stored in -80°C freezer for future use.  The laboratory 
should be notified at least 1 day prior to the arrival of the sample and be provided shipping 
details and tracking numbers for the shipment. 
Prior to shipment, a PK sample requisition form (containing the details of each sample / 
label identification included in the shipment) will be prepared.  All sample correspondence 
must contain the Study Number, Study Drug, and Site references (including emergency 
contact details and responsible shipment coordinator).  All of the sample details on this 
log must correspond with the details included on the individual sample labels, as each 
sample label will be checked against the list by Centre Laboratories’ sample coordination 
personnel.  The log should be reviewed by the preparer and a second individual for 
accuracy and signed/dated by both individuals.  (An example sample transfer sheet is used 
to document the general information regarding the shipment).  To avoid sample mix-ups 


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or misidentification, the samples in the shipment will be sorted by patient number and 
sample time using segmented cartons. 
Table 11 
Pharmacokinetic Sampling Time Points 
Visit Cycle and Day 
Time Point 
Cycle 1, Day 1 
Pre-dose ≤10 minutes 
Post-dose 1 hour (± 15 minutes) 
Post-dose 2 hours (± 15 minutes) 
Post-dose 4 hours (± 30 minutes) 
Post-dose 6 hours (± 60 minutes) 
Post-dose 8 hours (± 60 minutes) 
Cycle 1, Day 2 
Pre-dose ≤10 minutes 
 
 
Cycle 1, Day 15 
Pre-dose ≤10 minutes 
Post-dose 1 hour (± 15 minutes) 
Post-dose 2 hours (± 15 minutes) 
Post-dose 4 hours (± 30 minutes) 
Post-dose 6 hours (± 60 minutes) 
Post-dose 8 hours (± 60 minutes) 
Cycle1, Day 16 
Pre-dose ≤10 minutes 


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9 
SAFETY MONITORING 
9.1 
Definitions 
9.1.1 
Adverse Events and Serious Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational product or other protocol-imposed intervention, regardless 
of attribution. 
An SAE is defined as any life-threatening AE resulting in death, persistent or significant 
disability/incapacity, a congenital anomaly/birth defect, or any other important medical 
event requiring intervention, in-patient hospitalization or prolongation of existing 
hospitalization 
A SAE is any AE that is any of the following: 
• Fatal (ie, the AE actually causes or leads to death) 
• Life threatening (ie, the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• A congenital anomaly/birth defect in a neonate/infant born to a female patient or 
female partner of a male patient exposed to the investigational product(s) 
• Considered a significant medical event by the investigator (eg, may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious 
AEs. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor 
medical significance (such as severe headache).  “Serious” is a regulatory definition and 
is based on patient or event outcome or action criteria usually associated with events that 
pose a threat to a patient’s life or vital functions.  Seriousness (not severity) serves as the 
guide for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and SAEs 
on the CRF. 
9.1.2 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) 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.  Depending on the nature of the event, rapid communication by the trial sponsor to other 
parties (eg, regulators) might also be warranted.  


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9.2 
Reporting of Dose-Limiting Toxicity 
Investigators are required to report DLT events to the Sponsor within 48 hours of first 
awareness.  The communication must include an email that describes the event and 
indicates which DLT criterion was met (see Section 5.1.1.3, Definition of a Dose-Limiting 
Toxicity).  The Sponsor’s medical monitor must confirm that the event meets the DLT 
definition and communicate this back to the investigator by email.  A notification of each 
DLT event will be distributed by email to all investigators shortly after confirmation.  DLT 
events are again reviewed together with other safety data and PK data, at the dose escalation 
SRC meeting upon completion of the DLT window of each dose cohort. 
9.3 
Adverse Events Reporting Period 
After informed consent, but prior to initiation of study medications, only SAEs caused by 
a protocol-mandated intervention will be collected (eg, SAEs related to invasive procedures 
such as biopsies, medication washout, or no treatment run-in). 
After initiation of study medications, all AEs and SAEs regardless of attribution will be 
collected until 30 days following the last administration of study drug or study 
discontinuation/termination, whichever is later.  After this period, investigators should 
report only SAEs that are felt to be related to prior study drug. 
9.4 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted. Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
9.5 
Assessment of Severity 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs and 
SAEs, whether reported by the patient or noted by authorized study personnel, will be 
recorded in the patient’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable CRF, the investigator will make an 
assessment of seriousness, severity, and causality.  
• Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 
with unique clinical descriptions of severity for each AE based on this general 
guideline: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic    
observations only; intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
• 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. 


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Activities of Daily Living (ADL) 
*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. 
NOTE: The NCI CTCAE v 4.03 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 v 4.03, then the investigator should name the AE and report the severity 
based on the general guideline shown in the paragraph above. 
9.6 
Causality of Adverse Events 
The investigator will assess a causal relationship between the IP and each AE, and 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 investigational product?’ 
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 as ‘yes’. 
A guideline to the interpretation of the causality question is found in Appendix 5 to the 
Clinical Study Protocol. 
9.7 
Documenting Adverse Events 
When documenting an AE or SAE, the preferred medical terminology or concept should be 
used. Abbreviations and spoken language should be avoided.  All AEs (including SAEs) 
should be recorded in the CRF on the AE page. 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the CRF. Avoid colloquialisms and abbreviations. 
All AEs (including SAEs) would be recorded on the AE CRF, and the check box for 
“Serious” would be ticked for entries that fit the criteria of serious.  The investigator would 
also complete an SAE report and submit this to the sponsor or its designee within 24 hours 
of knowledge of the event. 
Only one medical concept should be recorded in the event field on the CRF. 
9.8 
Diagnosis vs Symptom and Signs 
If known, a diagnosis should be recorded on the CRF 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 CRF.  If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
9.9 
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 
CRF.  


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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 
CRF.  For example, if a severe gastrointestinal hemorrhage leads to renal failure, both 
events should be recorded separately on the CRF. 
9.10 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the CRF unless their 
severity increases.  If a persistent AE becomes more severe, it should be recorded again 
on an AE/SAE CRF.   
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 CRF. 
9.11 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (eg, abnormalities that require study drug dose 
modification, discontinuation of study drug, more frequent follow-up assessments, further 
diagnostic investigation, etc). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, 
alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the 
diagnosis (eg, cholecystitis) needs to be recorded on the AE/SAE CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF.  If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium level of 7.0 mmol/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, 
seriousness, or etiology changes.  
9.12 
Death 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, should be recorded on an AE/SAE CRF 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 AE and death being the outcome of the event on 
the AE/SAE CRF.  If the primary cause of death is unknown and cannot be ascertained at 
the time of reporting, record “Unknown Death” on the AE/SAE CRF. 
If the death is attributed to progression of cancer, record “Cancer Progression” as the AE 
term on the CRF.  
9.13 
Previously Existing Medical Condition 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History CRF. 


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A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on an AE/SAE CRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (eg, “more frequent headaches”). 
9.14 
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 preexisting medical 
condition that has not changed 
• Receive scheduled therapy for the target disease of the study 
9.15 
Pregnancy 
A female patient must be instructed to stop taking the study medication and immediately 
inform the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies within 24 hours to the sponsor or its designee.  The investigator 
should counsel the patient; discuss the risks of continuing with the pregnancy 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 
medication 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 CRF, and 
expeditiously reported to sponsor 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 investigational product should be recorded and reported as 
an SAE. 
9.16 
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 Adverse Event CRF and reported to the sponsor 


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or its designee within 1 working day after learning of the event as an SAE.  See 
Appendix 7 for important additional information.  
9.17 
Worsening of Solid Tumor 
Worsening and/or progression of the patient’s solid tumor should not be recorded as an AE 
or SAE unless resulted in death within the AE reporting period.  These data will be 
captured as efficacy assessment data only.  
9.18 
Expedited Reporting Requirements for Serious Adverse Events 
9.18.1 
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 investigational product will be telephoned to the Medical Monitor 
immediately, followed by submission of written case details on the SAE report Form within 
24 hours. 
9.19 
Adverse Event Follow-Up Duration 
The investigator should follow all unresolved AEs and SAEs until the events are resolved 
or stabilized, the patient is lost to follow-up, or it has been determined that the study drug 
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 CRF and in the patient’s medical record 
to facilitate source data verification (SDV).  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 Adverse Event CRF. 
For some SAEs, additional case details deemed necessary to appropriately evaluate the SAE 
report (eg, hospital discharge summary, consultant report, or autopsy report) may be 
followed-up by telephone, fax, email, and/or a monitoring visit to obtain. 
9.20 
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 drug.   
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 
felt to be related to prior study drug.  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 in a subsequently conceived offspring of a patient that participated in this study.  
 
 


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10 
STATISTICAL ANALYSIS 
All statistical analysis will be performed under the direction of Hutchison MediPharma 
personnel.  Any data analysis carried out independently by the investigator should be 
submitted to Hutchison MediPharma prior to publication or presentation. 
The final analysis will be based on patient data collected through study discontinuation or 
study termination.  There is no planned formal interim analysis.  However, the accrued 
data may be analyzed for internal decision-making purposes, for example to provide 
information for a potential Phase 3 study design.  
Final analysis for each cohort will occur once the last patient had been followed for 
sufficient time for the analysis of primary endpoint.  For instance, for Arm A, final 
analysis will occur when the last patient had been on treatment for at least 16 weeks or 
discontinued early following discontinuation criteria.  Timing of final analyses for cohorts 
may be combined if they occur close together.  Details of the statistical analysis and data 
reporting will be provided in the Statistical Analysis Plan (SAP) document finalized prior 
to database lock. 
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.  Information regarding 
compliance with efficacy testing and availability of data will be documented. Graphical 
techniques (eg, waterfall plots, Kaplan-Meier curves) will be used when such methods are 
appropriate and informative.  The baseline value used in each analysis will be the last 
(most recent) pre-treatment value.  Time to event variables will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Analyses will be based upon the 
observed data unless methods for handling missing data are specified.  Analyses will be 
performed using SAS® (Version 9.1 or higher). 
10.1 
Determination of Sample Size 
The total number of patients enrolled will depend on the number of dose escalations and 
the need to further characterize individual cohorts in the expansion phase. 
The planned enrollment for this study is approximately 95 to 150 patients, including 
35 patients in the dose escalation phase, and approximately 115 patients for the dose 
expansion phase.  Dose expansion phase will enroll patients in specific disease cohorts, 
30 patients in the BTC Arm, at least 15 patients each in the pNET and epNET arms, and 55 
patients in the STS arm (10 patients with LMS, 10 patients with UPS, 10 patients with 
epithelioid sarcoma, 10 patients with angiosarcoma, 10 patients with SS, and 5 patients with 
PVNS). 
Sample size for Arm A: BTC cohort in dose expansion phase: 
The PFS rate at 16 weeks was selected as the primary endpoint for the expansion phase of 
the study in patients with BTC.  The PFS rate at 16 weeks is defined as the percent of 
patients without evidence of disease progression or death after 16 weeks on study among 
the PFS-evaluable patients.  
For a BTC cohort with at least 30 evaluable patients, the treatment effect may be considered 
positive if there are at least 9 evaluable patients without evidence of progression or death 
after 16 weeks on study.  This event will occur with probabilities 90.6% (true positive 


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rate) if the true PFS rate at 16 weeks is 40%, and 2.8% (false positive rate) if the true PFS 
rate at 16 weeks is 15%.   
In addition, for a cohort with 30 evaluable patients, if 9 (30.0%) patients, or 
10 (33.3%) patients without progression or death at 16 weeks are observed, then the lower 
limit of the 80% two-sided CIs for PFS rate at 16 weeks would be 19.0% and 21.8%, 
respectively. 
Sample size for Arm B: pNET cohort in dose expansion phase: 
For a pNET cohort with at least 15 evaluable patients, the treatment effect may be 
considered positive if there are at least 6 evaluable patients without evidence of disease 
progression or death after 11 months on study.  This event will occur with probabilities 
84.9% (true positive rate) if the true PFS rate at 11 months is 50%, and 4.9% (false positive 
rate) if the true PFS rate at 11 months is 19%.   
In addition, for a cohort with 15 evaluable patients, if the 6 (40%) patients or 
7 (47%) patients without progression or death at 11 months are observed, the lower limit of 
the 80% two-sided CIs for PFS rate at 11 months would be 22.6% and 28.2%, respectively.  
Sample size for Arm C: epNET cohort in dose expansion phase: 
For a pNET cohort with at least 15 evaluable patients, the treatment effect may be 
considered positive if there are at least 6 evaluable patients without evidence of disease 
progression or death after 11 months on study.  This event will occur with probabilities 
84.9% (true positive rate) if the true PFS rate at 11 months is 50%, and 4.9% (false positive 
rate) if the true PFS rate at 11 months is 19%.   
In addition, for a cohort with 15 evaluable patients, if the 6 (40%) patients or 
7 (47%) patients without progression or death at 11 months are observed, the lower limit of 
the 80% two-sided CIs for PFS rate at 11 months would be 22.6% and 28.2%, respectively. 
Sample size for Arm D: STS cohort in dose expansion phase: 
Arm D will consist of 6 cohorts of STS subtypes.  The LMS, UPS, epitheloid sarcoma, 
angiosarcoma, and SS cohorts will enroll at least 10 evaluable patients each.  The 
treatment effect may be considered positive if there are at least 3 evaluable patients in each 
cohort without evidence of disease progression or death after 4 months on study.  This 
event will occur with probabilities of 83.3% (true positive rate) if the true PFS rate at 
4 months is 40%, and 7% (false positive rate) if the true PFS rate at 4 months is 10%. 
For the PVNS cohort, it is planned to enroll 5 evaluable patients.  This sample size is based 
on feasibility. 
10.2 
Analysis Populations 
The following analysis populations have been defined for the study: 
• Note: the DLT Evaluable Set (dose escalation phase) is defined in Section 5.1.1. 
• Safety Analysis Set (SAS) – (All Treated Population): This population includes 
all patients who have received at least one dose of surufatinib.  Safety data will 
be evaluated based on this population’s outcome.  Patients in the SAS will be 
analyzed by their actual dose initially received.  If patients have dose reduction 
during the study, all data will be summarized/analyzed based on the initial dose of 


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study drug received.  Efficacy endpoints PFS and OS (OS applies to BTC and 
STS cohorts only) will be analyzed based on this population.  
• Pharmacokinetic Analysis Set (PKAS): This population will include all patients 
who received at least one dose of surufatinib and have at least one PK sample 
obtained and analyzed. 
• Efficacy Analysis Set (EAS): This population includes all patients who have 
received at least 1 dose of surufatinib and have had at least 1 post- baseline tumor 
assessment.  All efficacy endpoints will be analyzed will based on this analysis 
set, except for PFS and OS, which will be analyzed based on SAS. 
10.3 
Statistics and Analysis Method 
There is no formal hypothesis testing in this study.  In general, the study data will be 
summarized descriptively by dose group and disease cohort (ie, BTC arm, pNET arm, 
epNET arm, and STS arm), unless otherwise specified.  In general, all summaries will be 
presented by assigned dose level in the dose escalation phase and by disease cohort (BTC, 
pNET, epNET, and STS) in the dose expansion phase.  Where applicable, certain 
summaries may be provided by STS subtypes: LMS, UPS, epithelioid sarcoma, 
angiosarcoma, SS, and PVNS. 
A patient listing of all treated patients will be generated to describe site, patient number, 
screening date, first dosing date, duration of study treatment, analysis set in which the 
patient included and disposition.  In the patient disposition listing, reason for study drug 
discontinuation will be included.  A table will be created to summarize these categories in 
terms of number and percent for each of the analysis set defined above. 
Patient demographics and baseline characteristics, such as age, sex, race/ethnicity, weight, 
type of malignancy, duration of malignancy, site of metastatic disease, and baseline ECOG 
performance status, will be listed and summarized.  All summaries will be presented by 
dose level in the dose escalation phase and by disease cohort in the dose expansion phase. 
Major protocol deviations related to study inclusion or exclusion criteria, conduct of the 
trial, patient management, or patient assessment will be listed. 
Study drug administration data will be listed by dose level and by disease cohort, and any 
dose modifications will be flagged.  Descriptive information will be provided regarding 
number of cycles, total duration of study drug exposure, actual duration of study drug taken, 
cumulative dose of study drug, dose intensity and relative dose intensity and the number 
and timing of prescribed dose reductions and interruptions. 
The study endpoints are described in Section 4.  The planned analyses are described in 
detail in Sections 10.4 to 10.6. 
10.4 
Safety Analysis 
Safety will be assessed through summaries of AEs, changes in laboratory test results, 
changes in ECG/echocardiograms results and changes in vital signs.  All patients who 
receive at least one dose of surufatinib will be included in the safety analysis (ie, the Safety 
Analysis Set - All Treated Population). 
All AE data will be listed by individual patient and cohort.  All AEs will be graded using 
the NCI CTCAE (v.4.03) severity grading system.  All adverse events will be coded with 


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MedDRA.  The frequency of AEs will be summarized by MedDRA System Organ Class 
(SOC), Preferred Term (PT), and NCI CTCAE grade.  
Incidence rates of DLTs by SOC and PT will be summarized for DLT set defined as all 
treated patients who are evaluable for DLT assessment (see Section 5.1.1.2). 
Changes in laboratory data will be summarized by grade using the NCI CTCAE, v.4.03.  
Selected vital signs and selected laboratory data may be plotted over time for each patient. 
10.5 
Pharmacokinetic Analysis 
All patients whose plasma samples are collected for analysis of the plasma surufatinib 
concentration and derivation of PK parameters will be included in the Pharmacokinetic 
Analysis Set (PKAS). 
A non-compartmental model analysis will be performed for plasma concentration data by 
central lab using WinNonlin (enterprise version).  The following statistic data will also be 
reported: mean value, standard deviation, median value, minimum value, maximum value, 
geometric mean value, and geometric mean coefficient of variation. 
The individual and mean pharmacokinetic parameters determined following analysis of the 
surufatinib concentration versus time data, will include, but not be limited to total plasma 
exposure (AUC0-∞), Cmax, CL/F, and Vz/F.  The t1/2 will also be estimated.  Mean, 
standard deviation (SD) and coefficient of variation (CV) will be presented.  The actual 
times of plasma sample collection will be used in the determination of the pharmacokinetic 
parameters. 
The methods for calculating pharmacokinetic parameters of surufatinib: 
• Cmax: the maximum observed plasma concentration over the sampling period, 
taken directly from the data.  
• Tmax: time at which Cmax occurred, taken directly from the data.  
• Kel: the first-order rate constant associated with the negative slope of the terminal 
portion of the log-linear concentration-time curve.  A minimum of three points 
will be used. 
• Area under the plasma concentration versus time curve (AUC) to be determined 
by the linear trapezoidal rule, where AUClast is the AUC from time zero until the 
last concentration point and AUC0-∞ is the AUClast + last concentration point 
divided by Kel. 
• Half-life (t1/2) to be determined according to t1/2 =0.693/Kel where possible. 
• CL/F: systemic clearance to be determined according to Dose/AUC∞ 
• Vz/F: apparent volume of distribution, determined according to CL/F/Kel 
• Dose Proportionality: to be evaluated by investigating the linearity of the 
relationship between AUC and dose, and Cmax and dose. 
• Accumulation ratio: AUCDay15/AUCDay1 or AUCDay29/AUCDay1 
Where the concentration data are missing, or listed as less than Lower Limit of 
Quantification, they will be regarded as zero (0) if occurring before Cmax.  After Cmax, zero 
points will not be included in calculations. 
Individual and mean surufatinib concentrations will be plotted by dose level. 


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10.6 
Tumor Assessment 
Efficacy data will be summarized by dose group in the dose escalation phase and by disease 
cohort in the dose expansion phase.  For the dose expansion phase, all summaries of 
efficacy data will be presented separately for the BTC, pNET, epNET, and STS arms.  
The following efficacy endpoints will be analyzed:  
10.6.1 
Primary Efficacy Endpoints 
• Patients with BTC: PFS rate at 16 weeks (according to RECIST Version 1.1); 
• Patients with p-NET: PFS rate at 11 months (according to RECIST Version 1.1) 
• Patients with epNET: PFS rate at 11 months (according to RECIST Version 1.1) 
• Patients with STS: PFS rate at 4 months (according to RECIST Version 1.1). 
PFS is defined as the time from the start date of study drug until the date of objective disease 
progression or death (by any cause in the absence of progression). 
PFS will be described in tabular and graphical format using Kaplan-Meier method, 
including estimated median (in months) with 95% CI, 25th and 75th percentiles and 
Kaplan-Meier estimated probabilities with corresponding 80% and 95% CIs at several time 
points (including at least 16 weeks for BTC group and 11 months for pNET group).  
Censoring reasons will also be summarized.  
10.6.2 
Secondary Efficacy Endpoints 
• ORR, defined as the proportion of patients with a best overall response of 
complete response (CR) and partial response (PR) per RECIST Version 1.1.  To 
be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria 
for response are first met. 
• DCR, defined as the proportion of patients with best overall response of CR, PR, 
or SD per RECIST Version 1.1. 
• TTR, defined as the time between the start date of study drug until first 
documented response (CR or PR) according to RECIST Version 1.1. 
• DoR, 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). 
• Percent changes of tumor size from baseline of target lesion will be calculated at 
each visit, and the maximum percent per patient will be selected.  Waterfall plots 
will be used to depict the tumor shrinkage in target lesion.  These plots will 
display the best percentage change in target lesion size. 
ORR and DCR will be estimated and 95% exact CIs based on the Clopper-Pearson method 
will be presented.  The time to event endpoints, TTR and DoR will be described in tabular 
and graphical format using Kaplan-Meier method, including estimated median (in months) 
with 95% CI, 25th and 75th percentiles.   


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10.6.3 
Exploratory Endpoints 
• The values and changes from baseline in tumor markers will be summarized by 
tumor type (BTC, pNET, epNET, or STS) using descriptive statistics.  Other 
exploratory analyses may be performed as appropriate. 
• Overall survival is defined as the time interval between the start date of study drug 
and the date of death (any cause).  The final known date of survival will be used 
as the censoring date for patients who have not been reported to have died by the 
time of analysis cut-off date.  OS will be analyzed for only the BTC and STS 
cohorts based on the All Treated Population.  OS will be described in tabular and 
graphical format using Kaplan-Meier method, including estimated median (in 
months) with 95% CI, 25th and 75th percentiles. 


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11 
ETHICS 
11.1 
Good Clinical Practice 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, consensus and the ethical 
principles derived from international guidelines, including the following: Declaration of 
Helsinki and Council for International Organizations of Medical Sciences  International 
Ethical Guidelines and Applicable ICH GCP Guidelines that have their origin in the 
Declaration of Helsinki. 
11.2 
Ethics Review 
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must review 
the protocol and amendments, IB, ICF, study-relevant materials (such as advertisements for 
patient recruitment), and any other essential documents.  IEC/IRB approval is to be 
obtained prior to the start of the study at the site. 
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented.  All SAEs and other significant safety findings 
should be reported to the sponsor, the IEC/IRB, and applicable regulatory authorities as 
required.  During the study, protocol deviations that may increase a patient’s risk should 
be reported to the IEC/IRB in a timely manner. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation, except for changes necessary to eliminate an immediate hazard 
to study subjects. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
11.3 
Patient Informed Consent 
• Investigators or designees must obtain the signed ICF from patients prior to 
conducting any study-related procedures.  
• The investigator or his/her representative will explain the nature of the study to the 
participant or to their legally authorized representative and answer all questions 
regarding the study. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act  
requirements, where applicable, and the IRB/IEC or study center. 


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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 
authorized 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 electronic case report form (eCRF).  
• If the risk/benefit assessment changes after the safety analysis, the ICF needs to be 
reviewed and updated, and all updated information should be provided to patients 
(including patients who have already received the study drug). 
11.4 
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.  Electronic case report forms and other 
documents submitted to the sponsor should not contain the patient’s name.  
• Participants will be assigned a unique identifier by the sponsor.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information that would make the participant 
identifiable will not be transferred. 
• Patients are identified only by the unique identifier.  Investigators may retain the 
identification forms, which include patient numbers, names, and addresses.  ICFs 
and other documents should be documented properly, and should not be given to 
the sponsor. 
• The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law.  The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
11.5 
Disclosure 
Final study results will be published on a public clinical trial website according to applicable 
local guidelines and regulations.  


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11.6 
Data Quality Assurance 
• To ensure the safety of participants in the study, and to ensure accurate, complete, 
and reliable data, the investigator will keep records of laboratory tests, clinical 
notes, and patient medical records in the patient files as original source documents 
for the study. 
• All participant data relating to the study will be recorded on printed or eCRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data).  
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion 
Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
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 non-compliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs). 
11.7 
Biological Specimens and Data 
For participants who provide informed consent agreeing to participate in future biomedical 
research, any unused samples for study-related research, as well as unused PK samples, 
may be stored for no longer than 15 years, or other period as per local requirements, after 
the final date of the database lock.  After this storage period, any residual samples will be 
destroyed.  The sponsor will store the samples in a secure storage space with adequate 
measures to protect confidentiality.   
The unused samples may be utilized for future biomedical research as permitted by local 
regulations.  Permission will be required from subjects for prior to any new analysis to be 
conducted on the biological specimens that are not related to the current study .   
The results of these future biomedical research analyses will not be shared with patients and 
will not be presented in the clinical study report. 
If there are specific site or country requirements involving the pharmacogenomic analyses 
that the sponsor is unable to comply with, samples will not be collected at those sites. 
All samples will be single/double coded as defined by ICH guideline E15. 


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12 
OVERSIGHT 
12.1 
Independent Monitoring 
No independent data monitoring is planned for this study.  The sponsor will review study 
safety data on an annual basis, or more frequently, if safety concerns arise.  
12.2 
Quality Control and Assurance 
In accordance with ICH E6(R2), the sponsor is responsible for quality assurance to ensure 
that the study is conducted, and the data are generated, recorded, and reported in compliance 
with the protocol, GCP, and any applicable regulatory requirement(s).  The sponsor will 
ensure that all aspects of the trial are operationally feasible and will avoid unnecessary 
complexity, procedures, and data collection.  The sponsor is responsible for ensuring that 
the protocols, CRFs, and all other operational documents are clear, concise, and consistent. 
The investigator is responsible for supervising any individual or party to whom the 
investigator delegates trial-related duties and functions conducted at the trial site. 
The sponsor and investigator ensures that any individual or party who performs trial-related 
duties or functions on behalf of the sponsor/investigator is qualified to perform the trial-
related duties or functions. 
The planned quality assurance and quality control procedures for the study are described in 
this section. 
12.2.1 
Monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, the sponsor’s 
personnel (or designated CRO) will review the protocol and CRFs with the investigators 
and their staff.  During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to GCP, and the progress of enrollment, and to ensure that study drug 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 field 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 CRFs will be performed according to the study-specific monitoring plan. 
12.2.2 
Audits 
Authorized representatives of the sponsor, a regulatory/competent authority, and/or an 
IRB/IEC representative may visit the site to perform audits or inspections, including source 
data verification.  Should this occur, the investigator is responsible for: 
• 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 


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• 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, IRB/EC 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. 
12.2.3 
Records 
12.2.3.1 
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.  Data from ECG will be collected at 
the study sites, and the data will be transmitted to a designated CRO for centralized analysis, 
as well as for further processing and data reconciliation.  Imaging data will be collected at 
the study sites, and a designated CRO will perform further processing, data reconciliation, 
and holding. 
At all times, the principal investigator has final responsibility for the accuracy and 
authenticity of all clinical and laboratory data entered in the EDC.  Patient source 
documents are the investigator's/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. 
12.2.3.2 
Source Data 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 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). 


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12.2.3.3 
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.   
12.3 
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 subject/ within a reasonable period of time  
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable 
amendments), breach of the applicable laws and regulations, or breach of any 
applicable ICH guidelines 
• The total number of subjects required for the study are enrolled earlier than 
expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the ECs/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 subject and should assure 
appropriate subject therapy and/or follow-up. 


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13 
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 multi-center studies only in their entirety and not as individual site data.  In 
this case, a principal investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors authorship requirements. 


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14 
FINANCING AND INSURANCE 
Financing and insurance information are addressed in a separate agreement. 


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15 
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25. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American 
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31. Nielsen OS, Dombernowsky P, and Mouridsen H, et al.: High-dose epirubicin is 
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[PubMed]. 
33. Okuno S, Ryan LM, and Edmonson JH, et al.: Phase II trial of gemcitabine in 
patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative 
Oncology Group. Cancer 97 (8): 1969-73, 2003. [PubMed]. 
34. Lorigan P, Verweij J, and Papai Z, et al.: Phase III trial of two investigational 
schedules of ifosfamide compared with standard-dose doxorubicin in advanced or 
metastatic soft tissue sarcoma: a European Organisation for Research and 
Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25 
(21): 3144-50, 2007 [PubMed]. 
35. Nielsen OS, Dombernowsky P, Mouridsen H, et al.: High-dose epirubicin is not an 
alternative to standard-dose doxorubicin in the treatment of advanced soft tissue 
sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 
78 (12): 1634-9, 1998. [PMC free article] [PubMed]. 
36. Maki RG, Wathen JK, Patel SR, et al.: Randomized phase II study of gemcitabine 
and docetaxel compared with gemcitabine alone in patients with metastatic soft 
tissue sarcomas: results of sarcoma alliance for research through collaboration 
study 002 [corrected]. J Clin Oncol 25 (19): 2755-63, 2007. [PubMed]. 
37. Okuno S, Ryan LM, Edmonson JH, et al.: Phase II trial of gemcitabine in patients 
with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology 
Group. Cancer 97 (8): 1969-73, 2003. [PubMed]. 


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38. van der Graaf WT, Blay JY, and Chawla SP, et al.: Pazopanib for metastatic soft-
tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 
3 trial. Lancet 379 (9829): 1879-86, 2012. [PubMed].  
 


Si g nat ure Pa ge f or 
Si g nat ure Pa ge f or 
A p pr o val
1 9- Mar- 2 0 2 1 0 1: 2 4: 4 1 G M T + 0 0 0 0
A p pr o val
1 9- Mar- 2 0 2 1 1 6: 1 4: 5 7 G M T + 0 0 0 0
P P D
P P D
C CI
C CI

SAP_001.pdf: 
 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 of 7 0 
 
 
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
 
2 0 1 5- 0 1 2- 0 0 U S 0 1 
 
A M ulti- Ce nter, O pe n- La b el, Cli nical Trial t o E val uate t he Safe t y, T olera bilit y, a n d P har mac o ki netics of S ur ufati ni b 
( H M P L- 0 1 2), Pre vi o usl y Na me d S ulfati ni b i n A d va nce d S oli d T u m ors 
 
 
 
 
 
A U T H O R : 
 
V E R SI O N N U M B E R A N D D A T E : V 2. 2,  0 4 N O V 2 0 2 2 
 
 
 
 
 
 
 
 
 
 
P P D
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St ati sti c al A n al y si s Pl a n  
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M O DI FI C A TI O N H I S T O R Y 
 
U ni q ue 
I de ntifier f or 
t his Versi o n 
Date of t he 
D oc u me nt 
Versi o n 
A ut h or  
Si g nifica nt C ha n ges fr o m Pre vi o us A ut h orize d Versi o n  
0. 1  
2 5 Fe b 2 0 1 6 
 
N ot A p plica ble –  First Versi o n 
0. 2  
1 7 Mar 2 0 1 6 
 
U p date d per s p o ns or’s c o m me nts. Details ca n be f o u n d i n 
t he trac k c ha n ge versi o n. 
A d diti o nall y, f oll o wi n g u p dates perf or me d base d o n e mail 
c o m m u nicati o n:  
1. 
E C G part a d de d  
2. 
Baseli ne defi niti o n a d de d E C G ti me- p oi nt 
c o nsi derati o n  
3. 
S u bj ect dis p ositi o n ta ble m o difie d t o i ncl u de 
c o m pleti o n stat us of D L T o bser vati o n wi n d o w.  
4. 
N ote a d de d t o e x plai n E o T visit t u m or assess me nt 
will c o ntri b ute t o all efficac y e n d p oi nts  
0. 3  
2 6 A pr 2 0 1 6 
 
Acc or di n g t o s p o ns or’s c o m m e nts, u p date d R E CI S T relate d 
details r e gar di n g t u m or res p o nse c o nfir mati o n are a d de d t o 
t he S A P. 
O ne a d diti o nal u p date re gar di n g 2 or m ore missi n g 
c o nsec uti ve visits’ i m pact o n P F S.  
A d de d La b para meters gra di n g acc or di n g t o C T C - A E 
g ui deli ne.  
0. 4  
3 0 Se p 2 0 1 6 
 
U p date c o m me nts.  
U p date T L F acc or di n g t o ne w C R F.  
A d d descri pti o ns i n S A P f or eac h T L F. Pre vi o usl y, s o me 
T L Fs d o n’t ha ve c orres p o n di n g descri pti o n i n S A P.  
Re vise la y o ut  
0. 5  
2 4 N o v 2 0 1 6 
 
U p date c o m me nts  
C CI
P P D
P P D
P P D
P P D
P P D


 
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P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
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“ S hift T a ble of La b orat or y Gr a de fr o m Baseli ne” is 
re place d b y “ S hift i n T o xicit y Gra di n g fr o m Baseli ne t o 
W orst C T C A E Gra de”  
A d d fi g ures f or Q T c F a n d Q Tc B 
Mer ge lesi o n listi n gs  
Mer ge s o me la b orat or y listi n gs  
Re m o ve or mer ge s o me ta bles t o c o ntr ol t he n u m ber of 
T L Fs  
 
0. 6  
1 5 Fe b 2 0 1 7 
 
U p date c o m me nts  
U p date  ta ble “T E A Es b y Se verit y ” t o ha ve se verit y 
prese nte d u n der eac h S O C/ P T  
C o m bi ne ta ble f or “ o verall res p o nse” a n d “ O R R a n d D C R”  
Re m o ve ta ble f or D o O R a n d P F S  
U p date deri vati o n f or e x p os ur e i n Secti o n 1 4. 1 t o m ore 
ge neral descri pti o n as ne w f or m ulati o n, 2 0 0 m g, is use d.  
0. 7  
3 1J U L 2 0 1 7 
 
U p date w hile pre pari n g dr y r u n o ut p uts  
1. 
Dr o p A T C 2 n d le vel as A T C c o di n g is n ot use d f or 
t he st u d y. 
2. 
A d d baseli ne fla gs f or data listi n gs  
3. 
M o ve(a d d) defi niti o n f or res p o nse e val ua ble set t o 
secti o n 6 f or clear u n dersta n di n g 
4. 
U p date secti o n f or E C G (e xter nal data)  
5. 
U p date/ m o dif y ta ble s hells, es peciall y E C G a n d 
la b orat or y para meters. 
0. 8  
1 3 Ma y 2 0 1 9 
 
1.  U p date d st u d y title. 
2. 
U p date d st u d y pri mar y o bj ecti ve a n d sec o n dar y 
o bj ecti ve.  
3. 
U p date d st u d y desi g n.  
4. 
U p date d defi niti o n of D L T e val ua ble patie nts.  
5. 
U p date d a nal ysis p o p ulati o n a n d pr ot oc ol 
de viati o n.  
C CI
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P P D
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6. 
U p date d t he t otal sa m ple size i n t he d ose escalati o n 
p hase a n d d ose e x pa nsi o n p hases.  
7. 
U p date d t he n u m ber of i n vesti gati o nal ce nters.  
8. 
U p date d efficac y o bj ecti ves a n d e n d p oi nts.  
0. 9  
2 8 M A Y 2 0 1 9 
 
U p date d c o m me nts fr o m H utc his o n  
1. 0 
2 8 J U N 2 0 1 9 
 
  
U p date d c o m me nts fr o m H utc his o n  
1. 1  
0 1J U N 2 0 2 0 
 
1.  U p date d st u d y title. 
2.  U p date d pri mar y a n d sec o n dar y o bj ecti ves a n d 
e n d p oi nts descri pti o n base d o n pr ot oc ol versi o n 
6. 0 ( A me n d me nt 1 0). 
3.  U p date d t he n u m ber of patie nts t o be e nr olle d. 
4.  A d de d sarc o ma a nal ysis descri pti o n. 
5.  U p date d descri pti o n f or e x pl orat or y e n d p oi nts.  
2. 0  
0 1J U L 2 0 2 0 
 
1.  U p date d c o m me nts fr o m H utc his o n. 
2.  U p date d A p pe n di x 2 A E SI list. 
2. 1  
2 4 A U G 2 0 2 0 
 
1.  U p date d t he defi niti o n of D L T e val ua ble patie nt 
per s p o ns or’s n ote t o file o n 1 7 A u g 2 0 2 0.  
2.  A d de d t he defi niti o n of treat me nt-e mer ge nt 
a d verse e ve nt ( T E A E). 
2. 2  
0 4 N O V 2 0 2 2 
 
1.  U p date d t he A p pe n di x 2 A E SI list. 
2.  U p date d t he pr ot oc ol versi o n as 7. 0 ( A me n d me nt 
1 1) 
3.  U p date d t he Me d D R A a n d W H O- D D E versi o n  
4.  U p date d descri pti o ns base d o n t he w or di n g 
c ha n ges i n pr ot oc ol versi o n 7. 0 ( A me n d me nt 1 1)  
5.  A d de d a d diti o nal a nal ysis ite ms f or E C G i n secti o n 
4. 4 
6.  U p date d secti o n 1 6. 1. 2 f or B O R a n d a d d 
u nc o nfir me d C R a n d P R f or B O R 
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P P D
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P P D
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T A B L E O F C O N T E N T S  
1.  
LI S T O F A B B R E VI A TI O N S ............................................................................................ 9  
2.  
I N T R O D U C TI O N............................................................................................................. 1 2 
3.  
S T U D Y O B J E C TI V E S ..................................................................................................... 1 2  
3. 1.  
D ose Escalati o n P hase ......................................................................................................... ........................ 1 2 
3. 1. 1.  
Pri mar y O bj ecti ve ............................................................................................................. ................... 1 2 
3. 1. 2.  
Sec o n dar y O bj ecti ves .......................................................................................................... ................ 1 2 
3. 2.  
D ose E x pa nsi o n P hase .......................................................................................................... ....................... 1 3 
3. 2. 1.  
Pri mar y O bj ecti ve ............................................................................................................. ................... 1 3 
3. 2. 2.  
Sec o n dar y O bj ecti ves .......................................................................................................... ................ 1 3 
3. 2. 3.  
E x pl orat or y O bj ecti ve ......................................................................................................... ................. 1 4 
4.  
S T U D Y D E SI G N ............................................................................................................... 1 4  
4. 1.  
Ge neral Descri pti o n ........................................................................................................... .......................... 1 4 
4. 1. 1.  
D ose Escalati o n P hase ......................................................................................................... ................ 1 4 
4. 1. 2.  
D ose E x pa nsi o n P hase .......................................................................................................... ............... 1 5 
4. 2.  
Sa m ple Size ................................................................................................................... .............................. 1 6 
4. 3.  
Sc he d ule of E ve nts ............................................................................................................ .......................... 1 7 
4. 4.  
C ha n ges t o A nal ysis fr o m Pr ot oc ol ............................................................................................. ................ 1 7 
5.  
P L A N N E D A N A L Y S E S ................................................................................................... 1 7  
5. 1.  
Safet y Re vie w  C o m mittee ( S R C) ................................................................................................ ............... 1 7 
5. 2.  
I nteri m A nal ysis........................................................................................................................................... 1 8 
5. 3.  
S na p S h ot A nal ysis ............................................................................................................ .......................... 1 8 
5. 4.  
Fi nal A nal ysis ................................................................................................................ .............................. 1 8 
6.  
A N A L Y SI S S E T S A N D P R O T O C O L D E VI A TI O N S .................................................. 1 8  
6. 1.  
All P atie nts E nr olle d  Set [ E N R] .................................................................................................................. 1 9 
6. 2.  
Safet y A nal ysis Set ( S A S) –  ( All Treate d P o p ulati o n) ................................................................................ 1 9 
6. 3.  
D osi n g Li miti n g T o xicit y ( D L T) E val ua ble Set .................................................................................. ........ 1 9 
6. 4.  
Efficac y A nal ysis Set ( E A S) ................................................................................................... ..................... 1 9 
6. 5.  
Pr ot oc ol De viati o n ............................................................................................................ ........................... 2 0 
7.  
G E N E R A L C O N SI D E R A TI O N S ................................................................................... 2 0  
7. 1.  
Refere nce Start Date,  Refere nce E n d Date a n d St u d y Da y ....................................................................... .. 2 0 
7. 2.  
B aseli ne ...................................................................................................................... ................................. 2 1 
7. 3.  
E n d of Tr eat me nt .............................................................................................................. ........................... 2 1 
C CI


 
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P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 7 of 7 0 
 
7. 3. 1.  
E n d of St u d y .................................................................................................................. ...................... 2 1 
7. 4.  
Retests, U nsc he d ule d Visits a n d Earl y T er mi nati o n Data ........................................................................ ... 2 1 
7. 5.  
Visit Wi n d o ws C o n ve nti o ns ..................................................................................................... ................... 2 1 
7. 6.  
Statistical T ests ............................................................................................................. ............................... 2 2 
7. 7.  
C o m m o n Calc ulati o ns ........................................................................................................... ...................... 2 2 
7. 8.  
S oft ware Versi o n .............................................................................................................. ........................... 2 2 
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S ............................................................................ 2 2  
8. 1.  
M ultice nter St u dies ........................................................................................................... ........................... 2 2 
8. 2.  
Missi n g data .................................................................................................................. ............................... 2 2 
9.  
O U T P U T P R E S E N T A TI O N S ......................................................................................... 2 5  
1 0.  
DI S P O SI TI O N A N D WI T H D R A W A L S ........................................................................ 2 6  
1 1.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S ....................... 2 6  
1 1. 1.  
Deri vati o ns ................................................................................................................... ............................ 2 8 
1 2.  
M E DI C A L HI S T O R Y A N D O N C O L O G Y HI S T O R Y ................................................ 2 8  
1 2. 1.  
Deri vati o ns ................................................................................................................... ............................ 2 9 
1 3.  
M E DI C A TI O N S A N D P R O C E D U R E S ......................................................................... 2 9  
1 4.  
O N C O L O G Y T H E R A PI E S ............................................................................................. 2 9  
1 5.  
S T U D Y M E DI C A TI O N E X P O S U R E ............................................................................ 3 0  
1 5. 1 D E RI V A TI O N S .............................................................................................................. .... 3 1 
1 6.  
E F FI C A C Y O U T C O M E S................................................................................................ 3 2  
1 6. 1.  
Efficac y Varia ble(s) & Deri vati o n(s) .......................................................................................... ............. 3 2 
1 6. 1. 1.  
Pr o gressi o n- Free S ur vi val ..................................................................................................... ............... 3 2 
1 6. 1. 2.  
B est O verall Res p o nse ......................................................................................................... ................ 3 4 
1 6. 1. 3.  
O bj ecti ve Res p o nse Rate ....................................................................................................... .............. 3 6 
1 6. 1. 4.  
Disease C o ntr ol Rate .......................................................................................................... ................. 3 6 
1 6. 1. 5.  
Ti me t o Res p o nse .............................................................................................................. .................. 3 7 
1 6. 1. 6.  
D urati o n of O bj ecti ve Res p o nse ................................................................................................ .......... 3 7 
1 6. 1. 7.  
P erce nta ge C ha n ge i n T u m or Size ............................................................................................... ........ 3 7 
1 6. 2.  
Pri mar y A nal ysis of Ef ficac y Varia ble(s) ................................................................................................ 3 7 
1 6. 3.  
E x pl orat or y Efficac y .......................................................................................................... ...................... 3 8 
1 6. 3. 1.  
T u m or Mar kers ................................................................................................................. ................... 3 8 
1 6. 3. 2.  
O verall S ur vi val .............................................................................................................. ..................... 3 8 
1 6. 4.  
Se nsiti vit y A nal ysis of Efficac y Varia ble(s) .................................................................................. .......... 3 9 
1 7.  
S A F E T Y O U T C O M E S .................................................................................................... 3 9  
1 7. 1.  
A d verse E ve nts ................................................................................................................ ........................ 3 9 
C CI


 
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1 7. 1. 1.  
All T E A Es ..................................................................................................................... ...................... 4 0 
1 7. 1. 2.  
T E A Es Lea di n g t o Disc o nti n uati o n of St u d y Me dicati o n ................................................................... 4 1  
1 7. 1. 3.  
T E A Es Lea di n g t o St u d y Me dicati o n A dj ust me nt............................................................................... 4 1  
1 7. 1. 4.  
Seri o us T E A Es ................................................................................................................. .................... 4 1 
1 7. 1. 5.  
T E A Es Of S pecial I nter est ( T E A E SI) ................................................................................................. 4 2 
1 7. 1. 6.  
D ose Li miti n g T o xicit y ( D L T) .................................................................................................. .......... 4 2 
1 7. 1. 7.  
Deat hs ........................................................................................................................ .......................... 4 2 
1 7. 2.  
La b orat or y E val uati o ns ........................................................................................................ .................... 4 2 
1 7. 2. 1.  
La b orat or y S pecific Deri vati o ns ............................................................................................... ........... 4 3 
1 7. 2. 2.  
La b orat or y Refere nce Ra n ges a n d Mar ke dl y A b n or mal Criteria ........................................................ 4 3  
1 7. 2. 3.  
C T C A E Gra di n g f or La b orat or y Data ............................................................................................. .... 4 4 
1 7. 2. 4.  
Li ver F u ncti o n A b n or malit y .................................................................................................... ............ 4 4 
1 7. 3.  
E C G E val uati o ns ............................................................................................................... ...................... 4 5 
1 7. 3. 1.  
E C G S pecific Deri vati o ns ...................................................................................................... .............. 4 5 
1 7. 3. 2.  
E C G Mar ke dl y A b n or mal Crit eria ................................................................................................ ....... 4 5 
1 7. 3. 3.  
A nal ysis of Q T c C ha n ge fr o m Baseli ne ( Δ Q T c)  ................................................................................. 4 6 
1 7. 3. 4.  
A nal ysis of t he Relati o ns hi p B et wee n Q T/ Q T c a n d R R at Baseli ne ................................................... 4 6  
1 7. 4.  
Vital Si g ns ................................................................................................................... ............................ 4 7 
1 7. 4. 1.  
Vital Si g ns S pecific Deri vati o ns .............................................................................................. ............ 4 7 
1 7. 4. 2.  
Vital Si g ns Mar ke dl y A b n or mal Criteria ........................................................................................ ..... 4 7 
1 7. 5.  
P h ysical E xa mi nati o n .......................................................................................................... .................... 4 8 
1 7. 6.  
Ot her Safet y Assess me nts ...................................................................................................... .................. 4 8 
1 7. 6. 1.  
E C O G P erf or ma nce Stat us ....................................................................................................... ........... 4 8 
1 7. 6. 2.  
Ec h ocar di o gra m ................................................................................................................ ................... 4 8 
1 8.  
R E F E R E N C E S ..................................................................................................................  4 9  
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S .............................. 5 0  
I Q VI A O ut p ut C o n ve nti o ns...................................................................................................................................... 5 0 
D ates & Ti mes ................................................................................................................. ........................................... 5 0 
S pelli n g F or m at................................................................................................................ .......................................... 5 0 
Prese nt ati o n of Tre at me nt Gr o u ps .............................................................................................. ............................ 5 0 
Prese nt ati o n of Dise ase C o h ort ................................................................................................ ................................. 5 1 
Prese nti n g Or der .............................................................................................................. ......................................... 5 1 
A P P E N DI X 2.  A D V E R S E E V E N T S O F S P E CI A L I N T E R E S T ........................................ 5 1  
 
 
C CI


 
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1.  L I S T O F A B B R E VI A TI O N S  
Ter ms a n d A b bre vi ati o ns  
Defi niti o n  
A C S  
A b n or mal,  cli nicall y si g nifica nt 
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsa mi nase  
A N C S  
A b n or mal, n ot cli nicall y si g nifica nt 
a P T T  
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n o tra nsa mi nase 
A T C  
A nat o mical T hera pe utic C he mical  
B O R  
B est o verall res p o nse  
B T C  
Biliar y tract ca ncers  
C A 1 9 - 9 
Car b o h y drate a nti ge n 1 9 - 9 
C Cr  
Creati ni ne cleara nce  
C E A 
Carci n oe m br y o nic a nti ge n  
C g A 
C hr o m o gra ni n A  
CI  
C o nfi de nce i nter val  
C R  
C o m plete res p o nse 
C R F  
Case re p ort f or m  
C T C  
C o m m o n t o xicit y criteria   
C T C A E  
C o m m o n ter mi n ol o g y criteria f or a d verse e ve nts  
D B L  
Data base L oc k  
D B P  
Diast olic bl o o d press ure  
D C R  
Disease c o ntr ol rate  
DI LI  
Dr u g -i n d uce d li ver i nj ur y 
D L T  
D ose -li miti n g t o xicit y 
D o R 
D urati o n of Res p o nse 
E A S  
Efficac y a nal ysis set  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
C CI


 
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P a g e 1 0 of 7 0 
 
Ter ms a n d A b bre vi ati o ns  
Defi niti o n  
E N R  
All patie nts e nr olle d set  
e p N E T s 
E xtra p a ncreatic ne ur oe n d ocri ne t u m ors  
I C F 
I nf or me d c o nse nt f or m 
I N R 
I nter nati o nal n o n pr o prietar y rati o 
L E V F  
Left ve ntric ular ej ecti o n fracti o n  
L M S  
Lei o m y osarc o ma  
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
M T D  
Ma xi m u m t olerate d d ose  
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
N ot e val ua ble  
N S E 
Ne ur o n -s pecific e n olase 
O R R  
O verall res p o nse rate  
O S  
O verall s ur vi val  
P D  
Pr o gressi o n of disease  
P F S  
Pr o gressi o n -free s ur vi val  
P K  
p har mac o ki netic  
p N E T  
P a ncreatic ne ur oe n d ocri ne t u m ors  
P R  
P artial res p o nse  
R P 2 D  
Rec o m me n de d p hase II d ose 
P T  
Preferre d ter m ( Me d D R A)  
P V N S  
Pi g me nte d vill o n o d ular s y n o vitis  
Q T c  
Q T i nter val c orrecte d  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A S  
Safet y a nal ysis set  
S B P  
S yst olic bl o o d pre ss ure 
S Cr  
Ser u m creati ni ne  
C CI


 
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Ter ms a n d A b bre vi ati o ns  
Defi niti o n  
S D  
Sta ble disease  
S M Q  
Sta n dar dize d Me d D R A q ueries 
S O C  
S yste m or ga n class ( Me d D R A)  
S R C  
Safet y re vie w c o m mittee  
S T S  
S oft tiss ue sarc o ma  
S ur ufati ni b  
I nter nati o nal n o n- pr o prietar y na me assi g ne d t o s ulfati ni b b y t he W orl d 
Healt h Or ga nizati o n  
T S H 
T h yr oi d sti m ulati n g h or m o ne 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt 
T E A E SI  
Treat me nt -e mer ge nt a d verse e ve nt of s pecial i nterest 
T T R  
Ti me t o res p o nse  
U P S  
U n differe ntiate d ple o m or p hic sarc o ma  
V E G F  
Vasc ular e n d ot helial gr o wt h fact or  
W H O 
W orl d Healt h Or ga nizati o n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


 
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St ati sti c al A n al y si s Pl a n  
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2.  IN T R O D U C TI O N  
T his d oc u me nt d escri bes t he r ules a n d c o n ve nti o ns t o be use d  i n t he prese ntati o n a n d a nal ysis of efficac y a n d safet y 
data f or Pr ot oc ol 2 0 1 5- 0 1 2- 0 0 U S 1. It d escri bes t he data t o be s u m marize d a n d a nal yze d, i ncl u di n g s pecifics of t he 
statistical a nal yses t o be perf or me d.  
T his statistical a nal ysis p la n ( S A P) is base d o n prot oc ol versi o n 7. 0 (a me n d me nt 1 1) date d 1 9 Mar 2 0 2 1. 
T he p har mac o ki netics a nal ysis pla n will n ot b e i ncl u de d i n t his d oc u me nt. 
3.  S T U D Y O B J E C TI V E S  
3. 1.  D O S E E S C A L A TI O N P H A S E  
3. 1. 1.  Pri m ar y O bjecti ve 
T he pri mar y o bj ecti ve is t o e v al uate t he safet y a n d t olera bilit y of s ur ufati ni b i n patie nts wit h a d va nce d s oli d t u m ors 
of a n y t y pe, a n d t o deter mi ne t he ma xi m u m t olera ble d ose ( M T D) a n d/ or rec o m me n d e d p has e II d ose ( R P 2 D). 
Pri mar y E n d p oi nt: T he i nci de nce of D ose Li miti n g T o xicities ( D L Ts) i n eac h c o h ort. D L T is defi ne d i n Secti o n 6. 3. 
3. 1. 2.  Sec o n d ar y O bjecti ves 
T he sec o n dar y o bj ecti ves are: 
 
T o e val uate t he p har mac o ki netic ( P K) c haracteristics of m ulti ple- d ose s u r ufati ni b a n d t o i n vesti gate t he 
meta b olite pr ofile of s ur ufati ni b i n t he p las ma of patie nts wit h s oli d t u m ors. 
 
T o e val uate t he a ntica ncer acti vit y of s ur ufati ni b i n patie nts wit h a d va nce d s oli d t u m ors of a n y t y pe 
acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors
R E CI S T  Versi o n 1. 1. 
Sec o n dar y E n d p oi nts 
 
P K para meters: refer t o p har mac o ki netics a nal ysis pla n f or details. P K para meters are liste d bel o w:. 
o  
Ma xi m u m plas ma c o nce ntrati o n ( C
ma x ) 
o  
Ti me t o reac h ma xi m u m c o nc e ntrati o n ( T ma x ) 
o  
T er mi nal half-life (t 1/ 2) 
o  
Area u n der t he c o nce ntrati o n-ti me c ur ve i n a selecte d ti me i nter val ( A U C 0-t) 
o  
Area u n der t he c o nce ntrati o n-ti me c ur ve i n t he ti me i nter val fr o m 0 t o i nfi nit y ( A U C 0 ˗ ) 
o  
A p pare nt cleara nce ( C L/ F) 
o  
A p pare nt v ol u me of distri b uti o n ( V z/ F) 
o  
Mea n resi de nce ti me ( M R T) 
o  
Acc u m ulati o n i n de x base d o n A U C 
C CI


 
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St ati sti c al A n al y si s Pl a n  
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T he o bj ecti ve res p o nse rate ( O R R), disease c o ntr ol rate ( D C R), d urati o n of res p o nse ( D o R), pr o gressi o n-
free s ur vi val ( P F S), a n d perce nta ge c ha n ge i n t u m or size fr o m baseli ne acc or di n g t o R E CI S T V ersi o n 1. 1. 
3. 2.  D O S E E X P A N SI O N P H A S E  
3. 2. 1.  Pri m ar y O bjecti ve 
T he pri mar y o bj ecti ve is t o e v al uate t he a ntica ncer acti vit y  of s ur ufati ni b at t he rec o m me n de d P hase 2 d ose ( R P 2 D) 
fr o m t he d ose escalati o n p hase, i n patie nts wit h a d va nce d bili ar y tract ca ncer ( B T C), patie nts wit h a d va nce d 
P a ncreatic Ne ur oe n d ocri ne T u m ors ( p N E Ts), patie n ts wit h l ocall y a d va nce d, u nresecta ble, metastatic 
E xtra p a ncreatic Ne ur oe n d ocri ne T u m ors ( e p N E Ts), a n d patie nts wit h s oft tiss ue sarc o ma ( S T S) treate d at a d ose of 
3 0 0 m g Q D (ie, t he M T D/ R P 2 D was declare d i n Pr ot oc ol A m e n d me nt 7).  T he R P 2 D i n t his trial is t he sa me as t he 
R P 2 D use d i n cli nical trials i n C hi na. 
Pri mar y E n d p oi nts 
 
P atie nts wit h B T C ( Ar m A): pr o gressi o n-free s ur vi val ( P F S) at 1 6 wee ks (acc or di n g t o R E CI S T V. 1. 1.) 
 
P atie nts wit h p N E T ( Ar m B): P F S at 1 1 m o nt hs (acc or di n g t o R E CI S T V. 1. 1.) 
 
P atie nts wit h e p N E T ( Ar m C): P F S at 1 1 m o nt hs (acc or di n g t o R E CI S T V. 1. 1.) 
 
P atie nts wit h S T S ( Ar m D): P F S at 4 m o nt hs (acc or di n g t o R E CI S T V. 1. 1.) 
3. 2. 2.  Sec o n d ar y O bjecti ves 
T he sec o n dar y o bj ecti ves are: 
 
T o e val uate t he P K pr ofile of m ulti ple d ose s ur ufati ni b i n patie nts wit h a d va nce d B T C, patie nts wit h 
a d va nce d p N E T, patie nts wit h a d va nce d e p N E T, a n d patie nts wit h a d va nce d S T S. 
 
T o e val uate t he safet y of s ur ufati ni b i n patie nts wit h a d va nce d B T C, patie nts wit h a d va nce d p N E T, patie nts 
wit h a d va nce d e p N E T, a n d patie nts wit h a d va nce d S T S. 
 
T o e val uate t he a ntica ncer acti vit y of s ur ufati ni b i n patie nts wit h a d va nce d B T C, patie nts wit h a d va nce d 
p N E T, patie nts wit h a d va nce d e p N E T, a n d patie nts wit h a d va nce d S T S. 
Sec o n dar y E n d p oi nts: 
 
P har mac o ki netic para meters, w hic h i ncl u de b ut are n ot li mite d t o, C ma x , T ma x , first- or der rate c o nsta nt Kel, 
A U C, t 1/ 2, C L/ F, Vz/ F, acc u m ulati o n rati o, a n d d ose pr o p orti o nalit y bet wee n A U C a n d d ose a n d Cma x  a n d 
d ose. 
 
Safet y, as assesse d b y: 
 
T he fre q ue nc y a n d se verit y of a d verse e ve nts  
 
P h ysical e xa mi nati o n fi n di n gs 
 
Vital si g ns 
C CI


 
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St ati sti c al A n al y si s Pl a n  
P a g e 1 4 of 7 0 
 
 
La b orat or y test res ults (ie, he mat ol o g y, c he mistr y pa nel, a n d uri nal ysis) 
 
1 2-lea d electr ocar di o gra m 
 
Ec h ocar di o gra m 
 
O R R, D C R, ti me t o res p o nse ( T T R), D o R, a n d perc e nta ge c ha n ge i n t u m or size fr o m baseli ne defi ne d 
acc or di n g t o R E CI S T V 1. 1. 
3. 2. 3.  E x pl or at or y O bjecti ve 
T he e x pl orat or y o bj ecti ves are:  
 
T o assess selecte d t u m or mar kers base d o n t y pe of mali g na nc y. 
 
T o e val uate t he O verall S ur vi val ( O S) i n patie nt s wit h a d va nce d B T C a n d a d va nce d S T S. 
E x pl orat or y E n d p oi nt 
 
T u m or mar kers ma y i ncl u de, b ut are n ot li mite d t o, ser u m C E A a n d C A 1 9- 9 ( patie nts wit h B T C) 
ser u m c hr o m o gra ni n A ( C g A) a n d neur o n-s pecific e n olase ( N S E) f or patie nts wit h p N E T a n d e p N E T; 
a n d V E G F f or t he B T C, p N E T a n d e p N E T disease c o h orts. Assess me nt of t u m or mar kers will be 
perf or me d wit hi n 2 8 da ys pri or t o t he start of tr eat me nt wit h st u d y dr u g ( C 1 D 1) a n d at eac h t u m or 
assess me nt visit. 
 
O S li mite d t o patie nts e nr olle d t o  t he B T C a n d S T S c o h orts o nl y. 
4.  S T U D Y D E SI G N  
4. 1.  G E N E R A L D E S C RI P TI O N  
T his is a n o pe n-la bel, m ulti-ce nter cli nical trial of s ur ufati ni b ta ke n orall y o nce dail y ( Q D), a n d it c o nsists of 2 
p hases: a d ose escalati o n p has e i n patie nts wit h a d va nce d s o li d t u m ors of a n y t y pe, a nd a d ose e x pa nsi o n p hase i n 
patie nts wit h a d va nce d B T C ( Ar m A), a d va nce d p N E Ts ( Ar m  B), a d va nce d e p N E Ts ( Ar m C), or S T Ss ( Ar m D) f or 
w h o m sta n dar d t hera p y eit her d oes n ot e xist or ha s pr o ve n t o be i neffecti ve or i nt olera ble.  
A p pr o xi matel y 9 5- 1 5 0 patie nts will be e nr olle d i n t his 2- p hase st u d y: 3 5 patie nts i n t he d ose escalati o n p hase a n d 
a p pr o xi matel y 1 1 5 patie nts i n t he d ose e x pa nsi o n p hase. T h e t w o p hases will be c o n d u cte d as descri be d bel o w. 
4. 1. 1.  D ose Esc al ati o n P h ase 
I n t his p hase, a 3 + 3 desi g n will b e use d. E nr oll me nt of 3 5- 4 0 patie nts was pla n ne d. As of Pr ot oc ol A me n d me nt 7, a 
t otal of 3 5 e val ua ble patie nts ha ve bee n e nr olle d i n t he d ose escalati o n p hase. T he trial was t o e val uate 5 s ur ufati ni b 
d ose le vels at 5 0, 1 0 0, 2 0 0, 3 0 0 a n d 4 0 0 m g o n a Q D d osi n g sc he d ule. 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
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St ati sti c al A n al y si s Pl a n  
P a g e 1 5 of 7 0 
 
 
T he st u d y c o n d uct was t o f oll o w a 3 + 3 desi g n, wit h t he d ose li miti n g t o xicit y ( D L T) assess me nt wi n d o w bei n g 
C ycle 1, fr o m Da y 1 t o Da y 2 8. Detaile d descri pti o n of a 3 + 3 desi g n ca n be f o u n d i n pr ot oc ol secti o n 5. 1. 1. 
 
I n a d diti o n t o t he fi ve d ose le v els, i n t he occasi o n w here 2 or m ore D L Ts were o bser ve d i n t he 6 e val ua ble patie nts 
at a gi ve n d ose le vel, t he d ose escalati o n was t o be halte d. If t h is d ose le vel is greater t ha n or e q ual t o 5 0 % hi g her 
t ha n t he pre vi o us d ose le vel, a n i nter mediate d ose le vel was t o be e val uate d f or t o xicit y i n t he sa me ma n ner as a 3 + 3 
d ose le vel. If t he d ose le vel was less t h a n 5 0 % hi g her t ha n t he pr e vi o us d ose le vel, a d diti o na l patie nts were t o be 
e nr olle d at t he pre vi o us d ose le vel, if necessar y, t o f or m a d ose c o h ort of mi ni m u m 6 e val ua ble patie nts. T he M T D 
is t he hi g hest d ose reac he d wit h n o m ore t ha n 1 D L T a m o n g 6 e val ua ble patie nts. 
 
A n y patie nt w h o was c o nsi dere d n o n-e val ua ble f or D L T as defi ne d i n pr ot oc ol secti o n 5. 1. 1 ‘ D ose escalati o n p hase’ 
was t o be re place d b y a n a d diti o nal patie nt at t hat sa me d ose le vel. 
 
Safet y m o nit ori n g a n d e val uati o n f or d ose escalati o n will be carrie d o ut b y a Safet y Re vie w C o m mittee ( S R C) u p o n 
c o m pleti o n of t he D L T o bser vati o n peri o d of eac h d ose le vel. 
 
P atie nts w h o ha ve c o m plete d t he D L T o bser vati o n wi n d o w ( C ycle 1, da y 1- 2 8) a n d were d ee me d t o be be nefiti n g 
fr o m s ur ufati ni b treat me nt c o ul d ha ve bee n per mitte d, at t he i n vesti gat or’s discreti o n, t o c o nti n ue wit h s ur ufati ni b 
treat me nt u ntil disease pr o gressi o n, deat h, i nt olera ble t o xicity, pre g na nc y, or l oss of be nefit fr o m t he st u d y dr u g. 
I ntra- patie nt d ose escalati o n t o a hi g her d ose t hat ha d bee n cleare d was all o we d if t he s p o ns or a n d i n vesti gat or b ot h 
a gree d. 
 
T he M T D/ R P 2 D of s ur ufati ni b has bee n declare d at 3 0 0 m g Q D ( Pr ot oc ol A me n d me nt 7). 
4. 1. 2.  D ose E x p a nsi o n P h ase 
T he e x pa nsi o n p hase will e val uate t he a ntit u m or acti vit y of s ur ufati ni b, a n d e val uate t he safet y a n d t olera bilit y of 
s ur ufati ni b at t he R P 2 D deter mi ne d at t he e n d of t he d ose escal ati o n p hase. 
 
A p pr o xi matel y 1 1 5 a d diti o nal patie nts will  be e nr olle d i nt o t he 4 o pe n-la bel treat me nt ar ms d uri n g t his p hase: at 
least 3 0 patie nts wit h a d va nce d B T C t hat ha ve pr o gresse d o n sta n dar d first-li ne c he m ot hera p y will be assi g ne d t o 
Ar m A, at least 1 5 patie nts wit h a d va nce d p N E T t hat ha ve pr o g resse d o n eit her e ver oli m us, s u niti ni b, or b ot h will be 
assi g ne d t o Ar m B, a n d at least 1 5 patie nts wit h a d va nce d e p N E Ts t hat ha ve pr o gresse d o n e ver oli m us will be 
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St ati sti c al A n al y si s Pl a n  
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assi g ne d t o Ar m C, a n d at least 5 5 patie nts wit h S T S will be assi g ne d t o Ar m D. 
 
T he safet y of all e nr olle d patie nts will be cl osel y m o nit ore d fr o m t he ti me of t he i nitial d os e of i n vesti gati o nal 
treat me nt u ntil 3 0 da ys after t he last treat me nt d ose. A n y S A Es t hat occ ur after t he I C F is si g ne d, b ut bef ore t he first 
d ose of st u d y dr u g is ta ke n, s h o ul d als o be re p orte d. All A Es will be gra de d i n acc or da nce wit h t he N CI C T C A E v. 
4. 0 3.  
 
P atie nts will recei ve s ur ufati ni b c o nti n u o usl y b y 2 8- da y treat me nt c ycles u ntil disease pr o gressi o n (acc or di n g t o 
R E CI S T Versi o n 1. 1), deat h, i nt olera ble t o xicit y, or at i n vesti gat o r’s discreti o n t hat t he patie nt ca n n o l o n ger be nefit 
fr o m t he st u d y treat me nt. T u m or assess me nts will be c o n ducte d acc or di n g t o R E CI S T v. 1. 1 criteria at scree ni n g, 
C ycle 2 Da y 1 a n d e ver y 8 ( ± 1) wee ks t hereafter. C o nfir mati o n of C R a n d P R is re q uire d at n o less t ha n 4- wee k 
i nter vals bet wee n t he date of i nitial res p o nse/ pr o gressi o n a n d t he c o nfir mati o n assess me nt date. 
4. 2.  S A M P L E S I Z E 
T he t otal n u m ber of patie nts e nr olle d wi ll d e pe n d o n t he n u m ber of d ose escalati o ns a n d t he nee d t o f urt her 
c haracterize i n di vi d ual c o h orts i n t he e x pa nsi o n p hase. 
 
A p pr o xi matel y 9 5- 1 5 0 patie nts will be e nr olle d i n t his t w o- p hase st u d y: 3 5 patie nts i n t he d ose escalati o n p hase a n d 
a p pr o xi matel y 1 1 5 a d diti o nal patie nts i n t he d ose e x pa ns i o n p hase. T he act ual e nr oll me nt n u m ber ma y var y, 
de p e n di n g o n t he n u m ber of d ose le vels e val uate d a n d t he n u m ber of D L Ts o bser ve d i n ea c h c o h ort, as well as t he 
p ote ntial nee d t o f urt her c hara cterize i n di vi d u al c o h orts i n t he d ose e x pa nsi o n p hase. 
 
As per Pr ot oc ol A me n d me nt 7, a n a d diti o nal 1 5 patie nts will be e nr olle d i nt o Ar m A ( B T C) of t he e x pa nsi o n p hase, 
f or a t otal e nr oll me nt of at least 3 0 a d va nce d B T C patie nts. T he reas o n f o r i ncreasi n g e nr oll me nt i nt o Ar m A 
(a d va nce d B T C) is t hat preli mi nar y data fr o m t he o n g oi n g patie nts i n t his c o h ort ha ve s h o w n e nc o ura gi n g res ults. 
T he a d diti o nal patie nts will all o w f urt he r c haracterizati o n of t he safet y a n d efficac y of s ur ufati ni b i n t his patie nt 
p o p ulati o n. Ar m B ( p N E T) a n d Ar m C (e p N E T) will e nr oll at  least 1 5 patie nts eac h. If ne e de d, Ar m B a n d Ar m C 
c o ul d e nr oll a d diti o nal patie nts i n or der t o c haracterize f urt her t he safet y a n d efficac y of s ur ufati ni b i n t hese patie nt 
p o p ulati o ns. 
 
As per Pr ot oc ol A me n d me nt 8, 4 5 patie nts wit h S T S ( 1 0 p atie nts wit h Lei o m y osarc o ma ( L M S), 1 0 patie nts wit h 
U n differe ntiate d ple o m or p hic sarc o ma ( U P S), 1 0 patie nts wit h  e pit heli oi d sarc o ma, 1 0 patie nts wit h a n gi osarc o ma, 
1 0 patie nts wit h s y n o vial sarc o ma, a n d 5 patie nts wit h Pi g me nte d vill o n o d ular  s y n o vitis ( P V N S)) are pla n ne d t o be 
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e nr olle d.   
 
As per Pr ot oc ol A me n d me nt 1 0, a n a d d iti o nal 1 0 patie nts will be a d de d t o t he ar m D ( S T S) f or a t otal e nr ol me nt of 
5 5 patie nts. 
A d diti o nal details o n sa m ple size ca n be f o u n d i n Pr ot oc ol Secti o n 1 0. 1. 
4. 3.  S C H E D U L E O F E V E N T S  
Sc he d ule of e ve nts ca n be f o u n d i n Pr ot oc ol A p pe n di x 1 - St u d y Fl o wc harts. 
4. 4.  C H A N G E S T O A N A L Y SI S F R O M P R O T O C O L  
A d diti o nal A nal ysis f or E C G will b e i ncl u de d t he e val uati o n of c ha n ge fr o m baseli ne i n Q T c F ( Δ Q T c F) i nter vals  
a n d t he relati o ns hi p bet wee n Q T/ Q T c a n d R R i nter vals at b as eli ne will be e val uate d gra p hicall y. Refer t o t he secti o n 
1 7. 3. 3 a n d 1 7. 3. 4 f or t he details.  
5.  P L A N N E D A N A L Y S E S  
T he f oll o wi n g f or mal a nal yses are pla n ne d f or t he st u d y: 
5. 1.  S A F E T Y R E VI E W  C O M MI T T E E ( S R C) 
Safet y m o nit ori n g a n d e val uati o n f or d ose escalati o n will be carrie d o ut b y a Safet y Re vie w C o m mittee ( S R C) u p o n 
c o m pleti o n of t he D L T o bser vati o n peri o d of eac h c o h ort.  
T he S R C is c haire d b y t he S p o ns or’s Cl i nical Pr o gra m Lea der of t he s ur ufati ni b pr o gra m, a n d me m bers will i ncl u de 
t he pri nci pal i n vesti gat ors ( PIs), t he S p o ns or’s P K scie ntist, me dical m o nit or, a n d safet y scie ntist, a n d t he C R O’s 
me dical m o nit or. D ose escalati o n decisi o ns are base d o n sa fet y a n d P K data fr o m t his o n g oi n g trial, as well as 
c o nsi derati o n of safet y a n d P K d ata at c o m para ble dr u g e x p os ures fr o m patie nts i n pre vi o usl y c o n d ucte d cli nical 
trials i n C hi na. 
F or t he d ose e x pa nsi o n p hase of t he trial,  a se parate, s pecific S R C will be esta blis he d t o e ns ure t he safet y of all 
patie nts treate d wit h st u d y dr u g i n t he S T S c o h ort ( S T S - S C R). Re vie w of a vaila ble safet y la b orat ories, a d verse 
e ve nts, a n d a n y ot her perti ne n t d ata a vaila ble will be re vie we d after t he first 4 patie nts i n e ac h sarc o ma c o h ort ha ve 
c o m plete d at least 1 c ycle of tr eat me nt. T he rec o m me n dati o ns of t he S T S- S R C will be base d o n t he me m bers’ 
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P a g e 1 8 of 7 0 
 
cli nical assess me nt of t he c u m ulati ve safet y data pr o vi de d  f or re vie w. T he S R C will n ot be c har ge d wit h t he 
a p plicati o n of f or mal statistical st o p pi n g r ules f or safet y.  
5. 2.  IN T E RI M A N A L Y SI S  
A n i nf or mal i nteri m a nal ysis was perf or me d usi n g data c u t- off date of 3 0J U N 2 0 2 0. T his S A P c o vers t he a nal yses 
f or efficac y a n d safet y base d o n t he data c ut- off f or t he i nteri m a nal ysis. T he i nteri m a nal ysis was perf or me d usi n g 
clea ne d e C R F data c ollecte d u ntil data c ut- off date. I n a d d iti o n, S A Es were be s u m marize d base d o n all patie nts 
recr uite d i nt o st u d y o n or bef ore data c ut- off date. All S A E d ata t o be i ncl u de d i n t he i nteri m a nal ysis was t o be 
clea ne d. 
C o nsi deri n g t he g oal of t his i nteri m a nal ysis was t o s u p p ort re g ulat or y s u b missi o n, t he effi cac y a nal ysis f or t his 
i nteri m a nal ysis was li mite d t o p N E T a n d e p N E T c o h orts w hile t he safet y was c o ver all patie nts e nr olle d o n t he trial 
as of t he pla n ne d c ut- off date. 
 
I n a d diti o n, t he o verall s ur vi val a nal ysis f or B T C a n d S T S c oh orts were n ot i ncl u de d i n t his i nteri m a nal ysis. T he 
t u m or assess me nt after t he e n d of treat me nt was n ot a p plie d t o t his i nteri m a nal ysis as well. T he t u m or assess me nt 
data after t he e n d of treat me nt was c ut- off f or t his i nteri m a nal ysis. 
5. 3.  S N A P S H O T A N A L Y SI S  
A s na p s h ot a nal ysis was perf or me d usi n g data at c ut- off date of 1 4J u n 2 0 1 9.  
All s u m maries of safet y a n d efficac y data w ere prese nte d b y assi g ne d d ose le v el i n escalati o n p hase, a n d disease 
t y pe w hic h p o ole d t he patie nts w h o e nr olle d i n t he d ose e x pa nsi o n p hase a n d patie nts of t he sa me t u m or t y pe ( B T C, 
p N E T, e p N E T) at t he R P 2 D d ose le vel i n t he d ose escalati o n p hase.  
5. 4.  F I N A L A N A L Y SI S  
All fi nal, pla n ne d a nal yses i de ntifie d i n t his S A P will be per f or me d b y I Q VI A Bi ostatistics b y f oll o wi n g s p o ns or’s 
a ut h orizati o n of t his S A P a n d fi nal Data base L oc k ( D B L) f or t his st u d y. 
6.  A N A L Y SI S S E T S A N D P R O T O C O L D E VI A TI O N S  
A gree me nt a n d a ut h orizati o n of patie nts i ncl u de d/ e xcl u de d fr o m eac h a nal ysis set will be c o n d ucte d pri or t o t he 
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P a g e 1 9 of 7 0 
 
D B L f or t he fi nal a nal ysis of t he st u d y. 
All s u m maries will be prese nt e d b y assi g ne d d ose le vel i n  es calati o n p hase, a n d b y disease t y pe w hic h will p o ol t he 
patie nts w h o e nr olle d i n t he d ose e x pa nsi o n p hase a n d patie n ts of t he sa me t u m or t y pe ( B T C, p N E T, e p N E T, S T S) 
at t he R P 2 D d ose le vel i n t he d ose escalati o n p hase.  
All patie nts will be prese nte d acc or di n g t o t heir i nitial assi g ne d d ose le vel re gar dless of a n y d ose a dj ust me nt d uri n g 
st u d y c o n d uct. 
6. 1.  A L L P A TI E N T S E N R O L L E D S E T [ E N R] 
T he all patie nts e nr olle d set ( E N R) will i ncl u de all patie nts w h o si g ne d i nf or me d c o nse nt f or m (I C F) f or t his st u d y. 
6. 2.  S A F E T Y A N A L Y SI S S E T ( S A S) –  ( AL L T R E A T E D P O P U L A TI O N )  
T his a nal ysis set i ncl u des al l p atie nts w h o ha ve recei ve d at l east o ne d ose of s ur ufati ni b. S afet y data will be 
e val uate d base d o n t his a nal ysis set o utc o me. P atie nts i n t he S A S will be a n al yze d b y t heir act ual d ose i nitiall y 
recei ve d. If patie nts ha ve d ose re d ucti on d uri n g t he st u d y, all data will be s u m marize d/ a nal yze d base d o n t he i nitial 
d ose of st u d y me dicati o n recei ve d. 
All safet y a nal yses e xce pt f or D L T s u m maries will be base d o n t he S A S. Efficac y e n d p oi nts P F S a n d O S ( O S 
a p plies t o B T C a n d S T S c o h orts o nl y) will be  a nal yze d base d o n t his a nal ysis set. 
6. 3.  D O SI N G L I MI TI N G T O XI CI T Y ( D L T) E V A L U A B L E S E T  
T he D L T set c o m prises all S A S patie nts w h o are e val ua b le f or D L T assess me nt. D L T e val ua ble patie nts ca n be 
i de ntifie d via a ns wers t o t he q uesti o n “ D L T e val ua ble patie nts” o n C R F “ D L T Assess me nt” pa ge.  
D L T set (a n d s u m maries of D L Ts) o nl y a p plies t o d ose escalati o n p hase patie nts. 
A D L T e val ua ble patie nt has t o meet t he f oll o wi n g cr iteria, w hic h will n ot be c o nfir me d via pr o gra m mi n g: 
 
Has n ot recei ve d a n y pre ve nti ve treat me nt d uri n g t he D L T peri o d; A N D 
 
Has c o m plete d t he first 2 8- da y treat me nt c ycle wit h c o m plete safet y e val uati o ns a n d has r ecei ve d at least 
7 5 % of t he assi g ne d s ur ufati ni b d ose; O R 
 
Has a c o nfir me d D L T d uri n g t he first 2 8- da y treat me nt c ycle. 
6. 4.  E F FI C A C Y A N A L Y SI S S E T ( E A S) 
T his a nal ysis set i ncl u des al l patie nts w h o ha ve recei ve d at l east o ne d ose of s ur ufati ni b a n d ha ve ha d at least o ne 
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p ost- baseli ne t u m or assess me nt. 
All efficac y e n d p oi nts will be a nal yze d base d o n t his a nal ysis set e xce pt f or a nal ysis of P F S a n d O S, w hic h will be 
a nal yze d base d o n t he S A S. T he O S a nal ysis will be perf or me d f or t he B T C a n d S T S c o h orts o nl y.  
6. 5.  P R O T O C O L D E VI A TI O N  
Maj or pr ot oc ol d e viati o ns relate d t o st u d y i ncl usi o n or e x cl usi o n criteria, c o n d uct of t he tri al, patie nt ma na ge me nt, 
or patie nt assess me nt will be liste d f or S A S. 
T he st u d y tea m will disc uss, i de ntif y a n d classif y t he i m p orta nt eli gi bilit y criteria or p ost-e ntr y de viati o ns fr o m 
o perati o nal tea m m o nit or re p orts bef ore fi nal data base l oc k. 
7.  G E N E R A L C O N SI D E R A TI O N S  
7. 1.  R E F E R E N C E S T A R T D A T E ,  R E F E R E N C E E N D D A T E A N D S T U D Y D A Y  
Refere nce start d ate is defi ne d as t he date of t he firs t a d mi nistrati o n of st u d y me dicati o n. St u d y da y will be 
calc ulate d fr o m t he refere nce start d ate a n d will be use d t o s h o w start/st o p da y of t he assess me nts a n d e ve nts relati ve 
t o t he first a d mi nistr ati o n of st u d y me dicati o n.  
Refere nce e n d date will be defi ne d as t he da y of t he la st a d mi nistrati o n of st u d y me dicati o n wit hi n t he patie nt’s    
last treat me nt c ycle. 
St u d y da y ( Da y 1 is t he da y of t he first a d mi nistrati o n of  st u d y me dicati o n) will a p pear i n eac h listi n g w here a n 
assess me nt d ate or e ve nt d ate a p pears.  
If t he date of t he e ve nt is o n or after t he refere nce start date t he n:  
                St u d y da y = ( date of e ve nt –  refere nce start date) + 1. 
If t he date of t he e ve nt is pri or t o t he refere nce start date t he n:  
                St u d y da y = ( date of e ve nt –  refere nce start date). 
I n t he sit uati o n w here t he e ve nt d ate is partial or missi n g, t he date will a p pear pa rtial or missi n g i n t he listi n gs, St u d y 
da y, a n d a n y c orres p o n di n g d urati o ns will be prese nte d bas e d o n t he i m p utati o ns s pecifie d i n Secti o n 8. 2. 
I n a d diti o n t o t he o verall refer e nce start a n d e n d date, t he start a n d e n d of treat me nt wit hi n eac h c ycle will be 
i de ntifie d base d o n t he data c ollecte d o n t he e C R F f or m a n d will be use d w he n assi g ni n g e ve nts or assess me nts t o a 
partic ular treat me nt c ycle. 
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P a g e 2 1 of 7 0 
 
7. 2.  B A S E LI N E  
U nless ot her wise s pecifie d, baseli ne is defi ne d as t he last  n o n- missi n g meas ure me nt ta ke n pri or t o refere nce start 
date (i ncl u di n g u nsc he d ule d assess me nts). I n case w here t he last n o n- missi n g meas ure me nt a n d t he refere nce start 
date c oi nci de, t hat meas ure me nt will be c o nsi dere d as  baseli ne, b ut A Es a n d me dicati o ns c o m me nci n g o n t he 
refere nce start d ate will be c o nsi dere d p ost- baseli ne, t hat is, treat me nt-e mer ge nt or c o nc o mita nt ( “ w orst case” 
a p pr oac h). 
7. 3.  E N D O F T R E A T M E N T  
E n d of treat me nt reas o ns a n d treat me nt disc o nti n uati o n date are ca pt ure d o n C R F pa ge “ E n d of Treat me nt”.  
P atie nts w h o c o m plete or pre mat urel y disc o nti n ue t he st u d y me dicati 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 l ast d ose of s ur ufati ni b. Meas ure me nt s o btai ne d d uri n g t his visit will be c o nsi dere d as 
t he ‘E n d of Treat me nt ’ assess me nt. 
7. 3. 1.  E n d of St u d y 
A patie nt is c o nsi dere d t o ha v e c o m plete d t he st u d y o nce he  or s he has c o m plete d t he last visit, or t he last sc he d ule d 
pr oce d ure as o utli ne d i n t he S c he d ule of E ve nts i n Pr ot oc ol A p pe n di x 1. 
7. 4.  R E T E S T S , U N S C H E D U L E D V I SI T S A N D E A R L Y T E R MI N A TI O N D A T A  
I n ge neral, f or b y- visit s u m maries, data rec or de d at t he n o mi nal visit will be prese nte d. U nsc he d ule d meas ure me nts 
will n ot b e i ncl u de d i n b y- visit s u m maries. U nsc he d ule d  me as ure me nts will c o ntri b ute t o w orst-case s u m maries. 
I n t he case of a retest ( visit-s p ecific u nsc he d ule d visit n u m b er assi g ne d), t he latest n o n- missi n g meas ure me nt a m o n g 
all sc he d ule d a n d u nsc he d ule d meas ure me nts f or t hat visit will be use d f or b y- visit s u m maries.  
Earl y ter mi nati o n data of patie nts pre mat urel y disc o nti n ue d  fr o m st u d y me dicati o n will be prese nte d t o get her wit h 
t he e n d of treat me nt assess me nt f or st u d y me dicati o n c o m pl eters. 
B y- parie nt listi n gs will i ncl u d e sc he d ule d, u nsc h e d ule d, retest, a n d earl y disc o nti n uati o n data. 
7. 5.  V I SI T W
I N D O W S C O N V E N TI O N S  
U nless ot her wise i n dicate d, i n t he treat me nt p eri o d, d uri n g  C ycle 1 a n d C ycle 2, t he visit wi n d o w will be ± 1 da y. 
Fr o m C ycle 3 o n war d, t he visit wi n d o w will be ± 3 da ys.  I n  t he f oll o w- u p visit, t he visit wi n d o w is ± 7 da ys.  All 
data will be or ga nize d a n d a nal yze d acc o r di n g t o t he sc he d ul e d ti mes as o utli ne d i n t he pr ot oc ol a n d b y t he visit 
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St ati sti c al A n al y si s Pl a n  
P a g e 2 2 of 7 0 
 
de n ote d o n t he Case Re p ort F or m ( C R F). 
7. 6.  S T A TI S TI C A L T E S T S  
T here is n o f or mal statistical h y p ot hesis testi n g i n t his st u d y. T he c o nfi de nce i nter vals will be 9 5 %, u nless ot her wise 
s pecifie d i n t he descri pti o n of t he a nal ys es. 
7. 7.  C O M M O N C A L C U L A TI O N S  
F or q ua ntitati ve meas ure me nts, c ha n ge fr o m Baseli ne will b e calc ulate d as:  
 
 
C ha n ge fr o m baseli ne = T est Val ue at Visit X –  Baseli ne V al ue 
 
P erce nta ge c ha n ge fr o m baseli ne = [( T est Val ue at Visit X –  Baseli ne Val ue) / B aseli ne Val ue] * 1 0 0 
T he ti me fr o m Date of E ve nt A t o Date of E ve nt B ( years) is calc ulate d as: 
 
( Date of E ve nt B - Date of E ve nt A + 1)/ 3 6 5. 2 5. 
T he ti me fr o m Date of E ve nt A t o Date of E ve nt B ( m o nt hs) is calc ulate d as: 
 
( Date of E ve nt B - Date of E ve nt A + 1)/ 3 0. 4 3 7 5. 
7. 8.  S O F T W A R E V E R SI O N  
All a nal yses will be c o n d ucte d usi n g S A S ® Versi o n 9. 4 or hi g her.  
8.  S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1.  M
U L TI C E N T E R S T U DI E S  
T his st u d y will be c o n d ucte d b y m ulti ple i n vesti gat ors at a p pr o xi matel y 8- 1 5 sites. N o a dj ust me nt i n as pect of site 
effect will be perf or me d. Data fr o m all ce nters will be p o ole d pri or t o a nal ysis. 
8. 2.  M
I S SI N G D A T A 
Ge nerall y, t he missi n g efficac y a n d safet y data will n ot be i m p ute d e xce pt f or t he critical missi n g a n d i nc o m plete 
dates w hic h will be ha n dle d as descri be d i n t his secti o n. 
 
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 3 of 7 0 
 
F or partiall y missi n g dates, t he A ge ( Yea rs), D urati o n of mali g na nc y ( years) a n d D urati o n of metastasis ( years) will 
be base d o n i m p ute d val ues. F or all calc ulati o n ele me nts, if t he date part is missi n g w hile year a n d m o nt h prese nt, 
1 5 t h of t he m o nt h will be use d f or i m p utati o n. If b ot h date a n d m o nt h part are missi n g w hil e year prese nts, J ul y 1st 
will b e use d f or i m p utati o n. 
W he n n o i ma gi n g/ meas ure me nt was d o ne at all at a partic ul ar ti me p oi nt, t he patie nt is n ot e val ua ble at t hat ti me-
p oi nt. If o nl y a s u bset of lesi o n meas ure me nts were ma de at a n assess me nt, us uall y t he cas e is als o c o nsi dere d n ot 
e val ua ble at t hat ti me p oi nt, u nless a c o n vi nci n g ar g u me nt ca n be ma de t hat t he c o ntri b uti o n of t he i n di vi d ual 
missi n g lesi o n(s) w o ul d n ot c ha n ge t he assi g ne d ti me p oi nt r es p o nse. 
F or O R R a n d D C R calc ulati o n, patie nts wit h missi n g res p o n ses will be c o nsi dere d n o n-res p o n ders, t h us c o ntri b ute 
o nl y t o t he de n o mi nat or. 
 
I nitial Dia g n osis Date 
If year a n d m o nt h are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as 1 5. If o nl y ye ar is k n o w n, m o nt h a n d 
da y will be i m p ute d t o J ul y 1st. If t he dia g n osis date is c o m pletel y missi n g or t he year part is u n k n o w n, t he 
dia g n osis date will n ot b e i m p ute d. T he i m p ute d date will be c o m pare d t o refere nce start d ate. If it is later t ha n t he 
refere nce start d ate, t he i nc o m plete date will be i m p ute d as t he refere nce start date. 
 
A d verse E ve nts Date 
F or a d verse e ve nt, i nc o m plete s tart d ates a n d/ or st o p dates will be i m p ute d. Start date will be i m p ute d first w he n t he 
start d ate a n d st o p date are b ot h i nc o m plete f or a patie nt. If t he fiel d of year is missi n g, t he n n o val ue will be 
i m p ute d. T he f oll o wi n g r ules will b e a p plie d t o i m p ute t he i nc o m plete start date, ass u mi n g year is a vaila ble. 
 
Missi n g or i nc o m plete start d ate 
I n case t he start d ate of a n A E is c o m pletel y missi n g, or year part is u n k n o w n, t he start date of A E will n ot be 
i m p ute d.  
I n case t he start d ate of A E is i n t he sa me year as refere nce st art date ( w he n o nl y year is rec or de d), or t he start d ate 
is i n t he sa me m o nt h a n d year (if o nl y t he da y is missi n g) as t he refere nce start date, t he n t he start date of t he A E 
will b e i m p ute d b y t he mi ni m u m of t he refere nce star t date a n d t he A E res ol uti o n date. I n all ot her cases t he 
a vaila ble year a n d m o nt h are n ot e q ual t o t he c orres p o n di n g  year a n d m o nt h of t he refere nce start date or t he 
a vaila ble year is n ot e q ual t o t he c orres p o n di n g year of t he r efere nce start date, t he missi n g start da y will be i m p ute d 
b y t he 1 st da y of t he m o nt h a n d t he missi n g start m o nt h will be re place d b y J a n uar y.  
I n t he case o nl y t he m o nt h is missi n g w hile year a n d da y are rec or de d, t he n b ot h da y a n d m o nt h will be c o nsi dere d 
as missi n g. If t he year part of start d ate of a n A E occ urs i n t he sa me year as re fere nce start date, t he n t he start d ate of 
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 4 of 7 0 
 
t he A E will be i m p ute d b y t he mi ni m u m of t he refere nce start date a n d t he A E res ol uti o n d ate. If a n A E is o bser ve d 
o n differe nt year of t he refere nce start d ate, J a n uar y 1s t will be use d t o c o m plete t he start date of t he A E..  
 
Missi n g or i nc o m plete e n d dat e 
I nc o m plete e n d dates will b e i m p ute d t o t he last p ossi ble dat e. I n t he case t he year a n d m o nt h are k n o w n, A E e n d 
date will be i m p ute d as t he last d a y of t he m o nt h. I n t he ca se if o nl y t he year is k n o w n, A E e n d date will be i m p ute d 
as t he Dece m ber 3 1 st of t he ye ar. If t he i m p ute d A E e n d date is after t he deat h date, t he n t he date of t he deat h will be 
i m p ute d as t he A E e n d date. If t he e n d date is c o m pletel y missin g or t he year part is u n k n o w n, t he e n d date will n ot 
be i m p ute d. If t he i m p ute d e n d date is bef ore t he start date (i m p ute d or n o n-i m p ute d start date), t he n t he st o p date 
will b e i m p ute d usi n g start d at e.  
F or A E e ve nts c o nti n ui n g at t he c ut- off date,  t he e n d date will n ot be i m p ute d a n d will be re p orte d as “ o n g oi n g”. 
  
Me dicati o ns/ Pr oce d ures Date 
T here will be n o i m p utati o n f or c o m plete missi n g star t date or e n d date of me dicati o ns/ pr oce d ures. 
I m p ute i nc o m plete start d ate as earliest p ossi ble date, i.e. first da y of m o nt h if da y u n k n o w n or 1st J a n uar y if da y a n d 
m o nt h are u n k n o w n.  
I m p ute e n d date as latest p ossible date, i.e. last da y of m o nt h if da y u n k n o w n or 3 1 st Dece m ber if da y a n d m o nt h are 
u n k n o w n, if n ot res ulti n g i n a date later t ha n t he date of patie nt ’s deat h. I n t he latter case t he date of t he deat h will be 
use d t o i m p ute t he i nc o m plete st o p date. 
 
A b o ve r ules will b e a p plie d f or pri or/ c o nc o mita nt me dicati o ns/ pr oce d ures a n d pri or o nc ol o g y t hera pies. 
 
D urati o n will n ot b e calc ulate d i n case  eit her t he start date or e n d date is c o m pletel y missi n g, b ut it will be 
calc ulate d base d o n t he i m p ut e d start/ e n d date if eit her t he start date or e n d date is i nc o m plete. 
Last T u m or Assess me nt Date 
If year a n d m o nt h are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as t he first da y of t he m o nt h. If o nl y year 
is k n o w n or a date is c o m plete missi n g, t he date will n ot be i m p ute d. If t he date of deat h is c o m plete, t he i m p ute d 
date will be c o m pare d wit h t he deat h date, t he earlier date will be use d f o r t he date of last t u m or assess me nt. 
S u bse q ue nt A nti-t u m or T hera p y Date 
W he n a n i nc o m plete s u bse q ue nt a nti-t u m or  t hera p y start date is re p orte d, e ver y eff ort will be ma de t o i de ntif y t he 
prece d e nce relati o ns hi p of starti n g date of s u bse q ue nt a nti -t u m or t hera p y relati ve t o t he refere nce e n d date a n d t he 
date of disease pr o gressi o n (if ha p pe ne d ). Ge nerall y, rec or ds of s u bse q ue nt t hera p y s h o ul d all start after E O T/ P D. 
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 5 of 7 0 
 
 
C o n diti o n 
Refere nce e n d date 
( D 1) 
Date of earliest disease 
pr o gressi o n ( D 2)  
I m p ute d start date f or a nti-
t u m or t hera p y 
K n o w n part 
or cli nical 
e vi de nce t o 
s h o w 
prece d e nce 
relati o ns hi p  
1 
Bef ore 
Bef ore 
Mi ni m u m ( D 1, D 2) - 1 
2 
After 
After  
Ma xi m u m ( D 1, D 2) + 1 
3 
Bef ore 
After 
D 2 + 1 
4 
After 
Bef ore 
D 2- 1 
5 
N o or n ot a p plica ble 
Bef ore 
D 2- 1 
6 
N o or n ot a p plica ble 
After or ot hers 
D 2 + 1 
7 
Bef ore 
N o or n ot a p plica ble 
D 1- 1 
8 
After or ot hers 
N o or n ot a p plica ble 
D 1 + 1 
 
F or e xa m ple, c o n diti o n 3, if t he k n o w n part of t he a nti-t u m or t hera p y i n dicati o n t hat t he a nti-t u m or t hera p y starts 
bef ore refere nce e n d date b ut after date of disease pr o gressi o n, t he n i nc o m ple te start date of a nti-t u m or t hera p y will 
be i m p ute d as o ne da y p osteri or t o  date of disease pr o gressi o n. 
If t he i m p ute d start d ate is later t ha n date of deat h, t he n t he i m p ute d start date will be f urt her i m p ute d t o date of 
deat h. 
Deat h Date 
If year a n d m o nt h of deat h dat e are k n o w n b ut t he da y is u n k n o w n, da y will be i m p ute d as 1 5. If o nl y year is k n o w n, 
m o nt h a n d da y will be i m p ute d t o J ul y 1st. T here are t w o e xce pti o ns of t h e bel o w t w o sce nari os: 
- If t he i m p ute d deat h date is pri or t o t he last k n o w n ali ve date, t he n t he deat h date will be i m p ute d t o t he ne xt d a y of 
last k n o w n ali ve date. 
- If t he i m p ute d deat h date is after e n d of st u d y date wit h t he year a n d m o nt h are t he sa me as e n d of st u d y date, t he n 
t he deat h date will be i m p ute d t o t he date of e n d of st u d y. 
9.  O U T P U T P R E S E N T A TI O N S  
A p pe n di x 1 details t he c o n ve nti o ns f o r prese ntati o n of data i n o ut p uts.  
T he te m plates pr o vi de d wit h t his S A P descri be t he prese ntat i o ns f or t his st u d y a n d t heref ore t he f or mat a n d c o nte nt 
of t he s u m mar y ta bles, fi g ures a n d listi n g s t o be pr o vi de d b y I Q VI A Bi ostatistics. 
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, i.e., n u m ber of patie nts( n), mea n, me dia n, 
sta n dar d de viati o n ( S D), a n d r a n ges ( mi ni m u m, ma xi m u m).  
Q ualitati ve varia bles will be s u m marize d b y c o u nt(s) a n d perce nta ges ( %). U nless ot her wise state d, t he calc ulati o n 
of perce nta ges will be base d o n t he t otal n u m ber of i ncl u de d i n t he rele va nt a nal ysis set. 
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 6 of 7 0 
 
1 0.  D I S P O SI TI O N A N D W
I T H D R A W A L S 
All patie nts w h o si g ne d I C F will be i n v ol ve d i n t he a nal ys is of dis p ositi o n a n d wit h dra wals bei n g descri be d i n t his 
secti o n f or t his st u d y.   
T he n u m ber of patie nts w h o si g ne d I C F f or t he st u d y, scree n faile d patie nts al o n g wit h t he reas o n f or scree n fail ure, 
patie nts w h o passe d scree ni n g b ut wit h dra w bef ore t he fi rst d ose of st u d y treat me nt will als o be s u m marize d.  
T he n u m ber of patie nts i ncl u de d/e xcl u de d fr o m eac h a nal ysis  set as well as t he reas o n(s) f or e xcl usi o n (as descri be d 
i n Secti o n 6) will als o be s u m marize d b y d ose le vel i n escal ati o n p hase a n d b y disease c o h ort i n d ose e x pa nsi o n 
p hase. A c orres p o n di n g b y- patie nt listi n g will als o be pr o vi de d. 
T he n u m ber a n d perce nta ge of patie nts  w h o c o m plete d, disc o nti n ue d fr o m st u d y me dicati o n a n d reas o ns f or st u d y 
me dicati o n disc o nti n uati o n will be prese nte d f or eac h d os e le vel, b y disease c o h ort, a n d o verall f or t he S A S. 
Reas o ns f or disc o nti n uati o n of st u d y me dicati o n will be prese nte d as rec or de d o n t he C R F pa ge “E n d of Treat me nt ”. 
T he n u m ber a n d perce nta ge of p atie nts w h o c o m plete d, disc o nti n ue d fr o m st u d y a n d reas o ns f or st u d y 
disc o nti n uati o n will be prese nte d f or eac h d ose le vel, di seas e c o h ort, a n d o verall f or t he S A S. Reas o ns f or st u d y 
disc o nti n uati o n will be prese nte d as rec or de d o n t he C R F pa ge “ E n d o f St u d y”. 
A patie nt listi n g will b e ge ner ate d t o i ncl u de site, p atie nt n u m ber, i nf or me d c o nse nt i nf or mati o n ( date), scree ni n g 
date, first a n d last st u d y me dicati o n d os i n g date, d urati o n of st u d y me dicati o n, st u d y me dicati o n disc o nti n uati o n 
i nf or mati o n ( date a n d reas o n), a n d e n d of st u d y i nf or mati o n ( date, stat us, a n d reas o n f or disc o nti n uati o n if 
a p plica ble) will be pr o vi de d. B esi des, t he vi olati o n of i ncl usi o n/e xcl usi o n criteria will als o be liste d f or E N R 
a nal ysis set.  
Maj or pr ot oc ol d e viati o ns relate d t o st u d y i ncl usi o n or e x cl usi o n criteria, c o n d uct of t he tri al, patie nt ma na ge me nt, 
or patie nt assess me nt will be liste d.. 
1 1.  D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic data a n d ot her baseli ne c h aracteristics will be s u m marize d b y d ose c o h ort i n d ose escalati o n p hase a n d 
b y disease c o h ort i n d ose e x pa nsi o n p hase f or t he S A S. Data listi n g will als o be pr o vi de d. 
T he f oll o wi n g de m o gra p hic a n d ot her baseli ne c haracteris ti cs will be re p orte d a n d liste d f or t his st u d y: 
 
A ge ( years) - Calc ulate d relati ve t o date of I C F 
 
A ge gr o u p  
o  
< 6 5 years 
o  
≥6 5 years 
 
Ge n der 
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P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 7 of 7 0 
 
o  
Male 
o  
Fe male 
 
Wit h C hil d B eari n g P ote ntial  
 
Wit h o ut C hil d B eari n g P ote nti al 
 
U n differe ntiate d 
o  
U n k n o w n 
 
Race 
o  
A merica n I n dia n or Alas ka Nati ve 
o  
Asia n 
o  
Blac k or Africa n A merica n 
o  
Nati ve Ha waiia n or Ot her P acific Isla n ders 
o  
W hite 
o  
Ot her 
 
Et h nicit y 
o  
His pa nic or Lati n o 
o  
N ot His pa nic or Lati n o 
o  
N ot Re p orte d 
o  
U n k n o w n 
 
B aseli ne W ei g ht ( k g) 
 
B aseli ne Hei g ht ( m) 
 
B aseli ne B MI ( k g/ m 2) 
 
B aseli ne E C O G perf or ma nce s tat us (refer Secti o n 1 7. 6. 1) 
o  
0 
o  
1 
o  
> 1 
 
B aseli ne S u m of Dia meters of T ar get Lesi o ns ( m m)  
Ot her baseli ne c haracteristics relate d t o t he o nc o l o g y hist or y will be descri be d i n Secti o n 1 2. 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 8 of 7 0 
 
1 1. 1.  D E RI V A TI O N S  
 
B MI ( k g/ m 2) = wei g ht ( k g)/ hei g ht ( m)2 
 
A ge ( Years) = ( Date of I nf or me d C o nse nt Si g ne d –  Date of Birt h + 1)/ 3 6 5. 2 5 
1 2.  M E DI C A L H I S T O R Y A N D O N C O L O G Y H I S T O R Y 
Pre- e xisti n g me dical c o n diti o ns are rec or de d  o n t he “ Me dical Hist or y” C R F pa ge. 
Me dical hist or y (e xcl u di n g o nc ol o g y hist or y) will be s u m marize d b y s yste m or ga n class ( S O C) a n d preferre d ter m 
( P T) f or t he S A S set. Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) ce ntral c o di n g dicti o nar y, Versi o n 
2 3. 0 ( Me d D R A 2 3. 0) or hi g her will be use d f or c o di n g. N u m ber a n d perce nta ge will be prese nte d i n fre q ue nc y 
ta bles b y d ose c o h ort i n d ose escalati o n p hase a n d disease c o h ort i n d ose e x pa nsi o n p hase, a n d or dere d b y pri mar y 
S O C a n d P T i n desce n di n g or der of t he fre q ue nc y i n t otal wit hi n eac h cate g or y. F or S O Cs or P Ts wit h t he sa me 
fre q ue nc y i n t otal, cate g ories will b e s orte d al p ha beticall y. 
O nc ol o g y hist or y i nf or mati o n will b e ca pt ure d o n C R F pa ge “ O nc ol o g y Hist or y” a n d t he f oll o wi n g o nc ol o g y hist or y 
i nf or mati o n will be s u m mariz e d:  
 
T y pe of mali g na nc y 
 
D urati o n of mali g na nc y ( years) –  Calc ulate d relati ve t o date of I C F 
 
Ti me si nce t he i nitial dia g n osis t o first a d mi nistrati o n of st u d y me dicati o n ( years) –  Calc ulate d relati ve t o 
date of first a d mi nistrati o n of st u d y me dicati o n 
 
Sta ge of t he disease at t he ti me of i nitial dia g n osis 
o  
Sta ge I 
o  
Sta ge II 
o  
Sta ge III 
o  
Sta ge I V 
 
Metastasis Stat us ( Yes, N o)  
 
D urati o n of Metastasis ( Years) –  Calc ulate d relati ve t o date of I C F 
 
Pri or o nc ol o g y treat me nts 
o  
O nc ol o g y C he m ot hera p y a n d Me dicati o n 
o  
O nc ol o g y Ra diati o n T hera p y 
o  
O nc ol o g y S ur ger y a n d Pr oce d ures 
Me dical hist or y a n d o nc ol o g y hist or y will be liste d f or t he S A S.  
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 9 of 7 0 
 
1 2. 1.  D E RI V A TI O N S  
 
D urati o n of mali g na nc y ( years) = ( Date of I nf or me d C o nse nt Si g ne d –  Date of first c o nfir me d mali g na nc y 
+ 1)/ 3 6 5. 2 5. 
 
Ti me si nce t he i nitial dia g n osis t o first a d mi nistrati o n of st u d y me dicati o n ( years) = ( Date of first 
a d mi nistrati o n of st u d y me dic ati o n –  I nitial pri mar y dia g n osis date f or s oli d t u m or + 1)/ 3 6 5. 2 5. 
 
D urati o n of metastasis ( years) = ( Date of I nf or me d C o nse nt Si g ne d –  Date of metastasis o bser ve d + 
1)/ 3 6 5. 2 5. 
1 3.  M E DI C A TI O N S A N D P R O C E D U R E S  
Pri or me dicati o ns are me dicati o ns w hic h e n de d pri or t o t h e first d osi n g date of st u d y me dic ati o n. C o nc o mita nt 
me dicati o ns/ pr oce d ures are me dicati o ns/ pr oce d ures w hic h star te d n o later t ha n 3 0 + 7 da ys f oll o wi n g t he last d ose 
a d mi nistrati o n, a n d e n de d o n or after t he date of first d ose  of me dicati o n or were o n g oi n g at t he e n d of t he st u d y. 
Rele va nt i nf or mati o n is c ollecte d o n C R F pa ge “ Pri or a n d C o nc o mita nt Me dicati o ns”, “ C o nc o mita nt Pr oce d ures” . 
Pri or a n d c o nc o mita nt me dicati o ns will b e c o de d usi n g W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y E n ha nce d 
( W H O- D D E), versi o n Mar 2 0 2 0 or latest versi o n. A nat omic al T hera pe utic C he mical ( A T C ) le vel 2 classificati o n a n d 
Preferre d ter m ( P T) will b e us e d f or c o di n g. 
C o nc o mita nt me dicati o ns will be s u m mari ze d b y A T C le vel 2 a n d P T f or eac h d ose c o h ort i n d ose escalati o n p hase 
a n d eac h disease c o h ort i n d ose e x pa nsi o n p hase f or t he S A S. P T will be s orte d i n desce n di n g fre q ue nc y of t he t otal 
n u m ber of patie nts wit h at least o ne me dicati o n i n t he c orres p o n di n g cate g or y, P Ts will be prese nte d al p ha beticall y 
f or P Ts of t he sa me t otal fre q ue nc y.  
C o nc o mita nt pr oce d ures will be c o de d b y Me d D R A 2 3. 0 or hi g her a n d will be prese nte d b y P T b y d ose c o h ort i n 
d ose escalati o n p hase a n d b y disease c o h ort i n d ose e x pa nsi o n p hase. P T will be s orte d i n desce n di n g fre q ue nc y of 
t he t otal n u m ber of patie nts wit h at least o ne pr oce d ure i n t he c orres p o n di n g cate g or y, P Ts will be prese nte d 
al p ha b eticall y f or P Ts of t he s a me t otal fre q ue nc y. 
Pri or a n d c o nc o mita nt me dicati o ns will b e prese nte d i n lis ti n gs wit h fla g t o differe ntiate w het her t he me dicati o n was 
pri or me dicati o n or c o nc o mita nt me dicati o n.  Si milar f or pri or a n d c o nc o mita nt pr oce d ures i nf or mati o n.   
1 4.  O N C O L O G Y T H E R A PI E S  
Pri or o nc ol o g y t hera pies i ncl u de o nc ol o g y c he m ot hera p y  a n d me dicati o n, o nc ol o g y ra di ot hera p y, a n d o nc ol o g y 
s ur ger y a n d pr oce d ures. O nc ol o g y c he m o t hera p y a n d me dicati o n will be ca pt ure d o n “ O n c ol o g y C he m ot hera p y a n d 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 0 of 7 0 
 
O nc ol o g y Me dicati o n” C R F p a ge, o nc ol o g y ra di ot hera p y will be ca pt ure d o n “ O nc ol o g y Ra di ot hera p y ” C R F pa ge, 
a n d o nc ol o g y s ur ger y a n d pr oce d ures will be ca pt ure d o n “ O nc ol o g y S ur ger y a n d Pr oce d ure” C R F pa ge.  
Pri or o nc ol o g y c he m ot hera pies a n d me dicati o ns will be c o de d usi n g W H O- D D E, versi o n Mar 2 0 2 0 or latest versi o n, 
a n d will be prese nte d b y A T C le vel 2 classsificati o n a n d P Ts f or eac h d ose c o h ort i n d ose escalati o n p hase a n d eac h 
disease c o h ort i n d ose e x pa nsi o n p hase f or t he S A S.  P T will be s orte d i n desce n di n g fre q ue nc y of t he t otal n u m ber 
of patie nts wit h at least o ne c o n diti o n i n t he c orres p o n di n g  c ate g or y, P Ts will be prese nte d al p ha beticall y f or P Ts of 
t he sa me t otal fre q ue nc y. I n a d diti o n, n u m ber a n d perce nt a ge of patie nts w h o recei ve d pri or o nc ol o g y 
c he m ot hera pies a n d me dicati o ns, n u m ber of  re gi me ns, best res p o nse, treat me nt fail ure i nf or mati o n a n d a p peara nce 
of a d verse reacti o n wit h se verit y a b o ve gra d e 3 will be s u m marize d f or pri or o nc ol o g y c he m ot hera pies a n d 
me dicati o ns. 
T he n u m ber a n d perce nt a ge of patie nts  w h o recei ve d pri or o nc ol o g y ra di ot hera p y, p ur p ose, best res p o nse, a n d 
a p peara nce of a d verse reacti o n wit h se verit y a b o ve gra d e 3 will be s u m marize d f or pri or o nc ol o g y ra di ot hera p y. 
Pri or o nc ol o g y s ur ger y a n d pr oce d ure will be c o de d usi n g Me d D R A 2 3. 0 or hi g her, a n d will be s u m marize d b y 
S O C a n d P T f or eac h disease c o h ort i n d ose e x pa nsi o n p has e a n d d ose escalati o n p hase f or t he S A S.  S O C a n d P T 
will b e s orte d i n desce n di n g fre q ue nc y of t he t o tal n u m ber of patie nts wit h at least o ne c o n diti o n i n t he 
c orres p o n di n g cate g or y, S O Cs/ P Ts will be prese nte d al p ha beticall y f or S O Cs/ P Ts of t he sa me t otal fre q ue nc y. 
Si nce o n-st u d y o nc ol o g y t hera pies are n ot all o we d, o nc ol o g y t hera pies will be classifie d a n d re p orte d as pri or.  A n y 
c o nc urre nt o nc ol o g y t hera p y will b e c o nsi d ere d a n d re p orte d as pr ot oc ol de viati o n. 
. All t he o nc ol o g y t hera pies as well as ge neral t hera pies will be liste d b y disease c o h ort i n d ose e x pa nsi o n p hase a n d 
d ose escalati o n p hase. 
O nc ol o g y c he m ot hera p y a n d o nc ol o g y me dicati o n, o nc ol o g y ra di ot hera p y, a n d o nc ol o g y s ur ger y a n d pr oce d ure will 
be liste d f or S A S. O nc ol o g y s ur ger y a n d pr oce d ure will be  liste d f or S A S a n d will be prese nte d se paratel y fr o m 
c o nc o mita nt pr oce d ures.     
Ne w a nti-t u m or t hera p y is defi ne d as a n y a nti-t u m or t hera p y starte d after first d ose of st u d y me dicati o n. Ne w a nti-
t u m or t hera p y will be fla g ge d i n t he listi n g of o nc ol o g y me dicati o n/ra di ot hera p y/s ur ger y. 
1 5.  S T U D Y M E DI C A TI O N E X P O S U R E  
T he e xte nt of e x p os ure t o st u d y me dicati o n will be prese nte d  b y d ose c o h ort a n d disease c o h ort f or c ycle 1 ( D L T 
wi n d o w) a n d o verall res pecti vel y f or t he S A S.  
St u d y me dicati o n e x p os ure calc ulati o n will be base d o n st u d y me dicati o n a d mi nistrati o n i nf or mati o n, w hic h is 
c ollecte d o n t he C R F pa ges “ St u d y Dr u g A d mi nistrati o n ”.  I n t he case of missi n g data o n t he e C R F or if deri vati o ns 
are re q uire d, t he “ St u d y Dr u g A d mi nistrati o n” or “ St u d y Dr u g Dis pe nsati o n a n d Ret ur n” f or m will be use d i n or der 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 1 of 7 0 
 
t o deter mi ne t he first a n d t he l ast date of st u d y me dicati o n. 
Descri pti ve i nf or mati o n will be pr o vi de d re gar di n g n u m ber of c ycles e x p os ure t o st u d y dr u g, t otal d urati o n of st u d y 
me dicati o n e x p os ure, act ual d urati o n of st u d y me dicati o n ta ke n, c u m ulati ve d ose of st u d y me dicati o n, d ose i nte nsit y 
a n d relati ve d ose i nte nsit y as b ot h c o nti n u o us varia b le a n d c ate g orical varia ble ( < 8 0 %, > = 8 0 % a n d < = 1 2 0 %, 
> 1 2 0 %). T he n u m ber a n d perce nta ge of patie nts wit h a n y pr escri be d ose i ncrease d, re d u cti o ns a n d i nterr u pti o ns will 
be prese nte d, t he ti mi n g of prescri be d ose i ncrease d, re d ucti o ns a n d i nterr u pti o ns a n d reas o ns f or d ose i ncrease d, 
re d ucti o ns a n d i nterr u pti o ns will b e s u m marize d as well. 
A d diti o nall y, t he relati ve d ose i nte nsit y calc ulate d f or D L T o bser vati o n wi n d o w ( 2 8 da ys si nce first d ose re gar dless 
of t he act ual date of C 2 D 1 visit) will facilitate t he deter mi nati o n of D L T set a n d will be prese nte d t o get her i n a 
listi n g wit h o verall st u d y me di cati o n e x p os ure. 
St u d y me dicati o n a d mi nistrati o n i n eac h c ycle will be ta ke n  fr o m C R F pa ge “ St u d y Dr u g A d mi nistrati o n” at eac h 
visit. 
St u d y dr u g a d mi nistrati o n dat a will be liste d b y d ose c o h ort i n d ose escalati o n p hase a n d b y disease c o h ort i n d ose 
e x pa nsi o n p hase. A n d a n y d ose m o dificati o ns will be fla g ge d.  
A n ot her listi n g of st u d y me dicati o n acc o u nta bilit y wit h rele v a nt i nf or mati o n will be pr o vi de d. 
1 5. 1  D E RI V A TI O N S  
 
T otal d urati o n of st u d y me dic ati o n ( Da ys) i n c y cle 1 = St o p date of a d mi nistrati o n i n c ycle 1 –  Start d ate of 
a d mi nistrati o n + 1 
 
T otal d urati o n of st u d y me dic ati o n ( Da ys) f or o ver all = St o p date of a d mi nistrati o n i n last c ycle –  Start d ate 
of a d mi nistrati o n + 1 
 
Act ual d urati o n of st u d y me di cati o n ( Da ys) i n c ycle 1 = s u m of da ys wit h t he a d mi nistrati o n of st u d y 
me dicati o n d uri n g c ycle 1, D ose i nterr u pti o n will be e xcl u de d fr o m act ual d urati o n of e x p os ure 
 
Act ual d urati o n of st u d y me di cati o n ( Da ys) f or o verall = s u m of da ys wit h t he a d mi nistrati o n of st u d y 
me dicati o n, D ose i nterr u pti o n will b e e xcl u de d fr o m act ual d urati o n of e x p os ure 
 
 
 C u m ulati ve d ose of st u d y me dicati o n ( m g) i n c ycle 1 = S u m [ Act ual Dail y D ose ( m g/ da y) * ( Start Date of 
A d mi nistrati o n –  St o p Date of A d mi nistrati o n + 1) of ea c h r ec or d i n c ycle 1 i n “ St u d y Dr u g 
A d mi nistrati o n” f or m . F or patie nts w h o di d n ot recei ve a n y d ose of st u d y me dicati o n, t he c u m ulati ve d ose 
will b e set t o zer o 
 
C u m ulati ve d ose of st u d y me dicati o n ( m g) f or o verall =  S u m [ Act ual Dail y D ose ( m g/ da y) * ( Start Date of 
A d mi nistrati o n –  St o p Date of A d mi nistrati o n + 1) of eac h r ec or d i n “ St u d y Dr u g A d mi nistrati o n” f or m. 
F or patie nts w h o di d n ot recei ve a n y d ose of st u d y me dicati o n, t he c u m ulati ve d ose will b e set t o zer o 
 
 
 D ose i nte nsit y ( %) = C u m ulati ve d ose of st u d y me dicati o n/ T otal d urati o n of st u d y me dic ati o n f or eac h 
peri o d (c ycle 1 or o verall) 
 
 
 Relati ve d ose i nte nsit y ( %) = 1 0 0 % * D ose i nte nsit y/ pla n ne d d ose i nte nsit y, i n t his st u d y, pla n ne d d ose 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 2 of 7 0 
 
i nte nsit y i n eac h d ose le vel is j ust t he pla n ne d d ose wit h u nit of m g/ da y. 
1 6.  E F FI C A C Y O U T C O M E S  
Efficac y data will be s u m mari ze d b y d ose c o h ort i n d ose esc alati o n p hase a n d b y  disease c o h ort i n d ose e x pa nsi o n 
p hase. P F S a n d O S will be a n al yze d f or t he S A S. T he ot her efficac y varia bles ( B O R, O R R, D C R, T T R, a n d D O R) 
will b e a nal yze d f or E A S. 
Treat me nt efficac y will be e val uate d b y  usi n g t u m or res p o ns es w hic h will be assesse d a n d d oc u me nte d at Scree ni n g, 
Da y 1 of C ycle 2 a n d e ver y 8 ( +/- 1 wee k) wee ks o n Da y 1 of e ver y ot her c ycles after war ds (i.e. C ycle 4, 6 … etc), 
u ntil t he occ urre nce of pr o gressi ve disease ( P D) acc or di n g t o t he sta n dar d of Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T) Versi o n 1. 1. C o nfir mati o n of C R a n d P R is re q uire d at n o less t ha n 4- wee k i nter vals bet wee n t he 
date of i nitial res p o nse/ pr o gressi o n a n d t he c o nfir mati o n ass ess me nt date. W he n t he patie nt i nterr u pts st u d y 
me dicati o n d ue t o A Es or ot her reas o ns, t he e val uati o n s h o ul d  be c o n d ucte d as sc he d ule d. F or s us pecte d cases of P D 
bef ore t he start of t he ne xt sc he d ule d assess me nt, a d diti o nal t u m or assess me nts will be d o ne.  
T u m or res p o nses data are ca pt ure d o n C R F pa ge “ T u m or Meas ure me nt - T ar get Lesi o ns”, “ T u m or Assess me nt - 
N o n- T ar get lesi o ns”, “ T u m or Assess me nt - Ne w Lesi o ns” a n d “ Assess me nt of Disease”. T he c o nfir me d best o verall 
res p o nse ( B O R, refer Secti o n 1 6. 1. 2) will be s u m marize d f or E A S a n d will be prese nte d t o get her wit h s u m maries 
f or o bjecti ve res p o nse rate ( O R R) a nd disease c o ntr ol rate ( D C R). 
T he baseli ne s u m of dia meters will be prese n te d  wit h ot her baseli ne c haracteristics. 
T u m or assess me nts f or tar get l esi o n, n o n-tar get lesi o n, a n d ne w lesi o n will be prese nte d i n a listi n g. I n a d diti o n, a 
listi n g of o verall res p o nse i ncl u di n g lesi o n res p o nses, s u m of dia meters, a n d t he c orres p o n di n g c ha n ge fr o m baseli ne 
i n t u m or dia meter will b e pr o vi de d. 
T u m or assess me nt p erf or me d at t he treat me nt c o m pleti o n visit ( details ca n be f o u n d i n  S A P Secti o n 7. 3) is a n 
eli gi ble data p oi nt f or t he deri vati o n of all efficac y e n d p oi nt s, f oll o wi n g t he deri vati o n r ul es descri be d i n Secti o n 
1 6. 1. 
1 6. 1.  E F FI C A C Y V A RI A B L E (S ) &  D E RI V A TI O N (S ) 
1 6. 1. 1.  P r o gressi o n- F ree S ur vi v al 
Pr o gressi o n-free s ur vi val ( P F S) is defi ne d as t he ti me (i n m o nt hs) fr o m t he start date of st u d y me dicati o n ( Da y 1) 
u ntil t he date of o bj ecti ve dise ase pr o gressi o n as defi ne d b y R E CI S T Versi o n 1. 1 or deat h ( b y a n y ca use i n t he 
a bse nce of pr o gressi o n), w hic he ver occ urre d earlier.  
T he P F S ti me will al wa ys be deri ve d base d o n sca n/asse ss me nt dates a n d n ot base d o n visit dates. R E CI S T 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 3 of 7 0 
 
assess me nts/sca ns c o ntri b uti n g t o war ds a partic ular visit, w hic h c o nsists of assess me nt f or “N o n- T ar get lesi o ns”, 
“ T ar get lesi o ns”, a n d “ Ne w lesi o ns ” , ma y be perf or me d o n differe nt dates. T he f oll o wi n g r ules will be a p plie d: 
 
Date of pr o gressi o n will be deter mi ne d base d o n t he ea rliest of t he dates of t he ra di ol o gical c o m p o ne nt t hat 
tri g gere d t he pr o gressi o n. 
 
W he n ce ns ori n g a patie nt f or P F S t he patie nt will be ce ns or e d at t he latest of t he dates c o ntri b uti n g t o a 
partic ular o verall visit assess me nt. 
If a patie nt has n ot e x perie nce d pr o gressi ve disease ( P D) or die d bef ore t he e n d of st u d y f or a n y reas o n, pr o gressi o n-
free s ur vi val will be ce ns ore d at t he date of t he last e val uabl e t u m or assess me nt o n or pri or t o t he P D, w hic h is n ot 
necessaril y c o nfir me d.  
T hree a d diti o nal r ules a p pl y t o P F S o nl y:  
 
If a patie nt misses t w o or m ore c o ns ec uti ve t u m or assess me nt visits, a n d s h o we d P D or deat h after war ds, 
P F S will b e ce ns ore d at t he date of last t u m or assess me nt pri or t o t he c o nsec uti ve misse d visits. T w o 
c o nsec uti ve misse d/ n o n-e val ua ble t u m or assess me nt visit wi n d o w is calc ulate d as 2 *( 8 we e ks + 1 wee k 
wi n d o w ti me), w hic h is 1 2 6 da ys. 
 
If a patie nt re p orts n o baseli ne t u m or assess me nts or has n o e val ua ble t u m or assess me nt visits after t he first 
d ose of st u d y me dicati o n, P F S will be ce ns ore d at t he s tart date of st u d y me dicati o n u nless t he y die wit hi n 
t w o c o nsec uti ve t u m or assess me nts si nce t he first d ose of st u d y me dicati o n, i.e., P F S = 1 da y. 
 
Of n ote t hat t u m or assess me nts after t he first ne w a nti-ca ncer treat me nt (sa me da y i ncl usi ve) will be 
c o nsi dere d i na d e q uate. If a patie nt starts ne w a nti -t u m or t hera p y i nitiate d pri or t o d oc u me nte d disease 
pr o gressi o n or deat h o n st u d y, P F S will be ce ns ore d at t he date of t he last t u m or assess me nt pri or t o or o n 
t he date of ne w a nti-t u m or t hera p y. 
See T a ble 1 f or t he detaile d i nf or mati o n of e ve nt/ce ns ori n g r ules f or P F S: 
T a ble 1: P F S E ve nts/ce ns ori n g r ules  
 
Descri pti o n  
E ve nt/ Ce ns or 
Date of E ve nt/ Ce ns or  
D oc u me nte d pr o gressi o n bef ore start use of 
ne w a nti -t u m or t hera p y a n d n o t w o c o nsec uti ve 
misse d t u m or assess me nt visits 
E ve nt  
Date of d oc u me nte d disease pr o gressi o n 
Deat h wit h o ut pr o gressi o n a n d wit h o ut use of 
ne w a nti -t u m or t hera p y a n d wit h o ut missi n g 
t w o c o nsec uti ve t u m or assess me nt visits 
E ve nt  
Date of deat h  
Deat h or pr o gressi o n after t w o or m ore 
c o nsec uti ve misse d t u m or assess me nts 
Ce ns or  
Date of last e val ua ble t u m or assess me nt 
pri or t o t he c o nsec uti ve misse d t u m or 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 4 of 7 0 
 
assess me nt visits  
N o e val ua ble baseli ne or p ost- baseli ne t u m or 
assess me nt a n d n o ne w lesi o n f o u n d a n d n o  
deat h wit hi n t w o sc he d ule d t u m or assess me nt 
visits p ost- baseli ne  
Ce ns or  
Date of first d osi n g of st u d y me dicati o n  
N e w a nti-t u m or t hera p y starte d pri or t o 
d oc u me nte d disease pr o gressi o n or deat h o n 
st u d y 
Ce ns or  
Date of last e val ua ble t u m or assess me nt 
bef ore start use of ne w a nti -t u m or thera p y 
N o pr o gressi o n a n d n o deat h b ef ore  e n d of 
st u d y or data c ut- off 
Ce ns or  
Date of last e val ua ble t u m or assess me nt 
N ote: S y m pt o matic deteri orati o n will n ot b e re gar de d as a pr o gressi o n e ve nt.  
T he P F S will be pr o gra m mati call y deri ve d as f oll o ws: 
1. If a patie nt ha d disease pr o gressi o n or deat h, t he n 
P F S ( m o nt h) = ([ date of earliest e vi de nce of disease pr o gressi o n or deat h (i ncl u di n g deat h fr o m a n y ca use) –  start 
date of st u d y me dicati o n] + 1)/ 3 0. 4 3 7 5; Ot her wise, 
2. If t he patie nt was k n o w n t o ha ve de vel o pe d o ne of a b o ve ce ns ori n g criteria, t h e n t he P F S is ce ns ore d a n d  
P F S ( m o nt h) = ([ date of ce ns ori n g –  start date of st u d y me di cati o n] + 1)/ 3 0. 4 3 7 5. 
3. S pecial sce nari o s uc h as t w o or m ore c o nsec uti ve miss i n g t u m or assess me nt visits or ne w a nti-ca ncer treat me nt 
will b e ha n dle d acc or di n g t o t he r ules pr o vi de d i n T a ble 1. 
1 6. 1. 2.  Best O ver all Res p o nse 
B est o verall res p o nse ( B O R) will b e calc ulate d base d o n  t he o verall visit res p o nses o btai ne d u p u ntil R E CI S T 
pr o gressi o n is d oc u me nte d, irres pecti ve of w het her patie nts disc o nti n ue d st u d y me dicati o n. I n t he a bse nce of 
R E CI S T pr o gressi o n, B O R is deter mi ne d b y usi n g visit re s p o nses u p u ntil t he last e val ua ble o verall visit res p o nse. 
N ote, C R or P R res p o nse(s) after recei vi n g s u bse q ue nt a nti-c a ncer t hera p y will n ot be i ncl u de d. 
A patie nt ’s o verall best o bj ecti ve res p o nse will be deter mi ne d: 
 
C R: At least o ne visit res p o ns e of C R c o nfir me d b y  s u bse q ue nt i ma gi n g at least 2 5 da ys ( 4 wee ks –  3 da ys 
wi n d o w) later wit h n o e vi de nc e of pr o gressi o n bet wee n c o nfir mati o n visits. It is re q uire d t hat t here is n o 
ot her o verall res p o nse, e xce pt C R a n d N E, bet wee n t he first C R a n d t he s u bse q ue nt c o nfir mi n g C R w hic h 
meet t he c o nfir me d C R criteri a, i.e. C R- N E- C R is t he c o nfir me d C R. 
 
P R: At least o ne visit res p o nse of P R c o nfir me d b y  s u bse q ue nt i ma gi n g at least 2 5 da ys ( 4 wee ks –  3 da ys 
wi n d o w) later wit h n o e vi de nc e of pr o gressi o n bet wee n c o nfir mati o n visits. It is re q uire d t hat t here is n o 
ot her o verall res p o nse, e xce pt C R or P R or N E, bet wee n t he first P R a n d t he s u bse q ue nt c o nfir mi n g C R or 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 5 of 7 0 
 
P R w hic h meet t he c o nfir me d C R or P R criteria, i.e P R- N E- P R is t he c o nfir me d P R. If t he first P R 
f oll o we d b y S D a n d n o matter t he re q uire me nt of S D is satisfie d or n ot, i.e. P R- S D- P R, t he s u bse q ue nt P R 
will n ot b e q ualifie d as c o nfir me d P R. 
 
S D nee ds t o s ustai n f or at least 8 wee ks: Sta ble disease re c or de d at least 5 3 da ys after start of treat me nt ( 8 
wee ks fr o m start of treat me nt, a n d als o all o wi n g a 3- da y visit wi n d o w). F or e xa m ple, a n o verall visit 
res p o nse of S D o n da y 2 8 will n ot b e c o nsi dere d as S D. 
 
P D: Pr o gressi o n, or deat h i n t he a bse nce of C R/ P R or S D. 
 
N E: N o e vi de nce of C R/ P R or S D or P D or deat h. 
 
U nc o nfir me d C R: If t he B O R is n ot q ualifie d as c o nfir me d C R or P R b ut wit h at least o ne visit res p o nse of 
C R pri or t o s u bse q ue nt ne w a nti-t u m or t hera p y or P D, t he n it will be c o nsi dere d as u nc o nfir me d C R. 
 
U nc o nfir me d P R: If t he B O R is n ot q ualifie d as c o nf ir me d C R or P R b ut wit h at least o ne visit res p o nse of 
P R pri or t o s u bse q ue nt ne w a nti-t u m or t hera p y or P D, t he n it will be c o nsi dere d as u nc o nfir me d P R. 
 
I n a d diti o n, f oll o wi n g s pecial s ce nari os s hall be c o nsi dere d f or t he deter mi nati o n of B O R: 
 
If a patie nt recei ves ne w a nti-t u m or t hera p y(s), f or t hat patie nt, t u m or assess me nts after t he first ne w a nti-
t u m or t hera p y (sa me da y i ncl usi ve) will be c o nsi dere d i na de q uate, t h us n ot c o u nte d t o war ds t he 
deter mi nati o n of B O R. 
  
T he ta ble bel o w ill ustrates t he deri vati o n of B O R ( wit h c o nfir me d res p o nse) a n d B O R (re gar dless of c o nfir mati o n).  
Cate g or y of c o nfir me d res p o nse is de pe n de nt o n res p o nse at t he s u bse q ue nt ti me- p oi nt, a n d w het her t he mi ni m u m 
d urati o n criteri o n f or S D has b ee n satisfie d. 
 
O verall Res p o nse 
at First Ti me -
p oi nt  
O verall Res p o nse at 
S u bse q ue nt Ti me-
p oi nt  
S D S ustai ni n g 
D urati o n Met at 
First Ti me -p oi nt 
B O R Base d o n 
t he T w o Visits 
B O R Re gar dless of 
C o nfir mati o n (f or 
U nc o nfir me d C R or 
P R)  
C R  
C R  
Yes/ N o  
C R  
C R  
C R  
P R  
Yes/ N o  
S D/ P D  
C R  ( U nc o nfir me d) 
C R  
S D  
Yes/ N o  
S D/ P D  
C R  ( U nc o nfir me d) 
C R  
P D  
Yes/ N o  
S D/ P D  
C R  ( U nc o nfir me d) 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 6 of 7 0 
 
C R  
N E  
Yes/ N o  
S D/ N E  
C R  ( U nc o nfir me d) 
P R  
C R  
Yes/ N o  
P R/ P R  
P R  
P R  
P R  
Yes/ N o  
P R  
P R  
P R  
S D  
Yes/ N o  
S D/ S D  
P R  ( U nc o nfir me d) 
P R  
P D  
Yes/ N o  
S D/ P D  
P R  ( U nc o nfir me d) 
P R  
N E  
Yes/ N o  
S D/ N E  
P R  ( U nc o nfir me d) 
N E  
N E  
Yes/ N o  
N E  
N E  
      C R = C o m plete Res p o nse; N E = N ot E val ua ble; O R R = O bj ecti ve Res p o nse Rate; P D = Pr o gressi ve Disease; 
P R = P artial Res p o nse; S D = Sta ble Disease.  
F or patie nts w h o pr o gress a n d s u bse q ue nt l y ha ve a res p o nse, t he n t he best o bjecti ve res p o nse is o nl y deri ve d fr o m 
assess me nts u p t o a n d i ncl u di n g t he ti me of t he pr o gressi o n (i.e., it will n ot i ncl u de t he res p o nse after t he patie nt has 
pr o gresse d). 
T u m or res p o nse data f or d ose d patie nts  t hat ha d n o n- meas ur a ble disease at baseli ne (i.e. di d n ot meet st u d y 
i ncl usi o n criteria 7) will be fla g ge d a n d re vie we d acc or di n g t o pr oce d ures descri be d i n A p pe n di x 3 of t he pr ot oc ol. 
1 6. 1. 3.  O bjecti ve Res p o nse R ate 
O bj ecti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of patie nts wit h a best o verall c o m plete res p o nse ( C R) or 
partial res p o nse ( P R) per R E CI S T V. 1. 1. T o be assi g ne d a st at us of P R or C R, c ha n ges i n t u m or meas ure me nt m ust 
be c o nfir me d b y re p eat assess me nt p erf or me d n o less t ha n  4 wee ks after t he criteria f or res p o nse are first met. O R R 
(re gar dless of c o nfir mati o n) will als o be c o m p ute d se paratel y, i ncl u di n g i n t he n u merat or s u bj ects w h o ha ve C R, 
u nc o nfir me d C R, P R or u nc o nfir me d P R.  T he de n o mi nat or f or t he calc ulati o n of O R R a n d O R R re gar dless of 
c o nfir mati o n will i ncl u de all p atie nts i n E A S.  
1 6. 1. 4.  Dise ase C o ntr ol R ate 
Disease c o ntr ol rate ( D C R) is defi ne d as t he pr o p orti o n of  patie nts w h ose best o verall res p o nse fr o m baseli ne is 
eit her C R, P R, or S D p er R E CI S T v. 1. 1. T he de n o mi nat o r f or t he calc ulati o n of D C R will i ncl u de all patie nts i n 
E A S s u bset of res p o nse e val ua ble patie n ts. Res p o nse e val ua ble patie nts refer t o patie nts wit h a baseli ne R E CI S T 
assess me nt. 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 7 of 7 0 
 
1 6. 1. 5.  Ti me t o Res p o nse   
Ti me t o res p o nse ( T T R) is defi ne d as t he ti me bet wee n t he st art date of st u d y me dicati o n u ntil first d oc u me nte d 
res p o nse ( C R or P R, w hic h is s u bse q ue ntl y c o nfir me d) acc or di n g t o R E CI S T v. 1. 1. Ti me t o res p o nse is o nl y 
a p plica ble t o patie nts w h ose B O R is eit her C R or P R. T T R ( m o nt hs) will be calc ulate d as ( First C R/ P R date –  start 
date of st u d y me dicati o n + 1) / 3 0. 4 3 7 5.  
1 6. 1. 6.  D ur ati o n of O bjecti ve Res p o nse 
D urati o n of o bj ecti ve res p o nse ( D o R) is defi ne d as t he ti me fr o m t he first ti me t hat t he o bjecti ve res p o nse reac hes 
C R or P R, w hic he ver c o mes first, u ntil t he occ urre nce of P D  or deat h (if t he deat h of t he patie nt occ urs bef ore 
rec or di n g t he P D). If t he res p o nse is n ot c o nfir me d, it will n ot be i ncl u de d. If a patie nt d oes n ot pr o gress ( or d oes n ot 
pr o gress bef ore recei vi n g ne w a nti-ca ncer treat me nt) f oll o wi n g a res p o nse, t he n t heir d urati o n of res p o nse will use 
t he P F S ce ns ori n g ti me. 
F or t h ose patie nts wit h c o nfir me d res p o nse, t he date of res p o nse will be t he date of first d oc u me nte d res p o nse, n ot 
t he date of c o nfir mat or y t u m or assess me nt f or t hat res po nse. T he D o R ( m o nt hs) will be calc ulate d as ( P D/ Deat h 
date - First C R/ P R date + 1) / 3 0. 4 3 7 5 w he n a patie nt is dee me d t o e x peri e nce a P F S e ve nt after first C R/ P R, or 
calc ulate d as ( P F S ce ns ori n g d ate - First C R/ P R date + 1 )/ 3 0. 4 3 7 5 w he n a patie nt is dee me d t o be ce ns ore d. 
1 6. 1. 7.  P erce nt a ge C h a n ge i n T u m or Size 
P erce nta ge c ha n ge i n t u m or si ze will be deter mi ne d f or patie n ts wit h meas ura ble disease at baseli ne a n d is deri ve d at 
eac h visit b y t he perce nta ge c ha n ge i n t he s u m of t he dia meters of tar get lesi o ns c o m pare d t o baseli ne. Best 
( mi ni m u m) perce nta ge c ha n ge fr o m baseli ne ( P C F B) i n t um or size will be s u m marize d b y d ose c o h ort a n d disease 
c o h ort usi n g descri pti ve statistics a nd a waterfall pl ot will be prese nte d als o. T he s u m of di a meters will be ta ke n 
fr o m t he fiel d “ S u m of Dia meters of T ar get Lesi o ns” i n “ Assess me nt of Disease ( Acc or di n g t o R E CI S T 1. 1) ( R S)” 
f or m of e C R F or be calc ulate d fr o m t he fiel d “ Meas ure d Dia meter” i n “ T u m or Res ults: T ar get Lesi o n ( T A R G E T)” 
f or m of e C R F.  
1 6. 2.  P RI M A R Y A N A L Y SI S O F E F FI C A C Y V A RI A B L E (S ) 
F or eac h d ose le vel i n d ose es calati o n p has e a n d eac h diseas e c o h ort i n d ose e x pa nsi o n p hase, P F S will be descri be d 
i n ta b ular a n d gra p hical f or mat usi n g Ka pla n- Meier met h o ds, i ncl u di n g esti mate d me dia n (i n m o nt hs) wit h 9 5 % CI, 
2 5 t h a n d 7 5t h perce ntiles, mi ni m u m, ma xi m u m. T he 9 5 % CI f or t he me dia n s ur vi val ti me will be deri ve d usi n g t he 
l o g-l o g tra nsf or mati o n base d o n Br o o k me yer a n d Cr o wle y met h o d. 
B esi des, Ka pla n- Meier esti mate d pr o ba bilities wit h c orres p o n di n g 8 0 % a n d 9 5 % CIs at se veral ti me p oi nts 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 8 of 7 0 
 
(i ncl u di n g 4 M o nt hs/ 1 6 W ee ks a n d 1 1 m o nt hs) will als o be pr o vi de d a n d t he 8 0 % a n d 9 5 % CIs will be deri ve d 
usi n g t he l o g-l o g tra nsf or mati o n base d o n Gree n w o o d’s  f or m ula.  
 
Ce ns ori n g reas o ns will als o be s u m mar ize d b y cate g ories t hat will be deter mi ne d usi n g t he treat me nt c o m pleti o n 
pa ge, t he st u d y e val uati o n c o m pleti o n pa ge a n d s ur vi val pa ge.  
T he ot her e n d p oi nts i ncl u di n g T T R a n d D o R will be a nal yz e d i n t he sa me wa y w here a p pr o priate. I n case t he 
n u m ber of res p o nses i n eac h tr eat me nt gr o u p is ver y s mall, D o R a n d T T R ma y be liste d o nl y. 
O R R a n d D C R will be esti mat e d a n d 9 5 % e xact c o nfi de nce i nter vals ( CIs) base d o n t he Cl o p per- P ears o n met h o d 
will b e prese nte d. 
 
T he ti me t o e ve nt/ce ns ori n g a n d t he ce ns ori n g stat us f or P F S will be liste d f or t he S A S, a n d f or D O R a n d B O R will 
be liste d f or t he E A S. 
1 6. 3.  E X P L O R A T O R Y E F FI C A C Y  
1 6. 3. 1.  T u m or M ar kers 
T u m or mar kers ma y i ncl u de, b ut are n ot li mite d t o, ser u m C E A a n d C A 1 9- 9 ( patie nts wit h B T C) ser u m 
c hr o m o gra ni n A ( C g A) a n d ne ur o n-s pecific e n olase ( N S E) f o r patie nts wit h p N E T a n d e pN E T; a n d ser u m or plas ma 
V E G F f or all diseases c o h orts. Assess me nt of t u m or mar kers will be perf or me d wit hi n 2 8 da ys pri or t o t he start of 
treat me nt wit h st u d y dr u g ( C 1 D 1) a n d at eac h t u m or assess me nt visit. 
 
T he val ues a n d c ha n ge fr o m b aseli ne i n t u m or mar ker s will be s u m marize d b y disease c o h ort ( B T C, p N E T, or 
e p N E T, or S T S) usi n g descri pti ve statistics. T he i n di vi d u al t u m or mar ker test res ults will b e liste d b y d ose c o h orts 
i n eac h p hase a n d b y patie nts. Ot her e x pl orat or y a nal yses ma y be perf or me d as a p pr o priate. 
1 6. 3. 2.  O ver all S ur vi v al 
O verall s ur vi val ( O S) (i n m o nt hs) is defi ne d as t he ti me i nte r val bet wee n t he start date of st u d y dr u g a n d t he date of 
patie nt d eat h (a n y ca use). T he fi nal k n o w n date ali ve will be  use d as t he ce ns ori n g date f or patie nts w h o ha ve n ot 
bee n re p orte d t o ha ve die d b y t he ti me of a nal ysis c ut- off dat e. O S will be a nal yze d f or o nl y t he B T C a n d S T S 
c o h orts base d o n t he S A S. 
 
P atie nts w h o fail t o pr o vi de a n y f oll o w- u p i nf or mati o n will be  ce ns ore d o n t he date of e nr ol me nt. O S ( m o nt hs) will 
be calc ulate d as ( Date of deat h –  start d ate of st u d y me dicati o n + 1) / 3 0. 4 3 7 5. 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 9 of 7 0 
 
 
Me dia n, 2 5
t h a n d 7 5t h Q uartiles, mi ni m u m a n d ma xi m u m will be pr o vi de d f or O S. Ka pla n- Meier esti mate d 
pr o ba bilities wit h c orres p o n di n g 8 0 % a n d 9 5 % CIs at se vera l ti me p oi nts (i ncl u di n g 1 6 we e ks, 6 m o nt hs, 8 m o nt hs 
a n d 1 1 m o nt hs f or B T C a n d S T S c o h ort) will be pr o vi de d. Ka pla n- Meier c ur ves  will be c o nstr ucte d t o pr o vi de a 
vis ual prese ntati o n of t he O S c ha n ge wit h ti me.  
1 6. 4.  S E N SI TI VI T Y A N A L Y SI S O F E F FI C A C Y V A RI A B L E (S ) 
N o se nsiti vit y or s u p p orti ve a nal ys es will be perf or me d o n efficac y varia bles. 
1 7.  S A F E T Y O U T C O M E S  
All o ut p uts f or safet y o utc o mes e xce pt D L T s u m mar y will b e  base d o n t he S A S. Safet y data will be s u m marize d b y 
d ose c o h ort i n escalati o n p has e a n d diseas e c o h ort i n d ose e x pa nsi o n p hase.  
1 7. 1.  A D V E R S E E V E N T S  
A n a d verse e ve nt ( A E) is a n y u nfa v o ra ble a n d u ni nte n d e d si g n, s y m pt o m, or disease te m p orall y ass ociate d wit h t he 
use of t he i n vesti gati o nal me di ci nal pr o d uct or ot her pr ot oc ol-i m p ose d i nter ve nti o n, re gar dless of attri b uti o n. 
Rele va nt i nf or mati o n is rec or de d o n C R F pa ge  “ A d verse E ve nt/ Seri o us A d verse E ve nt”. 
If a persiste nt A E bec o mes m ore se vere, it s h o ul d be rec or de d a gai n wit h t he u p date d se verit y. All rec urre nt A Es 
( A Es t hat occ urs a n d res ol ves bet wee n patie nt e val uati o n time p oi nts a n d s u bse q ue ntl y re c urs) s h o ul d be rec or de d 
o n “ A d verse E ve nt/ Seri o us A d verse E ve nt” C R F.  
A pre-e xisti n g me dical c o n diti o n s h o ul d be rec or de d as a n A E or S A E o nl y if t he fre q ue nc y, se verit y, or c haracter of 
t he c o n diti o n w orse ns d uri n g t he st u d y.  
After i nf or me d c o nse nt, b ut pri or t o i nitiati o n of st u d y me dic ati o ns, o nl y S A Es ca use d b y a pr ot oc ol- ma n date d 
i nter ve nti o n will be c ollecte d. 
After i nitiati o n of st u d y me dic ati o ns, all A Es a n d S A Es re gar d less of attri b uti o n will be c ollecte d u ntil 3 7 da ys ( 3 0 
da ys + 7 da ys wi n d o w) f oll o wi n g t he last a d mi nistrati o n of st u d y me dicati o n or st u d y disc o nti n uati o n/ter mi nati o n, 
w hic he ver is later.  After t his peri o d, i n vesti gat ors s h o ul d re p ort o nl y S A Es t hat are felt t o be relate d t o pri or st u d y 
treat me nt. 
Treat me nt-e mer ge nt A Es ( T E A Es) are defi ne d as A Es t hat s tarte d or w orse ne d i n se verit y o n or after t he first 
a d mi nistrati o n date of st u d y me dicati o n a n d n o later t ha n 3 0 ( + 7) da ys after t he last a d mi nistrati o n date of st u d y 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 0 of 7 0 
 
me dicati o n or i nitiati o n of ne w a nti-t u m or t hera p y ( w hic he ver occ urs first).  
A n e xce pti o n is t hat st u d y me dicati o n relate d S A Es c ollecte d later t ha n 3 7 da ys after t he l ast d osi n g date will be 
treate d as T E A Es. 
If t he start d ate c oi nci des wit h t he refere nce start date, a q uer y “ Pri or/ p ost 1st d ose” will b e use d t o i de ntif y T E A Es 
( o nl y w he n ‘ P ost 1st d ose’ will b e c o nsi dere d as T E A E, if ‘ Pri or’ t he n n ot T E A E). W he n t here is n o defi nite a ns wer 
t o t he q uer y, t he A E will be c o nsi dere d as a T E A E. See secti o n 8. 2 f or ha n dli n g of partial dates f or A Es. I n t he case 
w here it is n ot p ossi ble t o classif y a n A E  as treat me nt-e mer ge nt or n ot, t he A E will be classifie d b y t he w orst case; 
i.e. treat me nt-e mer ge nt.  
If a s u bj ect re p orts a T E A E m ore t ha n o nce i n t he S O C/P T, t he T E A E wit h hi g hest se verit y will be use d i n t he 
c orres p o n di n g s u m maries. 
A n o verall s u m mar y of n u m ber of patie nts wit hi n eac h of t h e cate g ories descri be d i n t he s u b-secti o n bel o w, will be 
pr o vi de d f or all A Es as s pecifi e d i n t he te m plates.  
F or all S O C/ P T s u m maries, A Es will be prese nte d i n al p ha b etic or der e xce pt t he u nc o de d S O C/ P T. U nc o de d 
S O C/ P T will be prese nte d a s “ U nc o de d ” a n d be prese nte d at t he e n d of rele va nt A E s u m maries.  
A Listi n g of all A Es wit h rele va nt i nf or mati o n bei n g re p orte d d uri n g st u d y wit h fla g t o disti n g uis h T E A E a n d N o n-
T E A E will be pr o vi de d. 
1 7. 1. 1.  All T E A Es  
I n t he a nal ysis of A Es, t he Me d D R A a d verse e ve nt dicti o nar y Versi o n 2 3. 0 or hi g her will be use d t o ma p ver bati m 
ter ms t o S O C a n d P T.  
A n o verall s u m mar y of T E A Es i ncl u di n g se verit y,  relati o ns hi p, acti o n ta ke n, a n d o utc o me will be pr o vi de d. 
I nci de nce of T E A Es will be prese nte d b y S O C a n d t he n P T a n d als o br o ke n d o w n f urt her b y ma xi m u m se verit y 
( Secti o n 1 7. 1. 1. 1) a n d relati o ns hi p t o st u d y me dicati o n ( Secti o n 1 7. 1. 1. 2) f or eac h d ose le vel, a n d eac h disease 
c o h ort. N u m ber ( n) a n d perce nta ge ( %) will be prese nte d  wit h t he % calc ulat e d relati ve t o t he t otal n u m ber of 
patie nts i n t he S A S. I n t he cas e t hat a patie nt re p ort m ulti ple T E A Es, t he T E A E wit h w orst se verit y a n d str o n gest 
relati o ns hi p (relate d t o st u d y me dicati o n) will be use d i n t he c orres p o n di n g s u m maries. 
1 7. 1. 1. 1 Se verit y 
T he se verit y of all T E A Es will b e gra d e d acc or di n g t o 5 gra des ( Gra de 1 t o Gra de 5) i n acc or da nce wit h t he 
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y criteria f or a d verse e ve nts ( N CI- C T C A E) V 4. 0 3 as defi ne d i n t he 
St u d y Pr ot oc ol Secti o n 7. 1. 5. 
T E A Es missi n g se verit y will b e classifie d as Gra de 3.  
T E A Es of eac h se verit y gra d e will b e s u m marize d usi n gi nci de nce (fre q ue ncies a n d pe rce nta ges) b y S O C a n d P T 
will b e s u m marize d b y d ose le vel i n t he d ose escalati o n p has e a n d b y disease c o h ort i n t h e d ose e x pa nsi o n p hase. If 
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a patie nt re p orts a T E A E m ore t ha n o nce wit hi n t hat S O C/ P T , t he A E wit h t he w orst case se verit y will be use d i n 
t he c orres p o n di n g se verit y s u m maries. 
1 7. 1. 1. 2 Rel ati o ns hi p t o St u d y Me dic ati o n 
As i n dicate d b y t he I n vesti gat or, ca usal relati o ns hi p bet w ee n A Es a n d st u d y me dicati o n will be classifie d as 
“reas o na bl y p ossi ble” or n ot. T E A Es wit h missi n g relati o ns hi p t o st u d y me dicati o n will b e re gar de d relate d.  
Relate d a n d N ot Relate d T E A Es will be s u m m arize d b y d ose le vel i n d ose escalati o n p has e, a n d b y disease c o h ort i n 
d ose e x pa nsi o n p hase usi n g i n ci de nce (fre q ue ncies a n d perce nta ges) b y S O C a n d P T. If a patie nt re p orts t he sa me 
A E m ore t ha n o nce wit hi n t hat S O C/ P T, t he A E wit h t h e w orst relati o ns hi p (ie, relate d) t o st u d y me dicati o n will be 
use d i n t he c orres p o n di n g relati o ns hi p s u m maries. 
1 7. 1. 2.  T E A Es Le a di n g t o Disc o nti n u ati o n of St u d y Me dic ati o n 
T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y me di cati o n will be i de ntifie d as t h ose rec or ds wit h a res p o nse 
of “ Dr u g Wit h dra w n” t o t he it e m “ Acti o n t a ke n wit h t he st u d y dr u g” o n t he “ A d verse E ve nt/ Seri o us A d verse E ve nt 
( A E/ S A E)” f or m of t he C R F.  
F or T E A Es lea di n g t o dr u g disc o nti n uati o n, s u m maries of i nci de nce (fre q ue ncies a n d perce nta ges) b y S O C a n d P T 
will b e pre p are d. S u m maries f or T E A Es lea di n g t o disc o nti n uati o n of st u d y me dicati o n b y S O C a n d P T will be 
f urt her br o ke n d o w n b y ma xi m u m se verit y a n d relati o ns hi p t o st u d y me dicati o n. 
1 7. 1. 3.  T E A Es Le a di n g t o St u d y Me dic ati o n A dj ust me nt 
T E A Es lea di n g t o st u d y me dic ati o n a dj ust me nt will be i de ntifie d as t h ose r ec or ds wit h a res p o nse of “ Dr u g 
i nterr u pte d” or “ D ose re d uce d ” or ‘ D ose increase d’  t o t he ite m “ Acti o n ta ke n wit h t he st u d y dr u g” o n t he A E/ S A E 
f or m of t he C R F.  
F or T E A Es lea di n g t o st u d y me dicati o n a dj ust me nt, s u m maries of i nci de nce (fre q ue ncies a n d perce nta ges) b y S O C 
a n d P T will be pre p are d. S u m maries f or T E A Es lea di n g t o  st u d y me dicati o n a dj ust me nt b y S O C a n d P T will be 
f urt her br o ke n d o w n b y ma xi m u m se verit y a nd str o n gest relati o ns hi p t o st u d y me dicati o n. 
1 7. 1. 4.  Seri o us T E A Es 
A seri o us a d verse e ve nt ( S A E) is defi ne d as a n y life-t hreate ni n g A E res ulti n g i n deat h, persiste nt or si g nifica nt 
disa bilit y/i nca pacit y, a c o n ge nital a n o mal y/ birt h defect, or a n y ot her i m p orta nt me dical e ve nt re q uiri n g i nter ve nti o n, 
i n- patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n. 
Detaile d defi niti o n of S A Es ca n be f o u n d i n Pr ot oc ol Secti o n 9. 1. 1. 
O n t he C R F, S A Es are t h ose e ve nts wit h a res p o nse of “ Yes ” f or t he ite m “ D o es t he A d verse E ve nt meet seri o us ness 
criteria? ”.  S u m maries of i nci de nce (fre q ue ncies a n d p erce nta ges) of seri o us T E A Es b y S O C a n d P T will be 
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pre p are d. I n a d diti o n, s u m maries f o r seri o us T E A Es b y S O C a n d P T will be f urt her br o ke n d o w n b y ma xi m u m 
se verit y a n d str o n gest relati o ns hi p t o st u d y me dicati o n. 
 S A Es will be fla g ge d a n d i ncl u de d i n a listi n g of A Es. 
1 7. 1. 5.  T E A Es Of S peci al I nterest ( T E A E SI) 
T he preferre d ter ms f or T E A E SI are i ncl u de d i n A p pe n di x 2. S u m maries of i nci de nce (fre q ue ncies a n d perce nta ges) 
of T E A E SIs b y Sta n dar dize d Me d D R A Q ueries ( S M Q) a n d P T base d o n t he A p pe n di x 2  will be pre pare d. T he 
br oa d searc h will be use d f or S M Q ter ms. Ti me t o T E A E SI o nset is defi ne d as ti me i nter val fr o m date of first 
a d mi nistrati o n of st u d y me dic ati o n t o t he earliest o nset date a m o n g T E A Es wit hi n t he sa me S M Q. Ti me t o T E A E SI 
o nset will be s u m marize d b y S M Q f or ea c h d ose c o h ort a nd disease c o h ort. 
A E SIs will be fla g ge d a n d i ncl u de d i n a listi n g of A Es. 
1 7. 1. 6.  D ose Li miti n g T o xicit y ( D L T)  
A detaile d defi niti o n of D L T ca n be f o u n d i n Pr ot oc ol Secti o n 4. 1. 2. O n t he C R F, D L T will be i de ntifie d a m o n g all 
A Es usi n g q uesti o n “Is it D L T ? ”, a n d details will be ca pt ure d o n C R F pa ge “ D L T Assess me nt”. I nci de nce of  D L Ts 
b y S O C a n d P T will be s u m marize d f or D L T set. Ti me bet wee n date of first d ose of st u d y me dicati o n a n d D L T 
e ve nt o nset will be prese nte d f or D L T e val ua ble set. 
All rele va nt i nf or mati o n of D L T assess me nt will be lis te d f or D L T e val ua ble set b y d ose c o h ort a n d b y patie nt. 
1 7. 1. 7.  De at hs 
If a n y patie nts die d uri n g t he st u d y c o n d uct, as rec or de d o n t he “ Deat h” C R F f or m, t he c o u nt a n d ca use of deat h a n d 
o n treat me nt deat h (e ve nt occ urs o n or after first st u d y me di cati o n d ose a n d pri or t o 3 7 da ys [ 3 0 da ys + 7 da ys 
wi n d o w] after t he last d ose) will be s u m marize d b y d ose le vel i n d ose escalati o n p hase, a n d b y disease c o h ort i n 
d ose e x pa nsi o n p hase. 
I n di vi d ual i nf or mati o n of s u bj ect I D, deat h date a n d pri mary reas o n f or deat h will be prese nte d i n t he listi n g. O n-
treat me nt d eat h will be fla g ge d. 
1 7. 2.  L A B O R A T O R Y E V A L U A TI O N S  
La b orat or y sa m ples will be a n al yze d at t he st u d y site’s l ocal la b orat or y .  La b orat or y assess me nts will i ncl u de t he 
f oll o wi n g: 
 
He mat ol o g y, w hic h is rec or de d o n C R F pa ge “ L A B –  He mat ol o g y”  
 
C oa g ulati o n, I N R a n d a P T T, w hic h is ca pt ure d o n C R F pa ge “ L A B - C oa g ulati o n”.  
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P a g e 4 3 of 7 0 
 
 
Ser u m c he mistr y, w hic h is rec or de d o n C R F pa ge “ L A B - Bl o o d C he mistr y”  
 
Ser u m pre g na nc y test at scree ni n g f or all w o me n of c hil d beari n g p ote ntial, w hic h is ca pt ure d o n C R F pa ge 
“ Pre g na nc y T est”  
 
Uri nal ysis, w hic h is rec or de d o n C R F pa ge “ L A B –  Uri nal ysis”  a n d “ L A B - 2 4 hrs Uri ne Pr otei n”  
 
T h yr oi d f u ncti o n: T S H, free T 3, free T 4, w hic h is ca pt ure d o n C R F pa ge “ L A B - T h yr oi d F u ncti o n T ests”  
 
St o ol occ ult bl o o d test, w hic h is rec or de d o n C R F pa ge “ L A B - Fecal Occ ult Bl o o d T est”  
T est n or mal ra n ges of all q ua ntitati ve tests a b o ve (ie, all tes ts e xcl u di n g st o ol occ ult bl o o d test a n d ser u m pre g na nc y 
test) are als o rec or de d o n c orresp o n di n g n or mal ra n ge C R F pa ges. 
Data rec or de d b y t he la b orat or y will be c o n verte d t o t he I n ter nati o nal S yste m of U nits ( SI) a n d all prese ntati o ns will 
use SI u nits. Q ua ntitati ve la b orat or y meas ure me nts re p orte d as “ < X”, i.e. bel o w t he l o wer li mit of n or mal ra n ge 
( L L N), or “ > X”, i.e. a b o ve t he u p per li mit of n or mal ra n ge ( U L N), will be c o n verte d t o X f or t he p ur p ose of 
q ua ntitati ve s u m maries, b ut will be prese nte d as rec or d e d, i.e. as “ < X” or “ > X” i n t he listi n gs.  
T he f oll o wi n g s u m maries will be pr o vi de d f or la b orat or y dat a: 
 
F or q ua ntitati ve res ults, act ual val ue of eac h sc he d ule d visit, c ha n ge fr o m baseli ne f or eac h p ost- baseli ne 
sc he d ule d meas ure me nt. 
 
F or q ua ntitati ve meas ure me nts a n d cate g orical meas ure me nts, I nci de nce of a b n or mal val ues assesse d b y 
i n vesti gat or. S hift fr o m baseli ne acc or di n g t o mar ke dl y a b n or mal criteria base d o n i n vesti gat ors’ 
assess me nt. 
 
S hift fr o m baseli ne t o w orst gr a d e i n C T C A E gra de acc or di n g t o C o m m o n T o xicit y ( C T C) gra di n g s yste m 
f or para meters of he mat ol o g y a n d ser u m bi oc he mistr y w h os e C T C A E scale is a vaila ble.  
 
Listi n g of all la b orat or y data b y patie nt, a b n or mal val ues  i de ntifie d acc or di n g t o n or mal ra n ge (l o w, n or mal 
a n d hi g h), a n d mar ke dl y a b n or mal criteria b y i n vesti gat ors’ assess me nt will be fla g ge d.  
1 7. 2. 1.  L a b or at or y S pecific Deri v ati o ns 
Creati ni ne cleara nce ( C Cr) will be calc ulate d b y usi n g t he ser u m creati ni n e ( S Cr) val ues ac c or di n g t o t he t he 
f oll o wi n g f or m ulas:  
 
Male:  C Cr = [( 1 4 0 - a ge) × wei g ht ( k g)] / [ 0. 8 1 8 × S Cr ( u m ol/ L)] 
 
Fe male: C Cr = [( 1 4 0 - a ge) × wei g ht ( k g)] / [ 0. 8 1 8 × S Cr ( u m ol/ L)] × 0. 8 5 
T he u nits f or creati ni ne cleara nce will be c o n verte d t o SI u nit: u m ol/ L. 
1 7. 2. 2.  L a b or at or y Refere nce R a n ges a n d M ar ke dl y A b n or m al Criteri a  
All la b orat or y assess me nts e xce pt ser u m pre g na nc y test a n d st o ol occ ult bl o o d test will be a nal yze d as f oll o wi n g. 
Q ua ntitati ve la b orat or y meas ure me nts will be c o m pare d wit h t h e rele va nt la b orat or y refer e nce ra n ges i n SI u nits a n d 
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cate g orize d as: 
 
L o w: B el o w t he l o wer li mit of t he la b orat or y refere nce ra n ge.  
 
N or mal: Wit hi n t he la b orat or y refere nce ra n ge ( u p per a n d l o wer li mit i ncl u de d). 
 
Hi g h: A b o ve t he u p per li mit of t he la b orat or y refere nce ra n ge. 
I n a d diti o n t o t he hi g h a n d l o w q ua ntitati ve la b orat or y assi g n me nts (as i de ntifie d b y mea ns of t he la b orat or y 
refere nce ra n ges), mar ke dl y a b n or mal q ua ntitati ve safet y (an d ot her) la b orat or y ass ess me nts will als o be e val uate d 
as n or mal/a b n or mal, n ot cli nic all y si g nifica nt ( N C S)/ a b n or mal, cli nicall y si g nifica nt ( C S) b y i n vesti gat or. F or 
la b orat or y assess me nts c ollect e d wit h b ot h q ua ntitati ve a n d q ualitati ve res ults, if m ost ass ess me nts are q ua ntitati ve, 
q ua ntitati ve assess me nts will b e s u m marize d, a n d vice vers a if m ost assess me nts are q ualitati ve, a n d all t he 
assess me nts will be liste d.  
1 7. 2. 3.  C T C A E Gr a di n g f or L a b or at or y D at a  
Q ua ntitati ve la b orat or y meas ure me nts will be gra de d ac c or di n g t o N CI C T C A E V 4. 0 3 w here ver a p plica ble. All 
gra di n g will be base d o n la b val ues ( bei n g direct or s o me deri ve d, c orrecte d val ues) O N L Y, re gar dless of its 
i nter ve nti o nal or s y m pt o matic c o nse q ue nces.  
S o me m o dificati o ns t o t he gra di n g s yste m will be a p plie d: 
 
Gra d e 5 refers t o fatal o utc o mes, w hic h ca n n ot be dete r mi ne d s olel y b y la b val ues, t heref ore will n ot a p pear 
i n t he gra di n g s yste m. I n a d diti o n t o t he us ual defi ne d cate g ories. 
 
A f urt her cate g or y de n ote d Gra d e 0 will i ncl u de all ot her la b orat or y val ues e xce pt missi n g v al ues.   
 
Missi n g res ults s hall be gra d e d as missi n g.  
F or s o me s pecific para meters wit h C T C A E gra di n g i n b ot h hi g h a n d l o w directi o n (e. g., c alci u m, gl uc ose, 
ma g nesi u m, p otassi u m, s o di u m), C T C A E i n hi g h a n d l o w di recti o ns will be prese nte d se p aratel y, i.e. h y per f or 
hi g her val ues of c o ncer n a n d h y p o f or l o wer val ues of c o nc er n. 
S hifts i n t o xicit y gra d e fr o m b aseli ne t o t he w orst t o xicit y gra de will be pr o vi de d f or t he S A S. 
1 7. 2. 4.  Li ver F u ncti o n A b n or m alit y 
Li ver f u ncti o n a b n or malit y is defi ne d i n Pr ot oc ol S ecti o n 7. 1. 7 a n d t he bel o w e ve n ts will be i de ntifie d via 
pr o gra m mi n g a n d s u m marize d b y cate g o ries a n d d ose c o h ort f or S A S. Se parate listi n gs f or patie nts wit h dr u g-
i n d uce d li ver i nj ur y ( DI LI) will als o be pr o vi de d. 
 
A L T/ A S T > 3 x U L N a n d ≤ 5 x U L N 
 
A L T/ A S T > 5 x U L N 
 
T otal Bilir u bi n > 2 x U L N 
 
A L T/ A S T > 3 x U L N A N D c o nc urre nt T otal bilir u bi n > 2 x U L N 
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1 7. 3.  E C G  E V A L U A TI O N S  
T he 1 2- Lea d Electr ocar di o gra m ( E C G) will be perf or me d at  scree ni n g, a n d o n Da ys 1 a n d 1 5 i n C ycle 1. w he n 
E C G data will be c ollecte d at pre- d ose a n d at 2 h o urs +- 1 5 mi n utes p ost- d ose (ar o u n d C ma x  after si n gle d ose a n d at 
stea d y state i n or der t o e val uat e c o nce ntrati o n- Q T relati o ns hip f or s ur ufati ni b). T he E C G val ues at C 1 D 1 pre- d ose 
will b e use d as ‘baseli ne ’ val ue i n t he a nal ysis. E C G will als o be c o n d ucte d o n Da y 1 of ea c h c ycle fr o m C ycle 2 
a n d o n war d, as well as t he tre at me nt c o m pleti o n visit. 
F or eac h ti me- p oi nt, f oll o wi n g meas ure me nts wit h c ha n ge  fr o m baseli ne val ues will be prese nte d f or t he S A S: 
 
Heart rate ( b p m) 
 
R R ( ms) 
 
P R ( ms) 
 
Q R S ( ms) 
 
Q T ( ms) 
 
Q T c orrecti o n b y B azett ( ms) 
 
Q T c orrecti o n b y Fri d ericia ( ms) 
 
O verall E C G i nter pretati o n 
o  
A b n or mal, cli nicall y si g nifica nt ( C S) 
o  
A b n or mal, n ot cli nicall y si g nifica nt ( N C S) 
o  
N or mal 
o  
I nc o m plete a nal ysis 
o  
U ni nter preta ble 
o  
N ot a p plica ble 
1 7. 3. 1.  E C G S pecific Deri v ati o ns 
T here will be n o s pecific deri vati o ns f or E C G. 
1 7. 3. 2.  E C G M ar ke dl y A b n or m al Criteri a 
T he n u m ber a n d perce nta ge of patie nts  wit h n ota ble E C G val ues at baseli ne a n d p ost- baseli ne will be s u m marize d.  
T hese s u m maries will be d o ne f or w orst p ost- baseli ne val u e f or ea c h cate g or y. T he criteria f or n ota ble E C G val ues 
are pr o vi de d i n T a ble 2 bel o w. 
T a ble 2  
N ot a ble E C G V al ues 
T est  
N ota ble E C G Val ues  
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Q T c F/ Q T c B 
(a bs ol ute) 
i nter val > 4 5 0 t o 4 8 0 msec 
i nter val > 4 8 0 t o 5 0 0 msec 
i nter val > 5 0 0 msec 
Heart rate  
(a bs ol ute) 
< 5 0 b p m  
> 1 0 0 b p m  
P R  
(a bs ol ute) 
i nter val > 2 0 0 msec 
Q R S  
(a bs ol ute) 
i nter val > 1 2 0 msec 
 
 
1 7. 3. 3.  A n al ysis of Q Tc C h a n ge fr o m B aseli ne ( Δ Q Tc)  
T he c ha n ge fr o m baseli ne i n Q T c F ( Δ Q T c F) i nter vals will be e val uate d as f oll o ws: 
 
Δ Q T c F at eac h ti me p oi nt will be liste d f or eac h patie nt a n d treat me nt. F or eac h ti me p oi nt of 
meas ure me nt, Δ Q T c F will be s u m marize d usi n g descri pti ve statistics ( mea n, S D, me dia n, mi n, ma x). 
 
T he i nci de nce of patie nts wit h Δ Q T c F i ncrease > 3 0 t o 6 0 ms ec a n d > 6 0 msec will be s u m marize d.  
 
T he i nci de nce of patie nts wit h Δ Q T c F i ncrease > 3 0 t o 6 0 ms ec a n d > 6 0 msec b y ti me- p oi nt i n C ycle 1 
will als o be s u m marize d.  
 
P atie nts wit h Δ Q T c F i ncrease > 6 0 msec will be liste d. 
 
Mea n Δ Q T c F vers us ti me pr ofile f or eac h d ose gr o u p will be pl otte d o n t he sa me gra p h. 
1 7. 3. 4.  A n al ysis of t he Rel ati o ns hi p Bet wee n Q T/ Q Tc a n d R R at B aseli ne 
T he relati o ns hi p bet wee n Q T/ Q T c a n d R R i nter vals at ba seli ne will be e val uate d gra p hicall y as f oll o ws: 
 
T he l o garit h m of baseli ne Q T val ues will be pl otte d a gai nst t he l o garit h m of c orres p o n di n g R R 
i nter vals. 
 
A li near re gressi o n m o del will be fitte d t o t he dat a wit h l o garit h m of baseli ne Q T c i nter val val ues as 
t he de p e n de nt varia ble a n d l o garit h m of R R as t he pre dict or. 
 
T he sl o pe of t he re gressi o n li ne a n d its sta n dar d err o r, al o n g wit h 2-si de d 9 5 % c o nfi de nce i nter vals f or 
t he sl o pe, will be esti mate d fr o m t his m o del. 
 
T he a nal ysis will be re p eate d f or Q T c B a n d Q T c F a n d pl otte d o n t he sa me gra p h f or Q T. 
C CI






 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 9 of 7 0 
 
sc he d ule d meas ure me nt will be prese nte d b y visit. O verall e val uati o n will be s u m marize d se paratel y. 
All ec h ocar di o gra p h y res ults i ncl u di n g c ha n ge fr o m ba seli ne f or L V E F a n d rele va nt i nf or mati o n will be liste d. 
1 8.  R E F E R E N C E S  
Pr ot oc ol 2 0 1 5- 0 1 2- 0 0 U S 1 Versi o n 7. 0 ( A me n d me nt 1 1), Date d 1 9 Mar 2 0 2 1 
Case Re p ort F or ms Versi o n 1 1  Date d 3 0 A u g 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 0 of 7 0 
 
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  
I Q VI A O U T P U T C O N V E N TI O N S  
O ut p uts will be prese nte d acc or di n g t o t he Q ui ntiles’ ge neral g ui deli nes a n d te m plate f or o ut p uts c o n ve nti o ns. 
D A T E S &  T I M E S 
De p e n di n g o n data a vaila ble, dates a n d ti mes w ill ta ke t he f or m D D M M M Y Y Y Y a n d H H: M M: S S. 
S P E L LI N G F O R M A T  
E n glis h U S. 
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S  
All s u m maries will be prese nt e d b y assi g ne d d ose le vel i n d ose escalati o n p hase. 
Tre at me nt Gr o u p  
F or T a bles, Listi n gs a n d Gr a p hs  
5 0 m g/ da y d ose le vel  
5 0 m g  
1 0 0 m g/ da y d ose le vel  
1 0 0 m g  
2 0 0 m g/ da y d ose le vel  
2 0 0  m g 
3 0 0 m g/ da y d ose le vel  
3 0 0 m g  
4 0 0 m g/ da y d ose le vel  
4 0 0 m g  
A d diti o nal i nter me diate d ose le vel  
X X X m g ( X X X = Act ual d ose le vel)  
Scree n fail ures (i n listi n gs o nl y)  
S F  
U ntreate d eli gi ble patie nts (i n listi n gs o nl y) 
N O T T R T  
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 1 of 7 0 
 
P R E S E N T A TI O N O F D I S E A S E C O H O R T  
All s u m maries will be prese nt e d b y dise ase c o h ort i n d ose e x pa nsi o n p hase. 
Dise ase C o h ort  
F or T a bles, Listi n gs a n d Gr a p hs  
Ar m A : Biliar y tract ca ncer 
B T C  
Ar m B : P a ncreatic ne ur oe n d o cri ne t u m or 
p N E T  
Ar m C:  E xtra p a ncreatic ne ur o e n d ocri ne t u m or 
e p N E T  
Ar m D: S oft tiss ue sarc o ma 
S T S  
 
P R E S E N TI N G O R D E R  
All listi n gs will b e or dere d b y t he f oll o wi n g ( u nless ot her wis e i n dicate d i n t he te m plate): 
 
Site P atie nt I D,  
 
Treat me nt gr o u p, i n t he or der as a b o ve ta ble, 
 
date ( w here a p plica ble) 
All ta bles c o ntai ni n g c o de d ter ms ( C M, M H, A E, etc), c o de d rec or ds will be s orte d i n desce n di n g or der of 
i nci de nce. 
 
A P P E N DI X 2.  A D V E R S E E V E N T S O F S P E CI A L IN T E R E S T   
A E SI S M Q 
P T T er m 
P T C o d e 
Ac ute re nal 
fail ure 
Ac ute ki d ne y i nj ur y 
Ac ute p h os p hate ne p hr o pat h y  
A n uria  
Az otae mia  
C o nti n u o us hae m o diafiltrati o n 
Dial ysis  
F oetal re nal i m pair me nt  
Hae m o dial ysis  
Hae m ofiltrati o n 
1 0 0 6 9 3 3 9 
1 0 0 6 9 6 8 8 
1 0 0 0 2 8 4 7 
1 0 0 0 3 8 8 5 
1 0 0 6 6 3 3 8 
1 0 0 6 1 1 0 5 
1 0 0 7 8 9 8 7 
1 0 0 1 8 8 7 5 
1 0 0 5 3 0 9 0 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 2 of 7 0 
 
Ne o natal a n uria 
Ne p hr o pat h y t o xic  
Oli g uria  
P erit o neal dial ysis  
Prere nal fail ure  
Re nal fail ure  
Re nal fail ure ne o natal  
Re nal i m pair me nt  
Re nal i m pair me nt ne o natal  
S u bac ute ki d ne y i nj ur y 
1 0 0 4 9 7 7 8 
1 0 0 2 9 1 5 5 
1 0 0 3 0 3 0 2 
1 0 0 3 4 6 6 0 
1 0 0 7 2 3 7 0 
1 0 0 3 8 4 3 5 
1 0 0 3 8 4 4 7 
1 0 0 6 2 2 3 7 
1 0 0 4 9 7 7 6 
1 0 0 8 1 9 8 0 
Hae m orr ha ges A b d o mi nal wall hae mat o ma 
A b d o mi nal wall hae m orr ha ge  
A b n or mal wit h dra wal blee di n g  
Ac he n bac h s y n dr o me  
Ac ute hae m orr ha gic le u k oe nc e p halitis  
Ac ute hae m orr ha gic ulcerati ve c olitis  
A d mi nistrati o n site br uise  
A d mi nistrati o n site hae mat o ma  
A d mi nistrati o n site hae m orr ha ge  
A dre nal hae mat o ma  
A dre nal hae m orr ha ge  
A nal f iss ure hae m orr ha ge 
A nal hae m orr ha ge  
A nal ulcer hae m orr ha ge  
A nast o m otic hae m orr ha ge  
A nast o m otic ulcer hae m orr ha ge  
A ne ur ys m r u pt ure d  
A n gi na b ull osa hae m orr ha gica  
A n orectal varices hae m orr ha ge  
A ntic oa g ula nt -relate d ne p hr o p at h y 
A ortic a ne ur ys m r u pt ure  
A ortic dissecti o n r u pt ure 
A ortic i ntra m ural hae mat o ma  
A ortic perf orati o n  
A ortic r u pt ure  
A p o ne ur osis c o nt usi o n  
A p plicati o n site br uise  
A p plicati o n site hae mat o ma  
A p plicati o n site hae m orr ha ge  
A p plicati o n site p ur p ura  
Arterial hae m orr ha ge  
Arterial i ntra m ural hae mat o ma 
Arterial perf orati o n  
Arterial r u pt ure  
Arteri o ve n o us fist ula site hae mat o ma  
Arteri o ve n o us fist ula site hae m orr ha ge  
Arteri o ve n o us graft site hae mat o ma 
1 0 0 6 7 3 8 3 
1 0 0 6 7 7 8 8 
1 0 0 6 9 1 9 5 
1 0 0 7 9 5 6 2 
1 0 0 5 8 9 9 4 
1 0 0 7 5 6 3 4 
1 0 0 7 5 0 9 4 
1 0 0 7 5 1 0 0 
1 0 0 7 5 1 0 1 
1 0 0 5 9 1 9 4 
1 0 0 0 1 3 6 1 
1 0 0 7 9 7 6 5 
1 0 0 4 9 5 5 5 
1 0 0 6 3 8 9 6 
1 0 0 5 6 3 4 6 
1 0 0 0 2 2 4 4 
1 0 0 4 8 3 8 0 
1 0 0 6 4 2 2 3 
1 0 0 6 8 9 2 5 
1 0 0 8 3 3 4 6 
1 0 0 0 2 8 8 6 
1 0 0 6 8 1 1 9 
1 0 0 6 7 9 7 5 
1 0 0 7 5 7 2 9 
1 0 0 6 0 8 7 4 
1 0 0 7 5 3 3 0 
1 0 0 5 0 1 1 4 
1 0 0 6 8 3 1 7 
1 0 0 7 2 6 9 4 
1 0 0 5 0 1 8 2 
1 0 0 6 0 9 6 4 
1 0 0 7 4 9 7 1 
1 0 0 7 5 7 3 2 
1 0 0 0 3 1 7 3 
1 0 0 5 5 1 5 0 
1 0 0 5 5 1 2 3 
1 0 0 5 5 1 5 2 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 3 of 7 0 
 
Arteri o ve n o us graft site hae m orr ha ge 
Astri n ge nt t hera p y  
Atrial r u pt ure  
A uric ular hae mat o ma  
B asal ga n glia  hae mat o ma 
B asal ga n glia hae m orr ha ge  
B asilar arter y perf orati o n  
Bla d der ta m p o na d e  
Blee di n g varic ose vei n  
Bl o o d blister  
Bl o o d l oss a nae mia  
Bl o o d uri ne  
Bl o o d uri ne prese nt  
Bl o o d y disc har ge  
Bl o o d y perit o neal effl ue nt  
B o ne c o nt usi o n  
B o ne marr o w hae m orr ha ge  
Brai n c o nt usi o n  
Brai n ste m hae mat o ma  
Brai n ste m hae m orr ha ge  
Brai n ste m micr o hae m orr ha ge  
Breast hae mat o ma  
Breast hae m orr ha ge  
Br oa d li ga me nt hae mat o ma  
Br o nc hial hae m orr ha ge  
Br o nc hial varices hae m orr ha ge  
B ull o us hae m orr ha gic der mat osis  
B ursal hae mat o ma  
Car dia c c o nt usi o n 
Car oti d a ne ur ys m r u pt ure  
Car oti d arter y perf orati o n  
Cat heter site br uise  
Cat heter site hae mat o ma  
Cat heter site hae m orr ha ge  
Ce ntral ner v o us s yste m hae m orr ha ge  
Ce p hal hae mat o ma  
Cere b ellar hae mat o ma  
Cere b ellar hae m orr ha ge  
Cere b ellar micr o hae m orr ha ge 
Cere bral a ne ur ys m perf orati o n  
Cere bral a ne ur ys m r u pt ure d s y p hilitic  
Cere bral arteri o ve n o us malf or mati o n hae m orr ha gic  
Cere bral arter y perf orati o n  
Cere bral c yst hae m orr ha ge  
Cere bral hae mat o ma  
Cere bral hae m orr ha ge  
Cere bral hae m orr ha ge f oetal 
1 0 0 5 5 1 2 6 
1 0 0 6 7 3 7 2 
1 0 0 4 8 7 6 1 
1 0 0 0 3 7 9 7 
1 0 0 7 7 0 3 1 
1 0 0 6 7 0 5 7 
1 0 0 7 5 7 3 6 
1 0 0 6 2 6 5 6 
1 0 0 0 5 1 4 4 
1 0 0 0 5 3 7 2 
1 0 0 8 2 2 9 7 
1 0 0 0 5 8 6 3 
1 0 0 1 8 8 7 0 
1 0 0 5 7 6 8 7 
1 0 0 6 7 4 4 2 
1 0 0 6 6 2 5 1 
1 0 0 7 3 5 8 1 
1 0 0 5 2 3 4 6 
1 0 0 7 3 2 3 0 
1 0 0 0 6 1 4 5 
1 0 0 7 1 2 0 5 
1 0 0 6 4 7 5 3 
1 0 0 0 6 2 5 4 
1 0 0 0 6 3 7 5 
1 0 0 6 5 7 3 9 
1 0 0 7 9 1 6 3 
1 0 0 8 3 8 0 9 
1 0 0 7 7 8 1 8 
1 0 0 7 3 3 5 6 
1 0 0 5 1 3 2 8 
1 0 0 7 5 7 2 8 
1 0 0 6 3 5 8 7 
1 0 0 5 5 6 6 2 
1 0 0 5 1 0 9 9 
1 0 0 7 2 0 4 3 
1 0 0 0 8 0 1 4 
1 0 0 6 1 0 3 8 
1 0 0 0 8 0 3 0 
1 0 0 7 1 2 0 6 
1 0 0 7 5 3 9 4 
1 0 0 0 8 0 7 6 
1 0 0 0 8 0 8 6 
1 0 0 7 5 7 3 4 
1 0 0 8 2 0 9 9 
1 0 0 5 3 9 4 2 
1 0 0 0 8 1 1 1 
1 0 0 5 0 1 5 7 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 4 of 7 0 
 
Cere bral hae m orr ha ge ne o natal 
Cere bral micr o hae m orr ha ge  
Cer vi x hae mat o ma uteri ne  
Cer vi x hae m orr ha ge uteri ne  
C hest wall hae mat o ma  
C h or oi dal hae mat o ma  
C h or oi dal hae m orr ha ge  
C hr o nic gastr oi ntesti nal blee di n g  
C hr o nic pi g me nte d p ur p ura  
Ciliar y b o d y hae m orr ha ge  
C oital blee di n g  
C ol o nic hae mat o ma  
C o nj u ncti val hae m orr ha ge  
C o nt usi o n  
C or neal blee di n g  
C ulle n's si g n  
C ystitis hae m orr ha gic  
Dee p dissecti n g hae mat o ma  
Diarr h oea hae m orr ha gic  
Disse mi nate d i ntra vasc ular c oa g ulati o n  
Di vertic ulitis i ntesti nal hae m orr ha gic  
Di vertic ul u m i ntesti nal hae m orr ha gic  
D u o de nal ulcer hae m orr ha ge  
D u o de nitis hae m orr ha gic  
D ysf u ncti o nal uteri ne blee di n g  
Ear hae m orr ha ge  
Ecc h y m osis  
E nce p halitis hae m orr ha gic  
E nter oc olitis hae m orr ha gic  
E pi d ural hae m orr ha ge  
E pista xis  
E xsa n g ui nati o n  
E xtra -a xial hae m orr ha ge 
E xtra d ural hae mat o ma  
E xtra d ural hae mat o ma e vac uati o n  
E xtra vasati o n bl o o d  
E ye c o nt usi o n  
E ye hae mat o ma  
E ye hae m orr ha ge  
E yeli d blee di n g  
E yeli d c o nt usi o n  
E yeli d hae mat o ma  
Fe m oral arter y perf orati o n  
Fe m oral vei n perf orati o n  
F oetal - mater nal hae m orr ha ge 
F ot her gill si g n p ositi ve  
Gastric hae m orr ha ge 
1 0 0 0 8 1 1 2 
1 0 0 6 7 2 7 7 
1 0 0 5 0 0 2 0 
1 0 0 5 0 0 2 2 
1 0 0 7 6 5 9 7 
1 0 0 6 8 6 4 2 
1 0 0 0 8 7 8 6 
1 0 0 5 0 3 9 9 
1 0 0 7 2 7 2 6 
1 0 0 5 7 4 1 7 
1 0 0 6 5 0 1 9 
1 0 0 0 9 9 9 6 
1 0 0 1 0 7 1 9 
1 0 0 5 0 5 8 4 
1 0 0 5 1 5 5 8 
1 0 0 5 9 0 2 9 
1 0 0 1 1 7 9 3 
1 0 0 7 4 7 1 8 
1 0 0 1 2 7 4 1 
1 0 0 1 3 4 4 2 
1 0 0 1 3 5 4 1 
1 0 0 1 3 5 6 0 
1 0 0 1 3 8 3 9 
1 0 0 1 3 8 6 5 
1 0 0 1 3 9 0 8 
1 0 0 1 4 0 0 9 
1 0 0 1 4 0 8 0 
1 0 0 1 4 5 8 9 
1 0 0 1 4 8 9 6 
1 0 0 7 3 6 8 1 
1 0 0 1 5 0 9 0 
1 0 0 1 5 7 1 9 
1 0 0 7 8 2 5 4 
1 0 0 1 5 7 6 9 
1 0 0 8 2 7 9 7 
1 0 0 1 5 8 6 7 
1 0 0 7 3 3 5 4 
1 0 0 7 9 8 9 1 
1 0 0 1 5 9 2 6 
1 0 0 5 3 1 9 6 
1 0 0 7 5 0 1 8 
1 0 0 6 4 9 7 6 
1 0 0 7 5 7 3 9 
1 0 0 7 5 7 4 5 
1 0 0 1 6 8 7 1 
1 0 0 8 1 7 4 9 
1 0 0 1 7 7 8 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 5 of 7 0 
 
Gastric ulcer hae m orr ha ge 
Gastric ulcer hae m orr ha ge, o bstr ucti ve  
Gastric varices hae m orr ha ge  
Gastritis alc o h olic hae m orr ha gic  
Gastritis hae m orr ha gic  
Gastr o d u o de nal hae m orr ha ge  
Gastr oi ntesti nal hae m or r ha ge 
Gastr oi ntesti nal p ol y p hae m orr ha ge  
Gastr oi ntesti nal ulcer hae m orr ha ge  
Gastr oi ntesti nal vasc ular malf or mati o n hae m orr ha gic  
Ge nital c o nt usi o n  
Ge nital hae m orr ha ge  
Gi n gi val blee di n g  
Graft hae m orr ha ge  
Gre y T ur ner's si g n  
Hae ma n gi o ma r u pt ure  
Hae mart hr osis  
Hae mate mesis  
Hae mat oc hezia  
Hae mat oc o ele  
Hae mat o ma  
Hae mat o ma e vac uati o n  
Hae mat o ma i nfecti o n  
Hae mat o ma m uscle  
Hae mat osal pi n x  
Hae mat os per mia  
Hae mat ot y m pa n u m  
Hae mat uria  
Hae mat uria tra u matic  
Hae m o bilia  
Hae m o perit o ne u m  
Hae m o p hilic art hr o pat h y  
Hae m o p hilic pse u d ot u m o ur 
Hae m o pt ysis  
Hae m orr ha ge  
Hae m orr ha ge c or o nar y arter y  
Hae m orr ha ge f oetal  
Hae m orr ha ge i n pre g na nc y  
Hae m orr ha ge i ntracra nial  
Hae m orr ha ge ne o natal  
Hae m orr ha ge s u bc uta ne o us  
Hae m orr ha ge s u be pi der mal  
Hae m orr ha ge uri nar y tract  
Hae m orr ha gic a dre nal i nfa rcti o n 
Hae m orr ha gic arteri o ve n o us malf or mati o n  
Hae m orr ha gic ascites  
Hae m orr ha gic breast c yst 
1 0 0 1 7 8 2 6 
1 0 0 1 7 8 2 9 
1 0 0 5 7 5 7 2 
1 0 0 1 7 8 5 7 
1 0 0 1 7 8 6 6 
1 0 0 5 3 7 6 8 
1 0 0 1 7 9 5 5 
1 0 0 7 4 4 3 7 
1 0 0 5 6 7 4 3 
1 0 0 8 0 5 6 1 
1 0 0 7 3 3 5 5 
1 0 0 6 1 1 7 8 
1 0 0 1 8 2 7 6 
1 0 0 6 3 5 7 7 
1 0 0 7 5 4 2 6 
1 0 0 8 4 0 4 0 
1 0 0 1 8 8 2 9 
1 0 0 1 8 8 3 0 
1 0 0 1 8 8 3 6 
1 0 0 1 8 8 3 3 
1 0 0 1 8 8 5 2 
1 0 0 6 0 7 3 3 
1 0 0 5 1 5 6 4 
1 0 0 5 5 8 9 0 
1 0 0 5 0 4 6 8 
1 0 0 1 8 8 6 6 
1 0 0 6 3 0 1 3 
1 0 0 1 8 8 6 7 
1 0 0 1 8 8 7 1 
1 0 0 5 8 9 4 7 
1 0 0 1 8 9 3 5 
1 0 0 6 5 0 5 7 
1 0 0 7 3 7 7 0 
1 0 0 1 8 9 6 4 
1 0 0 5 5 7 9 8 
1 0 0 5 5 8 0 3 
1 0 0 6 1 1 9 1 
1 0 0 1 8 9 8 1 
1 0 0 1 8 9 8 5 
1 0 0 6 1 9 9 3 
1 0 0 1 8 9 9 9 
1 0 0 1 9 0 0 1 
1 0 0 5 5 8 4 7 
1 0 0 7 9 9 0 2 
1 0 0 6 4 5 9 5 
1 0 0 5 9 7 6 6 
1 0 0 7 7 4 4 3 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 6 of 7 0 
 
Hae m orr ha gic cere bral i nfarcti o n 
Hae m orr ha gic c yst  
Hae m orr ha gic diat hesis  
Hae m orr ha gic disease of ne w b or n  
Hae m orr ha gic dis or der  
Hae m orr ha gic er osi ve gastritis  
Hae m orr ha gic he p atic c yst  
Hae m orr ha gic i nfarcti o n  
Hae m orr ha gic necr otic pa ncre atitis  
Hae m orr ha gic o varia n c yst  
Hae m orr ha gic str o ke  
Hae m orr ha gic t h yr oi d c yst  
Hae m orr ha gic tra nsf or mati o n str o ke  
Hae m orr ha gic t u m o ur necr osis  
Hae m orr ha gic urticaria  
Hae m orr ha gic  vasc ulitis 
Hae m orr h oi dal hae m orr ha ge  
Hae m ostasis  
Hae m ot h ora x  
He n oc h - Sc h o nlei n p ur p ura 
He p atic hae ma n gi o ma r u pt ure  
He p atic hae mat o ma  
He p atic hae m orr ha ge  
Here ditar y hae m orr ha gic tela n giectasia  
H y perfi bri n ol ysis  
H y p hae ma  
Iliac arter y perf orati o n 
Iliac arter y r u pt ure 
Iliac vei n perf orati o n 
I m m u ne t hr o m b oc yt o pe nia 
I m pla nt site br uisi n g 
I m pla nt site hae mat o ma 
I m pla nt site hae m orr ha ge 
I ncisi o n site hae mat o ma 
I ncisi o n site hae m orr ha ge 
I ncrease d te n de nc y t o br uise 
I n d uce d a b orti o n hae m orr ha ge 
I nferi or ve na ca va perf orati o n 
I nf usi o n site br uisi n g 
I nf usi o n site hae mat o ma 
I nf usi o n site hae m orr ha ge 
I nj ecti o n site br uisi n g 
I nj ecti o n site hae mat o ma 
I nj ecti o n site hae m orr ha ge 
I nstillati o n site br uise 
I nstillati o n site hae mat o ma 
I nstillati o n site hae m orr ha ge 
1 0 0 1 9 0 0 5 
1 0 0 5 9 1 8 9 
1 0 0 6 2 7 1 3 
1 0 0 1 9 0 0 8 
1 0 0 1 9 0 0 9 
1 0 0 6 7 7 8 6 
1 0 0 6 7 7 9 6 
1 0 0 1 9 0 1 3 
1 0 0 7 6 0 5 8 
1 0 0 6 0 7 8 1 
1 0 0 1 9 0 1 6 
1 0 0 7 2 2 5 6 
1 0 0 5 5 6 7 7 
1 0 0 5 4 0 9 6 
1 0 0 5 9 4 9 9 
1 0 0 7 1 2 5 2 
1 0 0 5 4 7 8 7 
1 0 0 6 7 4 3 9 
1 0 0 1 9 0 2 7 
1 0 0 1 9 6 1 7 
1 0 0 5 4 8 8 5 
1 0 0 1 9 6 7 6 
1 0 0 1 9 6 7 7 
1 0 0 1 9 8 8 3 
1 0 0 7 4 7 3 7 
1 0 0 2 0 9 2 3 
1 0 0 7 5 7 3 1 
1 0 0 7 2 7 8 9 
1 0 0 7 5 7 4 4 
1 0 0 8 3 8 4 2 
1 0 0 6 3 8 5 0 
1 0 0 6 3 7 8 0 
1 0 0 5 3 9 9 5 
1 0 0 5 9 2 4 1 
1 0 0 5 1 1 0 0 
1 0 0 2 1 6 8 8 
1 0 0 5 2 8 4 4 
1 0 0 7 5 7 4 2 
1 0 0 5 9 2 0 3 
1 0 0 6 5 4 6 3 
1 0 0 6 5 4 6 4 
1 0 0 2 2 0 5 2 
1 0 0 2 2 0 6 6 
1 0 0 2 2 0 6 7 
1 0 0 7 3 6 3 0 
1 0 0 7 3 6 0 9 
1 0 0 7 3 6 1 0 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 7 of 7 0 
 
I nter nal hae m orr ha ge 
I ntesti nal hae mat o ma 
I ntesti nal hae m orr ha ge 
I ntesti nal varices hae m orr ha ge 
I ntra-a b d o mi nal hae mat o ma 
I ntra-a b d o mi nal hae m orr ha ge 
I ntracere bral hae mat o ma e vac uati o n 
I ntracra nial hae mat o ma 
I ntracra nial t u m o ur hae m orr ha ge 
I ntra o c ular hae mat o ma 
I ntra p art u m hae m orr ha ge 
I ntra ve ntric ular hae m orr ha ge 
I ntra ve ntric ular hae m orr ha ge ne o natal 
Iris hae m orr ha ge 
J oi nt micr o hae m orr ha ge 
Ki d ne y c o nt usi o n  
Lacri mal hae m orr ha ge  
Lar ge i ntesti nal hae m orr ha ge  
Lar ge i ntesti nal ulcer hae m orr ha ge  
Lar y n geal hae mat o ma  
Lar y n geal hae m orr ha ge 
Li p hae mat o ma  
Li p hae m orr ha ge  
Li ver c o nt usi o n  
L o wer gastr oi ntesti nal hae m orr ha ge  
L o wer li m b arter y perf orati o n  
L y m p h n o de hae m orr ha ge  
Mall or y - W eiss s y n dr o me 
Me diasti nal hae mat o ma  
Me diasti nal hae m orr ha ge  
Me dical de vice site br uise  
Me dical  de vice site hae mat o ma 
Me dical de vice site hae m orr ha ge  
Melae na  
Melae na ne o natal  
Me ni n g orr ha gia  
Me n o metr orr ha gia  
Me n orr ha gia  
Mese nteric hae mat o ma  
Mese nteric hae m orr ha ge  
Metr orr ha gia  
M o ut h hae m orr ha ge  
M uc o c uta ne o us hae m orr ha ge  
M uc osal hae m orr ha ge  
M uscle c o nt usi o n 
M uscle hae m orr ha ge  
M y ocar dial hae m orr ha ge 
1 0 0 7 5 1 9 2 
1 0 0 6 9 8 2 9 
1 0 0 5 9 1 7 5 
1 0 0 7 8 0 5 8 
1 0 0 5 6 4 5 7 
1 0 0 6 1 2 4 9 
1 0 0 6 2 0 2 5 
1 0 0 5 9 4 9 1 
1 0 0 2 2 7 7 5 
1 0 0 7 1 9 3 4 
1 0 0 6 7 7 0 3 
1 0 0 2 2 8 4 0 
1 0 0 2 2 8 4 1 
1 0 0 5 7 4 1 8 
1 0 0 7 7 6 6 6 
1 0 0 2 3 4 1 3 
1 0 0 6 9 9 3 0 
1 0 0 5 2 5 3 4 
1 0 0 6 1 2 6 2 
1 0 0 7 0 8 8 5 
1 0 0 6 5 7 4 0 
1 0 0 6 6 3 0 4 
1 0 0 4 9 2 9 7 
1 0 0 6 7 2 6 6 
1 0 0 5 0 9 5 3 
1 0 0 7 5 7 3 0 
1 0 0 7 4 2 7 0 
1 0 0 2 6 7 1 2 
1 0 0 4 9 9 4 1 
1 0 0 5 6 3 4 3 
1 0 0 7 5 5 7 0 
1 0 0 7 5 5 7 7 
1 0 0 7 5 5 7 8 
1 0 0 2 7 1 4 1 
1 0 0 4 9 7 7 7 
1 0 0 5 2 5 9 3 
1 0 0 2 7 2 9 5 
1 0 0 2 7 3 1 3 
1 0 0 7 1 5 5 7 
1 0 0 6 0 7 1 7 
1 0 0 2 7 5 1 4 
1 0 0 2 8 0 2 4 
1 0 0 7 6 0 4 8 
1 0 0 6 1 2 9 8 
1 0 0 7 0 7 5 7 
1 0 0 2 8 3 0 9 
1 0 0 4 8 8 4 9 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 8 of 7 0 
 
M y ocar dial r u pt ure 
Nae v us hae m orr ha ge  
Nail be d blee di n g  
Nasal se pt u m hae mat o ma  
Ne o natal gastr oi ntesti nal hae m orr ha ge  
Ne p hritis hae m orr ha gic  
Ni p ple e x u date bl o o d y  
Oc ular retr o b ul bar hae m orr ha ge  
Oes o p ha geal  hae m orr ha ge 
Oes o p ha geal i ntra m ural hae mat o ma  
Oes o p ha geal ulcer hae m orr ha ge  
Oes o p ha geal varices hae m orr ha ge  
Oes o p ha gitis hae m orr ha gic  
O ptic disc hae m orr ha ge  
O ptic ner ve s heat h hae m orr ha ge  
Oral bl o o d blister  
Oral c o nt usi o n  
Oral m uc osa hae mat o ma  
Oral p ur p ura  
Or bital hae mat o ma  
Or bital hae m orr ha ge  
Oste orr ha gia  
O varia n hae mat o ma  
O varia n hae m orr ha ge  
P al pa ble p ur p ura  
P a ncreatic hae m orr ha ge  
P a ncreatic pse u d oc yst hae m orr ha ge  
P a ncreatitis hae m orr ha gic  
P a pillar y m uscle hae m orr ha ge  
P ara nasal si n us hae mat o ma  
P ara nasal s i n us hae m orr ha ge 
Parat h yr oi d hae m orr ha ge  
P ar oti d gla n d hae m orr ha ge  
P el vic hae mat o ma  
P el vic hae mat o ma o bstetric  
P el vic hae m orr ha ge  
P e nile c o nt usi o n  
P e nile hae mat o ma  
P e nile hae m orr ha ge  
P e ptic ulcer hae m orr ha ge  
P ericar dial hae m orr ha ge  
P eri neal hae mat o ma  
P eri or bital hae mat o ma  
P eri or bital hae m orr ha ge  
P eri osteal hae mat o ma  
Peri part u m hae m orr ha ge  
P eri p heral arter y a ne ur ys m r u pt ure 
1 0 0 2 8 6 0 4 
1 0 0 6 2 9 5 5 
1 0 0 4 8 8 9 1 
1 0 0 7 5 0 2 7 
1 0 0 7 4 1 5 9 
1 0 0 2 9 1 3 2 
1 0 0 2 9 4 1 8 
1 0 0 5 7 5 7 1 
1 0 0 3 0 1 7 2 
1 0 0 7 7 4 8 6 
1 0 0 3 0 2 0 2 
1 0 0 3 0 2 1 0 
1 0 0 3 0 2 1 9 
1 0 0 3 0 9 1 9 
1 0 0 3 0 9 4 1 
1 0 0 7 6 5 9 0 
1 0 0 7 8 1 7 0 
1 0 0 7 4 7 7 9 
1 0 0 8 3 5 3 3 
1 0 0 8 3 5 6 5 
1 0 0 3 1 0 4 5 
1 0 0 5 1 9 3 7 
1 0 0 3 3 2 6 3 
1 0 0 6 5 7 4 1 
1 0 0 5 6 8 7 2 
1 0 0 3 3 6 2 5 
1 0 0 8 3 8 1 3 
1 0 0 3 3 6 5 0 
1 0 0 5 9 1 6 4 
1 0 0 6 9 7 0 2 
1 0 0 8 0 1 0 8 
1 0 0 5 9 0 5 1 
1 0 0 5 1 1 6 6 
1 0 0 5 4 9 7 4 
1 0 0 3 4 2 4 8 
1 0 0 6 3 6 7 8 
1 0 0 7 3 3 5 2 
1 0 0 7 0 6 5 6 
1 0 0 3 4 3 0 5 
1 0 0 3 4 3 4 4 
1 0 0 3 4 4 7 6 
1 0 0 3 4 5 2 0 
1 0 0 3 4 5 4 4 
1 0 0 7 1 6 9 7 
1 0 0 7 7 3 4 1 
1 0 0 7 2 6 9 3 
1 0 0 7 9 9 0 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 9 of 7 0 
 
P eri p heral arter y hae mat o ma 
P erit o neal hae mat o ma  
P eri ve ntric ular hae m orr ha ge ne o natal  
P etec hiae  
P har y n geal c o nt usi o n  
P har y n geal hae mat o ma 
P har y n geal hae m orr ha ge  
Pit uitar y a p o ple x y  
Pit uitar y hae m orr ha ge  
Place nta prae via hae m orr ha ge  
P ol y me n orr ha gia  
P ost a b orti o n hae m orr ha ge  
P ost pr oce d ural c o nt usi o n  
P ost pr oce d ural hae mat o ma  
P ost pr oce d ural hae mat uria  
P ost pr oce d ural hae m orr ha ge  
P ost tr a nsf usi o n p ur p ura 
P ost me n o pa usal hae m orr ha ge  
P ost part u m hae m orr ha ge  
P ost -tra u matic p u nctate i ntrae pi der mal hae m orr ha ge 
Pre mat ure se p arati o n of place nta  
Pr oce d ural hae m orr ha ge  
Pr octitis hae m orr ha gic  
Pr ostatic hae m orr ha ge  
P ul m o nar y al ve olar hae m orr ha ge  
P ul m o nar y c o nt usi o n  
P ul m o nar y hae mat o ma  
P ul m o nar y hae m orr ha ge  
P ul m o nar y hae m orr ha ge ne o natal  
P u nct ure site br uise  
P u nct ure site hae mat o ma  
P u nct ure site hae m orr ha ge  
P ur p ura  
P ur p ura f ul mi na ns  
P ur p ura ne o natal  
P ur p ura n o n -t hr o m b oc yt o pe ni c 
P ur p ura se nile  
P uta m e n hae m orr ha ge 
Ra diati o n ass ociate d hae m orr ha ge  
Rectal hae m orr ha ge  
Rectal ulcer hae m orr ha ge  
Re nal arter y perf orati o n  
Re nal c yst hae m orr ha ge  
Re nal hae mat o ma  
Re nal hae m orr ha ge  
Res pirat or y tract hae m orr ha ge  
Res pirat or y tract hae m orr ha ge ne o natal 
1 0 0 8 1 0 7 7 
1 0 0 5 8 0 9 5 
1 0 0 7 6 7 0 6 
1 0 0 3 4 7 5 4 
1 0 0 8 3 1 7 6 
1 0 0 6 8 1 2 1 
1 0 0 3 4 8 2 7 
1 0 0 5 6 4 4 7 
1 0 0 4 9 7 6 0 
1 0 0 3 5 1 2 1 
1 0 0 6 4 0 5 0 
1 0 0 3 6 2 4 6 
1 0 0 7 3 3 5 3 
1 0 0 6 3 1 8 8 
1 0 0 6 6 2 2 5 
1 0 0 5 1 0 7 7 
1 0 0 7 2 2 6 5 
1 0 0 5 5 8 7 0 
1 0 0 3 6 4 1 7 
1 0 0 7 1 6 3 9 
1 0 0 3 6 6 0 8 
1 0 0 7 1 2 2 9 
1 0 0 3 6 7 7 8 
1 0 0 3 6 9 6 0 
1 0 0 3 7 3 1 3 
1 0 0 3 7 3 7 0 
1 0 0 5 4 9 9 1 
1 0 0 3 7 3 9 4 
1 0 0 8 2 1 9 4 
1 0 0 8 2 0 3 5 
1 0 0 8 1 9 5 7 
1 0 0 5 1 1 0 1 
1 0 0 3 7 5 4 9 
1 0 0 3 7 5 5 6 
1 0 0 3 7 5 5 7 
1 0 0 5 7 7 3 9 
1 0 0 3 7 5 6 0 
1 0 0 5 8 9 4 0 
1 0 0 7 2 2 8 1 
1 0 0 3 8 0 6 3 
1 0 0 3 8 0 8 1 
1 0 0 7 5 7 3 7 
1 0 0 5 9 8 4 6 
1 0 0 3 8 4 5 9 
1 0 0 3 8 4 6 0 
1 0 0 3 8 7 2 7 
1 0 0 3 8 7 2 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 0 of 7 0 
 
Reti nal a ne ur ys m r u pt ure 
Reti nal hae m orr ha ge  
Reti n o pat h y hae m orr ha gic  
Retr o perit o neal hae mat o ma  
Retr o perit o neal hae m orr ha ge  
Retr o place ntal hae mat o ma  
R u pt ure d cere bral a ne ur ys m  
Scleral hae m orr ha ge  
Scr otal hae mat oc o ele  
Scr otal hae mat o ma  
Scr otal hae m orr ha ge  
S h oc k hae m orr ha gic 
S ki n hae m orr ha ge  
S ki n ne o plas m blee di n g  
S ki n ulcer hae m orr ha ge  
S mall i ntesti nal hae m orr ha ge  
S mall i ntesti nal ulcer hae m orr ha ge  
S oft tiss ue hae m orr ha ge  
S per matic c or d hae m orr ha ge  
S pi nal c or d hae mat o ma  
S pi nal c or d hae m orr ha ge  
S pi nal e pi d ural hae mat o ma 
S pi nal e pi d ural hae m orr ha ge  
S pi nal s u barac h n oi d hae m orr ha ge  
S pi nal s u b d ural hae mat o ma  
S pi nal s u b d ural hae m orr ha ge  
S plee n c o nt usi o n  
S ple nic arter y perf orati o n  
S ple nic hae mat o ma  
S ple nic hae m orr ha ge  
S ple nic varices hae m orr ha ge  
S pli nter hae m orr ha ges  
S p o nta ne o us hae mat o ma  
S p o nta ne o us hae m orr ha ge  
St o ma site hae m orr ha ge  
St o matitis hae m orr ha gic  
S u barac h n oi d hae mat o ma  
S u barac h n oi d hae m orr ha ge  
S u barac h n oi d hae m orr ha ge ne o natal  
S u bca ps ular he p atic hae mat o ma  
S u bca ps ular re nal hae mat o ma  
S u bca ps ular s ple nic hae mat o ma 
S u bc h ori o nic hae mat o ma  
S u bc h ori o nic hae m orr ha ge  
S u bcla via n arter y perf orati o n  
S u bcla via n vei n perf orati o n  
S u bc uta ne o us hae mat o ma 
1 0 0 7 9 1 2 1 
1 0 0 3 8 8 6 7 
1 0 0 5 1 4 4 7 
1 0 0 5 8 3 6 0 
1 0 0 3 8 9 8 0 
1 0 0 5 4 7 9 8 
1 0 0 3 9 3 3 0 
1 0 0 5 0 5 0 8 
1 0 0 6 1 5 1 7 
1 0 0 3 9 7 4 9 
1 0 0 6 1 3 6 1 
1 0 0 4 9 7 7 1 
1 0 0 6 4 2 6 5 
1 0 0 6 0 7 1 2 
1 0 0 5 0 3 7 7 
1 0 0 5 2 5 3 5 
1 0 0 6 1 5 5 0 
1 0 0 5 1 2 9 7 
1 0 0 6 5 7 4 2 
1 0 0 7 6 0 5 1 
1 0 0 4 8 9 9 2 
1 0 0 5 0 1 6 2 
1 0 0 4 9 2 3 6 
1 0 0 7 3 5 6 4 
1 0 0 5 0 1 6 4 
1 0 0 7 3 5 6 3 
1 0 0 7 3 5 3 3 
1 0 0 7 5 7 3 8 
1 0 0 4 1 6 4 6 
1 0 0 4 1 6 4 7 
1 0 0 6 8 6 6 2 
1 0 0 4 1 6 6 3 
1 0 0 6 5 3 0 4 
1 0 0 7 4 5 5 7 
1 0 0 7 4 5 0 8 
1 0 0 4 2 1 3 2 
1 0 0 7 6 7 0 1 
1 0 0 4 2 3 1 6 
1 0 0 4 2 3 1 7 
1 0 0 8 3 3 8 3 
1 0 0 8 3 3 8 5 
1 0 0 8 3 3 8 4 
1 0 0 7 2 5 9 6 
1 0 0 7 1 0 1 0 
1 0 0 7 5 7 4 0 
1 0 0 7 5 7 4 3 
1 0 0 4 2 3 4 5 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 1 of 7 0 
 
S u b d ural hae mat o ma 
S u b d ural hae mat o ma e vac uati o n  
S u b d ural hae m orr ha ge  
S u b d ural hae m orr ha ge ne o nat al  
S u be n d ocar dial hae m o rr ha ge 
S u b galeal hae mat o ma  
S u b galeal hae m orr ha ge  
S u breti nal hae mat o ma  
S u peri or ve na ca va perf orati o n  
T estic ular hae m orr ha ge  
T hala m us hae m orr ha ge  
T hir d sta ge p ost part u m hae m orr ha ge  
T h oracic hae m orr ha ge  
T hr o m b oc yt o pe nic p ur p ura  
T hr o m b otic t hr o m b oc yt o pe nic p ur p ura 
T h yr oi d hae m orr ha ge  
T o n g ue hae mat o ma  
T o n g ue hae m orr ha ge  
T o nsillar hae m orr ha ge  
T o ot h p ul p hae m orr ha ge  
T o ot h s oc ket hae m orr ha ge  
Trac heal hae m orr ha ge  
Tra u matic hae mat o ma  
Tra u matic hae m orr ha ge  
Tra u matic hae m ot h ora x  
Tra u matic i ntracra nial hae mat o ma  
Tra u matic i ntracra nial hae m orr ha ge 
T u m o ur hae m orr ha ge  
Ulcer hae m orr ha ge  
U m bilical c or d hae m orr ha ge  
U m bilical hae mat o ma  
U m bilical hae m orr ha ge  
U p per gastr oi ntesti nal hae m orr ha ge  
Ureteric hae m orr ha ge  
Uret hral hae m orr ha ge  
Uri nar y bla d der hae mat o ma  
Uri nar y bla d der hae m orr ha ge 
Ur o ge nital hae m orr ha ge  
Uteri ne hae mat o ma  
Uteri ne hae m orr ha ge  
Vacci nati o n site br uisi n g  
Vacci nati o n site hae mat o ma  
Vacci nati o n site hae m orr ha ge  
Va gi nal hae mat o ma  
Va gi nal hae m orr ha ge  
Varic ose vei n r u pt ure d  
Vasc ular access site br uisi n g 
1 0 0 4 2 3 6 1 
1 0 0 4 2 3 6 3 
1 0 0 4 2 3 6 4 
1 0 0 4 2 3 6 5 
1 0 0 8 2 4 5 9 
1 0 0 6 9 5 1 0 
1 0 0 8 0 9 0 0 
1 0 0 7 1 9 3 5 
1 0 0 7 5 7 4 1 
1 0 0 5 1 8 7 7 
1 0 0 5 8 9 3 9 
1 0 0 4 3 4 4 9 
1 0 0 6 2 7 4 4 
1 0 0 4 3 5 6 1 
1 0 0 4 3 6 4 8 
1 0 0 6 4 2 2 4 
1 0 0 4 3 9 5 9 
1 0 0 4 9 8 7 0 
1 0 0 5 7 4 5 0 
1 0 0 7 2 2 2 8 
1 0 0 6 4 9 4 6 
1 0 0 6 2 5 4 3 
1 0 0 4 4 5 2 2 
1 0 0 5 3 4 7 6 
1 0 0 7 4 4 8 7 
1 0 0 7 9 0 1 3 
1 0 0 6 1 3 8 7 
1 0 0 4 9 7 5 0 
1 0 0 6 1 5 7 7 
1 0 0 6 4 5 3 4 
1 0 0 6 8 7 1 2 
1 0 0 4 5 4 5 5 
1 0 0 4 6 2 7 4 
1 0 0 6 5 7 4 3 
1 0 0 4 9 7 1 0 
1 0 0 8 3 3 5 8 
1 0 0 4 6 5 2 8 
1 0 0 5 0 0 5 8 
1 0 0 6 3 8 7 5 
1 0 0 4 6 7 8 8 
1 0 0 6 9 4 8 4 
1 0 0 6 9 4 7 2 
1 0 0 6 9 4 7 5 
1 0 0 4 6 9 0 9 
1 0 0 4 6 9 1 0 
1 0 0 4 6 9 9 9 
1 0 0 7 7 7 6 7 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 2 of 7 0 
 
Vasc ular access site hae mat o ma 
Vasc ular access site hae m orr ha ge  
Vasc ular access site r u pt ure  
Vasc ular a nast o m otic hae m orr ha ge  
Vasc ular graft hae m orr ha ge  
Vasc ular pse u d oa ne ur ys m r u pt ure d  
Vasc ular p ur p ura  
Vasc ular r u pt ure  
Vei n r u pt ure  
Ve n o us hae m orr ha ge  
Ve n o us perf ora ti o n 
Ve ntricle r u pt ure  
Verte bral arter y perf orati o n  
Vessel p u nct ure site br uise  
Vessel p u nct ure site hae mat o ma  
Vessel p u nct ure site hae m orr ha ge  
Vitre o us hae mat o ma  
Vitre o us hae m orr ha ge  
V ul val hae mat o ma  
V ul val hae mat o ma e vac uati o n  
V ul val hae m orr ha ge  
Wit h dra wal blee d  
W o u n d hae mat o ma  
W o u n d hae m orr ha ge 
1 0 0 7 7 6 4 7 
1 0 0 7 7 6 4 3 
1 0 0 7 7 6 5 2 
1 0 0 8 4 0 9 2 
1 0 0 7 7 7 2 1 
1 0 0 5 3 9 4 9 
1 0 0 4 7 0 9 7 
1 0 0 5 3 6 4 9 
1 0 0 7 7 1 1 0 
1 0 0 6 5 4 4 1 
1 0 0 7 5 7 3 3 
1 0 0 4 7 2 7 9 
1 0 0 7 5 7 3 5 
1 0 0 6 3 8 8 1 
1 0 0 6 5 9 0 2 
1 0 0 5 4 0 9 2 
1 0 0 7 1 9 3 6 
1 0 0 4 7 6 5 5 
1 0 0 4 7 7 5 6 
1 0 0 4 7 7 5 7 
1 0 0 6 3 8 1 6 
1 0 0 4 7 9 9 8 
1 0 0 7 1 5 0 4 
1 0 0 5 1 3 7 3 
C h olestasis a n d 
j a u n dice of 
he p atic ori gi n 
Bilir u bi n e xcreti o n dis or der 
C h olae mia  
C h olestasis  
C h olestatic li ver i nj ur y  
C h olestatic pr urit us  
Dr u g -i n d uce d li ver i nj ur y 
He p atitis c h olestatic  
H y per bilir u bi nae mia  
Icter us i n de x i ncrease d 
J a u n dice 
J a u n dice c h olestatic 
J a u n dice he p at ocell ular 
Mi xe d li ver i nj ur y  
Oc ular icter us  
P are nteral n utriti o n ass ociate d li ver disease 
1 0 0 6 1 0 0 9 
1 0 0 4 8 6 1 1 
1 0 0 0 8 6 3 5 
1 0 0 6 7 9 6 9 
1 0 0 6 4 1 9 0 
1 0 0 7 2 2 6 8 
1 0 0 1 9 7 5 4 
1 0 0 2 0 5 7 8 
1 0 0 2 1 2 0 9 
1 0 0 2 3 1 2 6 
1 0 0 2 3 1 2 9 
1 0 0 2 3 1 3 6 
1 0 0 6 6 7 5 8 
1 0 0 5 8 1 1 7 
1 0 0 7 4 1 5 1 
He p atic fail ure, 
fi br osis a n d 
cirr h osis a n d 
ot her li ver 
da ma ge -relate d 
c o n diti o ns 
Ac q uire d he p at ocere bral de ge nerati o n 
Ac ute he p atic fail ure 
Ac ute o n c hr o nic li ver fail ure  
Ac ute yell o w li ver atr o p h y  
Ascites  
Asteri xis  
B acterascites  
Biliar y cirr h osis 
1 0 0 8 0 8 6 0 
1 0 0 0 0 8 0 4 
1 0 0 7 7 3 0 5 
1 0 0 7 0 8 1 5 
1 0 0 0 3 4 4 5 
1 0 0 0 3 5 4 7 
1 0 0 6 8 5 4 7 
1 0 0 0 4 6 5 9 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 3 of 7 0 
 
Biliar y fi br osis 
Car di o he p atic s y n dr o me  
C h olestatic li ver i nj ur y  
C hr o nic he p atic fail ure  
C o ma he p atic  
Cr y pt o ge nic cirr h osis  
Dia b etic  he p at o pat h y 
Dr u g -i n d uce d li ver i nj ur y 
D u o de nal varices  
Gall bla d der varices  
Gastric variceal i nj ecti o n  
Gastric variceal li gati o n  
Gastric varices  
Gastric varices hae m orr ha ge  
Gastr o oes o p ha geal variceal ha e m orr ha ge pr o p h yla xis  
He p atect o m y  
He p atic atr o p h y  
He p a tic calcificati o n 
He p atic cirr h osis  
He p atic e nce p hal o pat h y  
He p atic e nce p hal o pat h y pr o p h yla xis  
He p atic fail ure  
He p atic fi br osis  
He p atic h y dr ot h ora x  
He p atic i nfiltrati o n e osi n o p hilic  
He p atic lesi o n  
He p atic necr osis  
He p atic steat o -fi br osis 
He p atic steat osis  
He p atitis f ul mi na nt  
He p at o biliar y disease  
He p at ocell ular f oa m y cell s y n dr o me  
He p at ocell ular i nj ur y  
He p at o p ul m o nar y s y n dr o me  
He p at ore nal fail ure  
He p at ore nal s y n dr o me  
He p at ot o xicit y  
I m m u ne- me diate d c h ola n gitis 
I m m u ne- me diate d he p atic dis or der 
I ntesti nal varices 
I ntesti nal varices hae m orr ha ge 
Li ver dial ysis  
Li ver dis or der  
Li ver i nj ur y  
Li ver o perati o n  
Li ver tra ns pla nt  
L u p oi d he p atic cirr h osis 
1 0 0 0 4 6 6 4 
1 0 0 8 2 4 8 0 
1 0 0 6 7 9 6 9 
1 0 0 5 7 5 7 3 
1 0 0 1 0 0 7 5 
1 0 0 6 3 0 7 5 
1 0 0 7 1 2 6 5 
1 0 0 7 2 2 6 8 
1 0 0 5 1 0 1 0 
1 0 0 7 2 3 1 9 
1 0 0 7 6 2 3 7 
1 0 0 7 6 2 3 8 
1 0 0 5 1 0 1 2 
1 0 0 5 7 5 7 2 
1 0 0 6 6 5 9 7 
1 0 0 6 1 9 9 7 
1 0 0 1 9 6 3 7 
1 0 0 6 5 2 7 4 
1 0 0 1 9 6 4 1 
1 0 0 1 9 6 6 0 
1 0 0 6 6 5 9 9 
1 0 0 1 9 6 6 3 
1 0 0 1 9 6 6 8 
1 0 0 6 7 3 6 5 
1 0 0 6 4 6 6 8 
1 0 0 6 1 9 9 8 
1 0 0 1 9 6 9 2 
1 0 0 7 7 2 1 5 
1 0 0 1 9 7 0 8 
1 0 0 1 9 7 7 2 
1 0 0 6 2 0 0 0 
1 0 0 5 3 2 4 4 
1 0 0 1 9 8 3 7 
1 0 0 5 2 2 7 4 
1 0 0 1 9 8 4 5 
1 0 0 1 9 8 4 6 
1 0 0 1 9 8 5 1 
1 0 0 8 3 4 0 6 
1 0 0 8 3 5 2 1 
1 0 0 7 1 5 0 2 
1 0 0 7 8 0 5 8 
1 0 0 7 6 6 4 0 
1 0 0 2 4 6 7 0 
1 0 0 6 7 1 2 5 
1 0 0 6 2 0 4 0 
1 0 0 2 4 7 1 4 
1 0 0 2 5 1 2 9 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 4 of 7 0 
 
Mi ni mal he p atic e nce p hal o pat h y 
Mi xe d li ver i nj ur y  
N o d ular re ge nerati ve h y per plasia  
N o nalc o h olic fatt y li ver diseas e  
N o n -alc o h olic steat o he p atitis 
N o n -cirr h otic p ortal h y perte nsi o n 
Oe d e ma d ue t o he p atic diseas e  
Oes o p ha geal varices hae m orr ha ge  
P eri pa ncreatic varices  
P ortal fi br osis  
P ortal h y perte nsi o n  
P ortal h y perte nsi ve c ol o pat h y  
P ortal h y perte nsi ve e nter o pat h y  
P ortal h y perte nsi ve gastr o pat h y 
P ortal vei n ca ver n o us tra nsf or mati o n  
P ortal vei n dilatati o n  
P ort o p ul m o nar y h y perte nsi o n  
Pri mar y biliar y c h ola n gitis  
Re ge nerati ve si der otic he p atic n o d ule  
Re nal a n d li ver tra ns pla nt  
Retr o gra d e p ortal vei n fl o w  
Re ye's s y n dr o me  
Re y n ol d' s s y n dr o me 
S ple nic varices  
S ple nic varices hae m orr ha ge  
Steat o he p atitis  
S u bac ute he p atic fail ure  
S u gi ura pr oce d ure  
Varices o es o p ha geal  
Varic ose vei ns of a b d o mi nal wall  
W hite ni p ple si g n 
1 0 0 7 6 2 0 4 
1 0 0 6 6 7 5 8 
1 0 0 5 1 0 8 1 
1 0 0 8 2 2 4 9 
1 0 0 5 3 2 1 9 
1 0 0 7 7 2 5 9 
1 0 0 4 9 6 3 1 
1 0 0 3 0 2 1 0 
1 0 0 7 3 2 1 5 
1 0 0 7 4 7 2 6 
1 0 0 3 6 2 0 0 
1 0 0 7 9 4 4 6 
1 0 0 6 8 9 2 3 
1 0 0 5 0 8 9 7 
1 0 0 7 3 9 7 9 
1 0 0 7 3 2 0 9 
1 0 0 6 7 2 8 1 
1 0 0 8 0 4 2 9 
1 0 0 8 0 6 7 9 
1 0 0 5 2 2 7 9 
1 0 0 6 7 3 3 8 
1 0 0 3 9 0 1 2 
1 0 0 7 0 9 5 3 
1 0 0 6 7 8 2 3 
1 0 0 6 8 6 6 2 
1 0 0 7 6 3 3 1 
1 0 0 5 6 9 5 6 
1 0 0 8 3 0 1 0 
1 0 0 5 6 0 9 1 
1 0 0 7 2 2 8 4 
1 0 0 7 8 4 3 8 
He p atitis, n o n-
i nfecti o us 
Ac ute graft vers us h ost diseas e i n li ver 
Aller gic he p atitis  
All oi m m u ne he p atitis  
A ut oi m m u ne he p atitis  
C hr o nic graft vers us h ost dise ase i n li ver  
C hr o nic he p atitis  
Graft vers us h ost disease i n li ver  
He p atitis  
He p atitis ac ute  
He p atitis c h olestatic  
He p atitis c hr o nic acti ve  
He p atitis c hr o nic persiste nt 
He p atitis f ul mi na nt  
He p atitis t o xic  
I m m u ne- me diate d he p atitis 
Isc hae mic he p atitis 
1 0 0 6 6 2 6 3 
1 0 0 7 1 1 9 8 
1 0 0 8 0 5 7 6 
1 0 0 0 3 8 2 7 
1 0 0 7 2 1 6 0 
1 0 0 0 8 9 0 9 
1 0 0 6 4 6 7 6 
1 0 0 1 9 7 1 7 
1 0 0 1 9 7 2 7 
1 0 0 1 9 7 5 4 
1 0 0 1 9 7 5 5 
1 0 0 1 9 7 5 9 
1 0 0 1 9 7 7 2 
1 0 0 1 9 7 9 5 
1 0 0 7 8 9 6 2 
1 0 0 2 3 0 2 5 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 5 of 7 0 
 
L u p us he p atitis 
N o n -alc o h olic steat o he p atitis 
Ra diati o n he p atitis  
Steat o he p atitis 
1 0 0 6 7 7 3 7 
1 0 0 5 3 2 1 9 
1 0 0 5 1 0 1 5 
1 0 0 7 6 3 3 1 
Li ver relate d 
i n vesti gati o ns, 
si g ns a n d 
s y m pt o ms 
Ala ni ne a mi n otra nsferase a b n or mal 
Ala ni ne a mi n otra nsferase i ncrease d  
A m m o nia a b n or mal  
A m m o nia i ncrease d 
Ascites  
As partate a mi n otra nsferase a b n or mal  
As partate a mi n otra nsferase i ncrease d  
A S T/ A L T rati o a b n or mal  
B acterascites  
Bile o ut p ut a b n or mal  
Bile o ut p ut d ecrease d  
Biliar y ascites  
Bilir u bi n c o nj u gate d a b n or mal  
Bilir u bi n c o nj u gate d i ncrease d  
Bilir u bi n uri ne prese nt  
Bi o ps y li ver a b n or mal  
Bl o o d bilir u bi n a b n or mal  
Bl o o d bilir u bi n i ncrease d  
Bl o o d bilir u bi n u nc o nj u gate d i ncrease d  
Br o m os ul p ht halei n test a b n or mal  
C hil d - P u g h- T urc otte sc ore a b n or mal 
C hil d - P u g h- T urc otte sc ore i ncrease d 
C o m p uterise d t o m o gra m li ver a b n or mal 
C o n gesti ve he p at o pat h y  
F oet or he p atic us  
Galact ose eli mi nati o n ca pacit y test a b n or mal  
Galact ose eli mi nati o n ca pacit y test decrease d  
Ga m ma - gl uta m yltra nsferase a b n or mal 
Ga m ma - gl uta m yltra nsferase i ncrease d 
G ua nase i ncrease d  
He p a plasti n a b n o r mal 
He p a plasti n decrease d  
He p atic arter y fl o w decrease d  
He p atic e nz y me a b n or mal  
He p atic e nz y me decrease d  
He p atic e nz y me i ncrease d  
He p atic f u ncti o n a b n or mal  
He p atic h y dr ot h ora x  
He p atic h y pertr o p h y  
He p atic mass  
He p atic pai n  
He p atic se q uestrati o n  
He p atic vasc ular resista nce i ncrease d 
1 0 0 0 1 5 4 7 
1 0 0 0 1 5 5 1 
1 0 0 0 1 9 4 2 
1 0 0 0 1 9 4 6 
1 0 0 0 3 4 4 5 
1 0 0 0 3 4 7 7 
1 0 0 0 3 4 8 1 
1 0 0 8 2 8 3 2 
1 0 0 6 8 5 4 7 
1 0 0 5 1 3 4 4 
1 0 0 5 1 3 4 3 
1 0 0 7 4 1 5 0 
1 0 0 6 7 7 1 8 
1 0 0 0 4 6 8 5 
1 0 0 7 7 3 5 6  
1 0 0 0 4 7 9 2 
1 0 0 5 8 4 7 7 
1 0 0 0 5 3 6 4 
1 0 0 0 5 3 7 0 
1 0 0 0 6 4 0 8 
1 0 0 7 7 0 2 0 
1 0 0 6 8 2 8 7 
1 0 0 7 8 3 6 0 
1 0 0 8 4 0 5 8 
1 0 0 5 2 5 5 4 
1 0 0 5 9 7 1 0 
1 0 0 5 9 7 1 2 
1 0 0 1 7 6 8 8 
1 0 0 1 7 6 9 3 
1 0 0 5 1 3 3 3 
1 0 0 1 9 6 2 1 
1 0 0 1 9 6 2 2 
1 0 0 6 8 9 9 7 
1 0 0 6 2 6 8 5 
1 0 0 6 0 7 9 4 
1 0 0 6 0 7 9 5 
1 0 0 1 9 6 7 0 
1 0 0 6 7 3 6 5 
1 0 0 7 6 2 5 4 
1 0 0 5 7 1 1 0 
1 0 0 1 9 7 0 5 
1 0 0 6 6 2 4 4 
1 0 0 6 8 3 5 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 6 of 7 0 
 
He p atic ve n o us press ure gra di e nt a b n or mal 
He p atic ve n o us press ure gra di e nt i ncrease d  
He p at o biliar y sca n a b n or mal  
He p at o me gal y  
He p at os ple n o me gal y  
H y pera m m o nae mia  
H y per bilir u bi nae mia  
H y perc h olia  
H y pertra nsa mi nasae mia  
Ka yser - Fleisc her ri n g 
Li ver f u ncti o n test a b n or mal  
Li ver f u ncti o n test d ecrease d  
Li ver f u ncti o n test i ncrease d  
Li ver i n d urati o n  
Li ver pal pa ble  
Li ver sca n a b n or mal  
Li ver te n der ness  
Ma g netic res o na nce i ma gi n g li ver a b n or mal  
Ma g netic res o na nce pr ot o n de nsit y fat fracti o n meas ure me nt 
Mit oc h o n drial as partate a mi n otra nsferase i ncrease d  
M olar rati o of t otal bra nc he d -c hai n a mi n o aci d t o t yr osi ne 
Oe d e ma d ue t o he p atic diseas e  
P eri he p atic disc o mf ort  
Retr o gra d e p ortal vei n fl o w  
T otal bile aci ds i ncrease d  
Tra nsa mi nases a b n or mal  
Tra nsa mi nases i ncrease d  
Ultras o u n d li ver a b n or mal  
Uri ne bilir u bi n i ncrease d  
W hite ni p ple si g n  
X-ra y he p at o biliar y a b n or mal 
1 0 0 8 3 1 7 2 
1 0 0 8 3 1 7 1 
1 0 0 6 6 1 9 5 
1 0 0 1 9 8 4 2 
1 0 0 1 9 8 4 7 
1 0 0 2 0 5 7 5 
1 0 0 2 0 5 7 8 
1 0 0 5 1 9 2 4 
1 0 0 6 8 2 3 7 
1 0 0 2 3 3 2 1 
1 0 0 2 4 6 9 0 
1 0 0 7 7 6 7 7 
1 0 0 7 7 6 9 2 
1 0 0 5 2 5 5 0 
1 0 0 7 5 8 9 5 
1 0 0 6 1 9 4 7 
1 0 0 2 4 7 1 2 
1 0 0 8 3 1 2 3 
1 0 0 8 2 4 4 3 
1 0 0 6 4 7 1 2 
1 0 0 6 6 8 6 9 
1 0 0 4 9 6 3 1 
1 0 0 5 4 1 2 5 
1 0 0 6 7 3 3 8 
1 0 0 6 4 5 5 8 
1 0 0 6 2 6 8 8 
1 0 0 5 4 8 8 9 
1 0 0 4 5 4 2 8 
1 0 0 5 0 7 9 2 
1 0 0 7 8 4 3 8 
1 0 0 5 6 5 3 6 
H y perte nsi o n 
Accelerate d h y perte nsi o n 
Bl o o d press ure a m b ulat or y i ncrease d  
Bl o o d press ure diast olic i ncre ase d  
Bl o o d press ure i na d e q uatel y c o ntr olle d  
Bl o o d press ure i ncrease d  
Bl o o d press ure ma na ge me nt  
Bl o o d press ure ort h ostatic i ncrease d 
Bl o o d press ure s yst olic i ncrease d  
Catec h ola mi ne crisis  
Dial ysis i n d uce d h y perte nsi o n  
Diast olic h y perte nsi o n  
Ecla m psia  
E n d ocri ne h y perte nsi o n  
Esse ntial h y perte nsi o n  
Gestati o nal h y perte nsi o n  
H E L L P s y n dr o me 
1 0 0 0 0 3 5 8 
1 0 0 0 5 7 3 2 
1 0 0 0 5 7 3 9 
1 0 0 5 1 1 2 8 
1 0 0 0 5 7 5 0 
1 0 0 6 3 9 2 6 
1 0 0 5 3 3 5 5 
1 0 0 0 5 7 6 0 
1 0 0 8 1 7 5 1 
1 0 0 6 3 0 6 7 
1 0 0 1 2 7 5 8 
1 0 0 1 4 1 2 9 
1 0 0 5 7 6 1 5 
1 0 0 1 5 4 8 8 
1 0 0 7 0 5 3 8 
1 0 0 4 9 0 5 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 7 of 7 0 
 
H y peral d oster o nis m 
H y perte nsi o n  
H y perte nsi o n ne o natal  
H y perte nsi ve a n gi o pat h y  
H y perte nsi ve car di o me gal y  
H y perte nsi ve car di o m y o pat h y  
H y perte nsi ve cere br o vasc ular disease  
H y perte nsi ve crisis  
H y perte nsi ve e mer ge nc y  
H y perte nsi ve e nce p hal o pat h y  
H y perte nsi ve e n d - or ga n da ma ge 
H y perte nsi ve heart  disease 
H y perte nsi ve ne p hr o pat h y  
H y perte nsi ve ur ge nc y  
La bile h y perte nsi o n  
Mali g na nt h y perte nsi o n  
Mali g na nt h y perte nsi ve heart disease  
Mali g na nt re nal h y perte nsi o n  
Mater nal h y perte nsi o n affecti n g f oet us  
Mea n arterial press ure i ncreas e d  
Meta b olic s y n dr o me  
Ne ur o ge nic h y perte nsi o n  
Ort h ostatic h y perte nsi o n  
Pa ge ki d ne y  
P ost o perati ve h y perte nsi o n  
Pre -ecla m psia 
Pre h y perte nsi o n  
Pr oce d ural h y perte nsi o n  
Re nal h y perte nsi o n  
Re nal s y m pat hetic ner ve a blati o n  
Re n o vasc ular h y perte nsi o n  
Reti n o pat h y h y perte nsi ve  
Sec o n dar y al d oster o nis m 
Sec o n dar y h y perte nsi o n  
S u pi ne h y perte nsi o n  
S yst olic h y perte nsi o n  
Wit h dra wal h y perte nsi o n 
1 0 0 2 0 5 7 1 
1 0 0 2 0 7 7 2 
1 0 0 4 9 7 8 1 
1 0 0 5 9 2 3 8 
1 0 0 2 0 8 0 1 
1 0 0 5 8 2 2 2 
1 0 0 7 7 0 0 0 
1 0 0 2 0 8 0 2 
1 0 0 5 8 1 7 9 
1 0 0 2 0 8 0 3 
1 0 0 7 9 4 9 6 
1 0 0 2 0 8 2 3 
1 0 0 5 5 1 7 1 
1 0 0 5 8 1 8 1 
1 0 0 4 9 0 7 9 
1 0 0 2 5 6 0 0 
1 0 0 2 5 6 0 3 
1 0 0 2 6 6 7 4 
1 0 0 2 6 9 2 4 
1 0 0 2 6 9 8 5 
1 0 0 5 2 0 6 6 
1 0 0 6 7 5 9 8 
1 0 0 6 5 5 0 8 
1 0 0 7 6 7 0 4 
1 0 0 5 0 6 3 1 
1 0 0 3 6 4 8 5 
1 0 0 6 5 9 1 8 
1 0 0 6 2 8 8 6 
1 0 0 3 8 4 6 4 
1 0 0 7 4 8 6 4 
1 0 0 3 8 5 6 2 
1 0 0 3 8 9 2 6 
1 0 0 3 9 8 0 8 
1 0 0 3 9 8 3 4 
1 0 0 7 8 9 3 2 
1 0 0 4 2 9 5 7 
1 0 0 4 8 0 0 7 
Pr otei n uria 
Al b u mi n gl o b uli n rati o i ncrease d 
Al b u mi n uri ne prese nt  
Al b u mi n uria  
B e nce J o nes pr otei n uri ne pres e nt  
B e nce J o nes pr otei n uria  
B eta 2 micr o gl o b uli n uri ne i ncrease d  
Gl o b uli n uria  
Micr oal b u mi n uria  
M y o gl o bi n uria  
Ort h ostatic pr otei n uria 
1 0 0 0 1 5 6 7 
1 0 0 0 1 5 8 2 
1 0 0 0 1 5 8 0 
1 0 0 5 3 1 1 2 
1 0 0 0 4 2 3 1 
1 0 0 0 4 5 0 1 
1 0 0 1 8 3 5 2 
1 0 0 2 7 5 2 5 
1 0 0 2 8 6 2 9 
1 0 0 3 1 1 2 9 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 8 of 7 0 
 
Pr otei n uri ne 
Pr otei n uri ne prese nt  
Pr otei n uria  
Uri ne al b u mi n/creati ni ne rati o i ncrease d  
Uri ne pr otei n/creati ni ne rati o a b n or mal  
Uri ne pr otei n/creati ni ne rati o i ncrease d 
1 0 0 3 7 0 1 8 
1 0 0 5 3 1 2 3 
1 0 0 3 7 0 3 2 
1 0 0 5 3 5 4 1 
1 0 0 5 3 5 3 9 
1 0 0 5 3 5 3 8 
T h yr oi d 
d ysf u ncti o n 
Base d o w's disease 
E n d ocri ne o p ht hal m o pat h y  
E x o p ht hal m os  
Has hit o xic osis  
H y pert h yr oi dis m  
I m m u ne- me diate d h y pert h yr oi dis m 
I na p pr o priate t h yr oi d sti m ulati n g h or m o ne secreti o n 
Mali g na nt e x o p ht hal m os  
Mari ne Le n hart s y n dr o me  
Pri mar y h y pert h yr oi dis m  
Sec o n dar y h y pert h yr oi dis m  
T h yr oi d der mat o pat h y  
T h yr oi d t u berc ul osis  
T h yr ot o xic car di o m y o pat h y  
T h yr ot o xic crisis  
T h yr ot o xic m y o pat h y  
T h yr ot o xic peri o dic paral ysis  
T o xic g oitre  
T o xic n o d ular g oitre  
A nti -t h yr oi d a nti b o d y 
A nti -t h yr oi d a nti b o d y p ositi ve 
A ntit h yr oi d art hritis s y n dr o me  
A ut oi m m u ne t h yr oi d dis or der  
A ut oi m m u ne t h yr oi ditis  
Bi o ps y t h yr oi d gla n d a b n or mal  
Bl o o d t h yr oi d sti m ulati n g h or m o ne a b n or mal 
Bl o o d t h yr oi d sti m ulati n g h or m o ne decrease d  
Bl o o d t h yr oi d sti m ulati n g h or m o ne i ncrease d  
B uta n ol -e xtracta ble i o di ne decrease d 
B uta n ol -e xtracta ble i o di ne i ncrease d 
C o n ge nital t h yr oi d dis or der  
E ut h yr oi d sic k s y n dr o me  
Free t h yr o xi ne i n de x a b n or mal 
Free t h yr o xi ne i n de x decrease d  
Free t h yr o xi ne i n de x i ncrease d  
Ga m ma ra diati o n t hera p y t o t h yr oi d  
G oitre  
Has hi m ot o's e nce p hal o pat h y  
I m m u ne- me diate d t h yr oi ditis 
I nfecti o us t h yr oi ditis 
I o di ne u pta ke a b n or mal 
1 0 0 0 4 1 6 1 
1 0 0 6 0 7 4 2 
1 0 0 1 5 6 8 3 
1 0 0 6 7 8 7 3 
1 0 0 2 0 8 5 0 
1 0 0 8 3 5 1 7 
1 0 0 7 5 0 0 7 
1 0 0 7 5 3 8 6 
1 0 0 6 8 8 2 8 
1 0 0 7 5 8 9 9 
1 0 0 5 3 2 6 0 
1 0 0 6 9 7 7 1 
1 0 0 4 3 7 7 4 
1 0 0 7 5 0 4 3 
1 0 0 4 3 7 8 6 
1 0 0 8 1 5 2 4 
1 0 0 4 3 7 8 8 
1 0 0 7 5 0 5 0 
1 0 0 4 4 2 4 2 
1 0 0 6 0 3 2 5 
1 0 0 6 0 3 1 0 
1 0 0 7 3 0 2 9 
1 0 0 7 9 1 6 5 
1 0 0 4 9 0 4 6 
1 0 0 0 4 8 8 9 
1 0 0 0 5 8 3 0 
1 0 0 0 5 8 3 2 
1 0 0 0 5 8 3 3 
1 0 0 0 6 8 1 8 
1 0 0 0 6 8 1 9 
1 0 0 7 6 6 0 2 
1 0 0 1 5 5 4 9 
1 0 0 5 0 7 4 7 
1 0 0 5 0 7 4 8 
1 0 0 5 0 7 4 9 
1 0 0 1 7 6 8 5 
1 0 0 1 8 4 9 8 
1 0 0 6 9 4 3 2 
1 0 0 8 3 0 7 1 
1 0 0 7 1 2 5 0 
1 0 0 2 2 9 1 8 
C CI


 
H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 9 of 7 0 
 
I o di ne u pta ke decrease d 
I o di ne u pta ke i ncrease d 
Or bital d ec o m pressi o n  
P h ot o n ra diati o n t hera p y t o t h yr oi d  
P ol y gla n d ular a ut oi m m u ne s y n dr o me t y pe II  
P ol y gla n d ular a ut oi m m u ne s y n dr o me t y pe III  
Pr otei n b o u n d i o di ne decrease d  
Pr otei n b o u n d i o di ne i ncrease d  
Ra di oacti ve i o di ne t hera p y  
Ra di ot hera p y t o t h yr oi d  
Re verse tri -i o d ot h yr o ni ne decrease d 
Re verse tri -i o d ot h yr o ni ne i ncr ease d 
Sile nt t h yr oi ditis  
T h yre ostatic t hera p y  
T h yr o gl o b uli n a bse nt  
T h yr o gl o b uli n decrease d  
T h yr o gl o b uli n i ncrease d  
T h yr o gl o b uli n prese nt  
T h yr oi d dis or der  
T h yr oi d d ysf u ncti o n i n pre g na nc y 
T h yr oi d electr o n ra diati o n t hera p y  
T h yr oi d f u ncti o n test a b n or mal  
T h yr oi d gla n d sca n a b n or mal  
T h yr oi d he mia ge nesis  
T h yr oi d h or m o ne re place me nt t hera p y  
T h yr oi d h or m o nes i ncrease d  
T h yr oi d o perati o n  
T h yr oi d pai n  
T h yr oi d releasi n g h or m o ne c halle n ge test a b n or mal 
T h yr oi d sti m ulati n g i m m u n o gl o b uli n i ncrease d  
T h yr oi d t hera p y  
T h yr oi dect o m y  
T h yr oi ditis  
T h yr oi ditis ac ute  
T h yr oi ditis c hr o nic  
T h yr oi ditis fi br o us c hr o nic  
T h yr oi ditis s u bac ute  
T h yr o xi n bi n di n g gl o b uli n a b n or mal  
T h yr o xi n bi n di n g gl o b ul i n decrease d 
T h yr o xi n bi n di n g gl o b uli n i ncrease d  
T h yr o xi ne a b n or mal  
T h yr o xi ne decrease d  
T h yr o xi ne free a b n or mal  
T h yr o xi ne free decrease d  
T h yr o xi ne free i ncrease d  
T h yr o xi ne i ncrease d  
T h yr o xi ne t hera p y 
1 0 0 2 2 9 2 0 
1 0 0 2 2 9 2 2 
1 0 0 7 2 1 4 1 
1 0 0 3 4 9 5 7 
1 0 0 3 6 0 7 3 
1 0 0 6 4 1 1 5 
1 0 0 3 7 0 0 1 
1 0 0 3 7 0 0 2 
1 0 0 3 7 7 8 4 
1 0 0 6 2 0 9 8 
1 0 0 6 0 3 0 7 
1 0 0 6 0 3 0 6 
1 0 0 7 9 0 1 2 
1 0 0 6 5 3 5 9 
1 0 0 5 4 0 2 5 
1 0 0 5 4 0 1 1 
1 0 0 5 4 0 1 0 
1 0 0 5 4 0 2 4 
1 0 0 4 3 7 0 9 
1 0 0 5 6 5 2 5 
1 0 0 4 3 7 2 2 
1 0 0 4 3 7 3 0 
1 0 0 6 2 1 4 9 
1 0 0 7 7 6 0 9 
1 0 0 6 8 0 7 6 
1 0 0 6 3 1 6 1 
1 0 0 6 2 1 2 6 
1 0 0 4 3 7 5 7 
1 0 0 4 3 7 6 4 
1 0 0 7 1 3 8 9 
1 0 0 6 5 3 5 8 
1 0 0 6 2 1 2 7 
1 0 0 4 3 7 7 8 
1 0 0 4 3 7 8 0 
1 0 0 4 3 7 8 1 
1 0 0 4 3 7 8 2 
1 0 0 4 3 7 8 4 
1 0 0 5 1 4 2 3 
1 0 0 5 1 4 2 1 
1 0 0 5 1 4 2 0 
1 0 0 4 3 8 1 4 
1 0 0 4 3 8 1 6 
1 0 0 5 5 1 5 8 
1 0 0 5 5 1 6 2 
1 0 0 5 5 1 6 3 
1 0 0 4 3 8 1 8 
1 0 0 5 2 7 0 2 
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H ut c hi s o n M e di P h ar m a Li mit e d 
P R O T O C O L 2 0 1 5- 0 1 2- 0 0 U S 1  
 
St ati sti c al A n al y si s Pl a n  
P a g e 7 0 of 7 0 
 
Tri-i o d ot h yr o ni ne a b n or mal 
Tri -i o d ot h yr o ni ne decrease d 
Tri -i o d ot h yr o ni ne free a b n or mal 
Tri -i o d ot h yr o ni ne free decrease d 
Tri -i o d ot h yr o ni ne free i ncreas e d 
Tri -i o d ot h yr o ni ne free n or mal 
Tri -i o d ot h yr o ni ne i ncrease d 
Tri -i o d ot h yr o ni ne u pta ke a b n or mal 
Tri -i o d ot h yr o ni ne u pta ke decrease d 
Tri -i o d ot h yr o ni ne u pta ke i ncr ease d 
Ultras o u n d t h yr oi d a b n or mal  
X- ra y t hera p y t o t h yr oi d 
A ut oi m m u ne h y p ot h yr oi dis m  
C o n ge nital h y p ot h yr oi dis m  
Ge neralise d resista nce t o t h yr oi d h or m o ne  
H y p ot h yr oi dic g oitre  
H y p ot h yr oi dis m  
I m m u ne- me diate d h y p ot h yr oi dis m 
M y x oe d e ma  
M y x oe d e ma c o ma  
P ost pr oce d ural h y p ot h yr oi dis m 
Pri mar y h y p ot h yr oi dis m  
Sec o n dar y h y p ot h yr oi dis m  
T ertiar y h y p ot h yr oi dis m  
T h yr oi d atr o p h y  
T h yr oi d sti m ulati n g h or m o ne deficie nc y  
Tra nsie nt h y p ot h yr o xi nae mia of pre mat urit y  
Atr o p hic t h yr oi ditis 
1 0 0 4 4 5 9 2 
1 0 0 4 4 5 9 4 
1 0 0 5 3 7 9 4 
1 0 0 5 3 7 9 1 
1 0 0 5 3 7 9 0 
1 0 0 5 3 7 9 3 
1 0 0 4 4 5 9 6 
1 0 0 6 2 2 1 5 
1 0 0 4 4 6 0 1 
1 0 0 4 4 6 0 2 
1 0 0 6 0 9 8 7 
1 0 0 4 8 2 0 7 
1 0 0 7 6 6 4 4 
1 0 0 1 0 5 1 0 
1 0 0 1 8 0 9 6 
1 0 0 5 9 8 4 4 
1 0 0 2 1 1 1 4 
1 0 0 8 3 0 7 5 
1 0 0 2 8 6 6 5 
1 0 0 6 0 8 1 9 
1 0 0 6 5 3 0 6 
1 0 0 3 6 6 9 7 
1 0 0 3 9 8 4 0 
1 0 0 4 3 2 8 9 
1 0 0 4 3 6 9 3 
1 0 0 7 8 5 6 4 
1 0 0 7 5 9 0 1 
1 0 0 7 7 1 7 2 
 
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C O N S E N T T O E L E C T R O NI C D E LI V E R Y A N D E X E C U TI O N O F D O C U M E N T S   
Fr o m ti me t o ti me, I Q VI A (“ w e” or “ us”) ma y pr o vi de y o u certai n writte n c o ntracts, n otices, 
discl os ures, a ut h orizati o ns, ac k n o wle d ge me nts or ot her d oc u me nts (c ollecti vel y, t he 
" D oc u m e nts") electr o nic all y. Please rea d t his c o nse nt f or m caref ull y. It e x plai ns t he ter ms a n d 
c o n diti o ns u n der w hic h s uc h D oc u me nts are pr o vi de d b y us a n d e x ec ute d b y y o u el ectr o nicall y 
t hr o u g h y o ur D oc u Si g n, I n c. (“ D oc u Si g n ”) user acc o u nt. If y o u c o nse nt t o t he deli ver y a n d 
e x ec uti o n of s uc h D oc u me nts electr o nicall y, please clic k t he "I A gree" b utt o n.  
D oc u me nts will be se nt t o y o u electr o nic all y  
If y o u c o nse nt t o ele ctr o nic deli ver y, D oc u m e nts will be se nt t o y o ur D o c u Si g n user acc o u nt. 
Y o u ma y re q u est a pa per c o p y of d oc u me nts pre vi o usl y ma de a vaila ble t hr o u g h y o ur D oc u Si g n 
user acc o u nt, b ut a n a d diti o nal c har ge ma y b e  i nc urre d. Alter n ati vel y, y o u ca n d o w nl oa d a n d 
pri nt d oc u me nts se nt t o y o ur D oc u Si g n us er acc o u nt. U nless ot her wise n ote d, y o u ca n access a 
D oc u me nt u p t o 3 0 da ys fr o m t he date we first se nt t he D oc u me nt t o y o u.  
Wit h h ol d C o nse nt or Wit h dr a wi n g C o nse nt t o Electr o nic Deli ver y  
If y o u wit h h ol d c o nse nt t o electr o nic d eli ver y or e x ec uti o n, or wit h dra w y o ur c o nse nt at a l ater 
date, all D oc u me nts will be se nt t o y o ur maili n g a d dress f oll o wi n g o ur recei pt of n otice of s uc h 
acti o n. T he f oll o wi n g secti o ns e x plai n t he c o nse q ue nces of wit h h ol di n g or wit h dra wi n g y o ur 
c o nse nt t o electr o ni c deli ver y a n d e x ec uti o n of  D oc u me nts, a n d als o t he pr oce d ures y o u m ust 
f oll o w i n or der t o effect u ate deli ver y t o y o ur m aili n g a d dress.  
C o nse q ue nces of Wit h dr a wi n g C o nse nt   
B y ele cti n g t o o nl y recei ve a n d e x ec ute D o c u me nts se nt t o y o ur maili n g a d dress, we will n ot be 
a ble t o carr y o ut tra nsacti o ns or ser vices as efficie ntl y. F or i nsta nce, s o me tra nsacti o ns or 
ser vices r e q uire y o ur e x press c o nse nt. We ca n perf or m t hese tra ns acti o n or ser vices o nl y if we 
first recei ve a n ac k n o wle d ge m e nt t hat i n dicates y o u recei v e d a n d c o ns e nt t o t he D oc u me nt 
relate d t o t he pr o p os e d tr a nsacti o n or ser vice.  
T o wit h h ol d c o nse nt n o w or wit h dra w c o ns e nt at a later date, please si g n D oc u Si g n's " Wit h dra w 
C o nse nt" f or m o n t he si g ni n g pa ge of y o ur D o c u Si g n user acc o u nt. T his will i n dicate t hat y o u 
ha ve wit h dra w n y o ur c o nse nt t o recei v e D oc u me nts electr o nicall y. O nce y o u si g n t he " Wit h dra w 
C o nse nt" f or m, y o u will n o l o n ger be a ble t o us e y o ur D oc u Si g n us er acc o u nt t o e x ec ute 
D oc u me nts electr o nicall y a n d we will se n d D oc u me nts t o y o ur maili n g a d dress. Wit h dra wal of 
c o nse nt d oes n ot affect t h e vali dit y of a n y D oc u me nts pre vi o usl y e x ec ute d electr o nicall y pri or t o 
s uc h wit h dra wal of C o nse nt. I n a d diti o n, s h o ul d y o u e x ec ute a n y D oc u m e nts electr o nicall y, y o ur 
e x ec uti o n of s uc h D oc u me nts s hall i n dicate y o ur c o nti n ue d c o nse nt t o e x ec ute s uc h D oc u me nts 
electr o nicall y.  
H o w t o c o nt act I Q VI A:  
If y o u w o ul d li ke us t o se n d t he D oc u me nts t o a differe nt e- mail a d dress, r e q uest pa per c o pies of 
D oc u me nts y o u ha ve pre vi o usl y recei ve d electr o nicall y, or wit h dra w y o ur c o nse nt t o recei ve 
electr o nic d o c u me nts, please f oll o w t he i nstr ucti o ns bel o w. If y o u ha v e a n y ot her q uesti o ns, 
please c o nta ct:
  
1. T o a d vise I Q VI A of y o ur ne w e- m ail a d dress  
If y o u w o ul d li ke y o ur D oc u me nts se nt t o a differe nt e- mail a d dress, y o u m ust se n d a n e- mail 
messa ge t o
 . I n t h e b o d y of t he e- mail please state t he f oll o wi n g: 
(i) y o ur pre vi o us e- mail a d dress, a n d (ii) y o ur ne w e- mail a d dress. N o ot her i nf or mati o n is 
re q uire d.  
P P D
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I n a d diti o n, y o u m ust n otif y D o c u Si g n of y o ur ne w e- mail a d dress. Please l o g i nt o y o ur 
D oc u Si g n user acc o u nt, a n d f oll o w t he i nstr ucti o ns t o u p date y o ur e- mail a d dress.  
2. T o re q uest p a per c o pies fr o m I Q VI A   
T o re q uest pa p er c o pi es of D oc u me nts y o u ha v e recei ve d pre vi o usl y t hr o u g h y o ur D oc u Si g n 
user acc o u nt, se n d a n e- mail t o 
  
I n t he b o d y of t he e- mail please state t he f oll o wi n g: (i) y o ur e- mail a d dress, (ii) f ull na me, (iii) 
U. S. P ostal a d dress, a n d (i v) tele p h o ne n u m ber. A d diti o nal c har ges ma y a p pl y f or s u c h pa p er 
c o pies. 
3. T o wit h dr a w y o ur c o nse nt wit h I Q VI A  
T o wit h dra w y o ur c o nse nt t o recei vi n g a n d e x ec uti n g D oc u me nts i n a n electr o nic f or mat, y o u 
ma y d o o n e of t he f oll o wi n g: 
i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur D oc u Si g n user acc o u nt, a n d o n t he 
s u bse q ue nt pa ge, s elect t he c hec k- b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o nse nt; or  
ii. se n d us a n e- mail t o 
 a n d i n t he b o d y of s uc h re q uest 
y o u m ust state y o ur e- mail, f ull na me, U S P o stal A d dress, tele p h o ne n u m ber, a n d acc o u nt 
n u m ber. N o a d diti o nal i nf or mati o n is necessar y.  
Re q uire d h ar d w are a n d s oft w are   
O perati n g S yst e ms: 
Wi n d o ws ® 2 0 0 0, Wi n d o ws ® X P, Wi n d o ws Vista ®; Mac O S ® X 
Br o ws ers:  
  I nter net E x pl orer ( Wi n d o ws O nl y) 8. 0 or a b o v e –  c o m pati bilit y m o de is 
s u p p orte d o nl y f or 9. 0 a n d a b o ve.  
  Wi n d o ws E d ge C urre nt Versi o n  
  M ozilla Firef o x C urre nt Versi o n  
  Safari ( Mac O S o nl y) 6. 2 or a b o ve  
  G o o gle C hr o m e C urre nt Versi o n  
P D F Rea der: 
Acr o bat ® or si milar s oft ware ma y b e re q uire d t o vie w a n d pri nt P D F files 
Scree n Res ol uti o n: 
1 0 2 4 x 7 6 8 Rec o m me n de d  
E na ble d Sec urit y 
Setti n gs: 
All o w per sessi o n c o o kies  
M o bile Si g ni n g: 
  A p ple i O S 7. 0 or a b o v e  
  A n dr oi d 4. 0 or a b o ve  
* * T hese mi ni m u m re q uire me nts are s u bject t o c h a n ge. If t h ese re q uire me nts c ha n ge, we will 
pr o vi de y o u wit h a n e- m ail messa ge at t he e- mail a d dress w e ha ve o n file f or y o u at t he ti me t he 
har d ware a n d s oft ware re q uire me nts are re vise d.  
Pre-rele ase (e. g. beta) versi o ns of o perati n g s yste ms a n d br o wsers are n ot s u p p orte d.  
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve m ateri als electr o nic all y  
T o c o nfir m y o u ca n access t his i nf or mati o n electr o nicall y a n d t hat y o u c o nse nt t o recei vi n g a n d 
e x ec uti n g D oc u m e nts electr o nicall y o n t he ter ms a n d c o n diti o ns descri be d a b o ve, please let us 
k n o w b y clic ki n g t h e "I A gree" b utt o n.  
B y clic ki n g t he "I A gree" b utt o n, y o u c o nfir m t hat  
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Y o u ca n access a n d rea d t his C o nse nt T o Electr o nic Deli ver y a n d E x ec uti o n of 
D oc u me nts; a n d  
 
Y o u ca n pri nt o n pa per t he discl os ure or sa ve or se n d t he discl os ure t o a pl ace w here y o u 
ca n pri nt it, f or f ut ure refere nce a n d access; a n d  
 
U ntil or u nless y o u n otif y I Q VI A as descri be d a b o ve, y o u c o nse nt t o t he deli ver y a n d 
e x ec uti o n of D oc u me nts electr o nicall y.