Clinical trial NCT05093322
Conditions: Solid Tumor Lymphoma Osteosarcoma Ewing Sarcoma Rhabdomyosarcoma Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
Sponsor: Hutchmed
Start date: 2021-11-30; Completion date: 2023-04-25
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of surufatinib, thereby identifying the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory solid tumors or lymphoma. The study will be conducted in 2 parts.

Detailed description:
The purpose of this study is to evaluate the safety and tolerability of surufatinib, thereby identifying the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory solid tumors or lymphoma. The study will be conducted in 2 parts:

Part 1 - evaluation of tolerability and safety of surufatinib administered in combination with gemcitabine, and confirmation of the recommended clinical dose of surufatinib in pediatric patients with recurrent or refractory solid tumors or lymphoma.

Part 2 - evaluation of anti-tumor activity and confirmation of tolerability of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or refractory osteosarcoma, Ewing sarcoma, RMS, and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

Part 1 will enroll 2 to 6 patients per dose level cohort (up to 4 cohorts) with recurrent or refractory solid tumors. During cycle 1, surufatinib will be administered, orally, once daily (QD), as a single agent for 14 days followed by surufatinib daily in combination with gemcitabine intravenously on days 15 and 22 (cycle 1 duration=35 days) and days 1 and 8 of all subsequent cycles (cycle duration=21 days). Assessment based on dose limiting toxicity (DLT) criteria will be performed in the first 35-day cycle (DLT Evaluation Period). This study will utilize a rolling 6 design for part 1, with 3 dose escalation levels and 1 de escalation level, if needed.

Part 2 of the study will use a Simon 2-stage design with a maximum of 18 patients per cohort (osteosarcoma, Ewing sarcoma, RMS, and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS)).

Surufatinib will be administered orally at identified MTD/RP2D daily in combination with gemcitabine (1000 mg/m2 weekly × 2 doses) intravenously on days 1 and 8.

In both parts 1 and 2, patients can remain on treatment until completing cycle 17, or until progressive disease, unacceptable toxicity, or death; whichever comes first.

Arms: arm 1: Dose escalation study with sequential dose escalation of surufatinib in combination with gemcitabine. Patients with any recurrent or refractory solid tumors or lymphoma, who have a known or expected dysfunction of VEGFR-1, -2, and -3; FGFR-1; or CSF-1R pathways may be enrolled. arm 2: Once the MTD/RP2D has been determined in the part 1 portion of the study, the part 2 disease specific cohorts for patients with refractory or recurrent osteosarcoma, Ewing Sarcoma, and RMS and NRSTS will open for enrollment.
Interventions: intervention 1: Surufatinib in combination with Gemcitabine
Intervention descriptions: intervention 1: Surufatinib in combination with Gemcitabine

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 2020-012-GLOB2
Surufatinib
Amendment 3
HUTCHMED Limited
Page 1
CONFIDENTIAL
Clinical Study Protocol
AN OPEN-LABEL, MULTICENTER PHASE 1/2 STUDY OF 
SURUFATINIB IN COMBINATION WITH GEMCITABINE IN 
PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH 
RECURRENT OR REFRACTORY SOLID TUMORS
Short Title:
A Study of Surufatinib in Combination with Gemcitabine 
in Pediatric, Adolescent, and Young Adult Patients with 
Recurrent or Refractory Solid Tumors
Investigational Product(s):
Surufatinib (HMPL-012)
Gemcitabine
Protocol Number:
2020-012-GLOB2
Clinical Phase:
Phase 1/2
Amendment:
3
Sponsor:
HUTCHMED Limited
Building 4, 720 Cailun Road
China (Shanghai) Pilot Free Trade Zone
Shanghai, China 201203
Regulatory Agency Identifier 
Number(s):
IND 
EudraCT 2021-003602-41
Issue Date:
24 January 2023
Confidentiality Statement
The information contained in this document is the confidential and proprietary information of 
HUTCHMED Limited, and except as may be required by applicable laws or regulation, may 
not be disclosed to others without prior written permission of HUTCHMED Limited.
CCI


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STATEMENT OF COMPLIANCE
The study will be conducted in compliance with this Clinical Study Protocol, Good Clinical 
Practice (GCP) as outlined by Internal Council for Harmonisation E6(R2), and all applicable local 
and national regulatory requirements.  Enrollment at any clinical study site may not begin prior to 
that site receiving approval from the ethics committee of record for the protocol and all materials 
provided to potential participants.
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment. Re-consent of previously enrolled participants may be 
necessary depending on the nature of the amendment.
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants.
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution.


Clinical Study Protocol 2020-012-GLOB2
Surufatinib
Amendment 3
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SPONSOR’S APPROVAL
Title
An Open-Label, Multicenter Phase 1/2 Study of Surufatinib in Combination with 
Gemcitabine in Pediatric, Adolescent, and Young Adult Patients with Recurrent or 
Refractory Solid Tumors
Protocol Number
2020-012-GLOB2
Amendment
3
Version
(for sponsor’s use only) 
1
The design of this study as outlined by this protocol has been reviewed and approved by the 
Sponsor’s responsible personnel as indicated in the signature table below.
Name: [last name, first name]
Title:
HUTCHMED International Corporation
Signature:
See appended signature page
Date: [DD Month YYYY]
PPD
PPD


Clinical Study Protocol 2020-012-GLOB2
Surufatinib
Amendment 3
HUTCHMED Limited
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CONFIDENTIAL
INVESTIGATOR’S AGREEMENT
I have read the protocol, appendices, and accessory materials related to Study 2020-012-GLOB2
and agree to the following:
x
To conduct this study as described by the protocol and any accessory materials
x
To protect the rights, safety, and welfare of the participants under my care
x
To provide oversight to all personnel to whom study activities have been delegated
x
To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products
x
To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by International Council for Harmonisation (ICH) E6(R2)
x
To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site
x
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
x
To maintain records of each patient’s participation and all data required by the protocol
Name [Last name, first name]
Title [Title at institution]
Institution [Address]
Signature
Date [DD Month YYYY]


Clinical Study Protocol 2020-012-GLOB2
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Amendment 3
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DOCUMENT HISTORY
Amendment
Issue Date
Original Protocol
02 Sep 2021
1
14 Oct 2021
2
03 Mar 2022


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Surufatinib
Amendment 3
HUTCHMED Limited
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AMENDMENT SUMMARY
This Protocol 2020-012-GLOB2
Amendment 3
replaces Protocol 2020-012-GLOB2
Amendment 2.  This amendment is considered to be 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 3 is to provide notification that enrollment to study 2020-
012-GLOB2 has been halted based upon the strategic evaluation of the clinical development of 
surufatinib in the United States and Europe with HUTCHMED as the study Sponsor.  This change 
is not based on any concern for patient safety or efficacy relative to surufatinib treatment.  
Currently enrolled patients who are deriving clinical benefit from treatment with surufatinib may 
continue to participate in the study as per the protocol.  There is no planned interruption in the 
supply of surufatinib to clinical trial sites with active patients. In addition, as no patients have 
enrolled in study Part 2 (dose expansion) as of the end of enrollment date (16 December 2022),
Part 2 is removed from the study design in this protocol Amendment 3. Part 1 (dose escalation) 
will continue as outlined in this protocol amendment. The changes made in this amendment are 
described in the table below.  Editorial and formatting changes are not included in this summary.
Details of changes made in prior amendments are summarized in Appendix 10.
Section Number
Summary of Change
Rationale for Change
Section 1 – Synopsis
Section 2.1.1 – Target 
Indication and Population
Section 5.1 – Recruitment
Language was added to indicate that 
enrollment was halted as of 16 December 
2022. Currently enrolled patients deriving 
clinical benefit from treatment may 
continue to participate in the study. 
This new language confirms that the 
study halted enrollment on 16
December 2022.  This language also 
confirms this change is not based on 
any patient safety or efficacy 
concerns, and to ensure patients 
deriving clinical benefit from study 
treatment may continue treatment. 
Section 1– Synopsis
Section 2 – Introduction
Section 3 – Objectives and 
Endpoints
Section 4 – Study Design
Section 5 – Population
Section 6 – Study Conduct
Section 7 – Study 
Interventions
Section 9 – Statistical 
Analysis
Remove all sub-sections and text 
presenting objectives, endpoints, disease 
cohorts, data collection/analysis and other 
information regarding study Part 2 Dose 
Expansion, including
x
Delete former Table 2 Schedule 
of Events for Part 2
x
Delete former Table 4 Schedule 
of Events for Pharmacokinetic 
Evaluation for Part 2
x
Delete former Table 8 Part 2 
Objectives and Endpoints
x
Delete Figure 4 Dosing 
Schematic for Part 2
x
Revise Figure 1 Study Schematic 
to remove Part 2: Simon’s 2 Stage
Design Combination Expansion.
In addition, although Dose Escalation part 
of study is retained, references to Dose 
Escalation as “Part 1” are removed.
To remove Part 2 Dose Expansion 
from protocol.


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Section Number
Summary of Change
Rationale for Change
Section 1– Synopsis
Section 2.1.1 – Target 
Indication and Population
Synopsis “Condition/Disease:” Delete 
osteosarcoma, Ewing sarcoma,
rhabdomyosarcoma, non-
rhabdomyosarcoma soft tissue sarcoma.
Synopsis “Health 
Measurement/Observation:” Delete 
efficacy time points for osteosarcoma, 
Ewing sarcoma, rhabdomyosarcoma, non-
rhabdomyosarcoma.
Removed the following sub-sections:
x
2.1.1.1 – Osteosarcoma 
x
2.1.1.2 – Ewing Sarcoma 
x
2.1.1.3 – Rhabdomyosarcoma 
x
2.1.1.4 – Non-
Rhabdomyosarcoma.
To remove identification/analysis 
of/background for disease cohorts for 
study Part 2, which have been 
removed by this amendment.
Section 1– Synopsis
Section 9.2.1 – Sample 
Size Rationale
Number of patients in study revised from 
“Up to 116 patients” to “Up to 36
patients”.
To decrease planned number of 
patients since study Part 2 will not be 
performed.
Section 1– Synopsis
Section 4.1 – Dose 
Escalation
Section 4.3 – Design 
Rationale
Statement regarding number of patients in 
each of the 2 age range strata of 
pharmacokinetic (PK) expansion cohort 
changed from “…at least 6 patients…” to 
“…up to 6 patients…”
For clarification.
Section 1– Synopsis
Section 3 – Objectives and 
Endpoints
Section 4 – Study Design
Section 6 – Study Conduct
Section 7 – Study 
Interventions
Section 9 – Statistical 
Analysis
Remove all sub-sections and text 
presenting information regarding
objectives, endpoints, sample 
collection/analysis and data analysis for 
gemcitabine PK, including
x
Delete secondary objective “To 
document the PK exposure of 
gemcitabine when used in 
combination with Surufatinib” 
and corresponding endpoint
“Observed plasma concentrations 
of gemcitabine”.
x
Remove gemcitabine PK sample 
collection schedule from former 
Table 3 Schedule of Events for 
Pharmacokinetic Evaluation for 
Part 1 (revised presentation is 
Table 2 in this Amendment 3).
To remove gemcitabine 
pharmacokinetic (PK) sample 
collection and analysis and analysis 
of gemcitabine PK data.


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Amendment 3
HUTCHMED Limited
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Section Number
Summary of Change
Rationale for Change
Section 1– Synopsis
Section 3 – Objectives and 
Endpoints
Section 9.3.7 –
Pharmacokinetics Analysis
The following secondary endpoint was 
deleted: “Observed plasma concentrations 
of surufatinib and estimated population PK 
and exposure parameters for Surufatinib.”
Delete paragraph describing population PK 
analysis.
To remove population PK analysis.
Section 1– Synopsis
Section 3 – Objectives and 
Endpoints
Section 6 – Study Conduct
Section 9 – Statistical 
Analysis
Remove all sub-sections and text 
presenting information regarding
objectives, endpoints, sample 
collection/analysis and data analysis for 
biomarkers, including
x
Delete exploratory objective “To 
correlate biomarkers to clinical 
response” and corresponding 
endpoint “Changes in circulating 
levels of, but not limited to, 
sVEGFR-2, VEGF, FGF, CSF-1, 
and IL‑34”.
x
Delete biomarker sampling row 
from Table 1 Schedule of Events.
x
Delete former Table 5 Schedule 
of Events for Biomarkers 
Evaluation: Part 1 and Part 2.
To remove biological sample 
collection for biomarkers and 
analysis of biomarker data.
Section 1– Synopsis
Section 6.1.6 – Safety 
Follow-up
Delete long-term follow-up at 6 months 
and 1 year from the last dose of protocol 
therapy, including removing these time 
points and activity “Telephone follow‑up” 
from Table 2 Schedule of Events.
To reduce required follow-up in the 
study to 30 days after end of 
treatment.
Section 9.3.1 – Disposition
Population for presentation of disposition
data changed from “the safety analysis set” 
to “all enrolled patients.”
For clarification.
9.3.4.1 – Objective 
Response Rate 
9.3.4.2 – Duration of 
Response
The following text was added: Both 
confirmed and unconfirmed responses will 
be evaluated.  To be assigned a status of 
confirmed PR or CR, the response must be 
confirmed by repeat assessments 
performed no less than 4 weeks after the 
criteria for response are first met.
Add statement that duration of response 
will be summarized separately for both 
confirmed and unconfirmed responders.
For clarification.
9.3.5 – Safety Analysis
Added definition of treatment-emergent 
change in laboratory tests graded by NCI 
CTCAE version 5.0 or higher: defined as
worsening of at least one grade from 
baseline.
For clarification
Section 2.1.4.3 –
Toxicology
Provide results of definitive juvenile 
toxicity study in rats.
To provide updated information.


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Section Number
Summary of Change
Rationale for Change
Section 4.1– Dose 
Escalation
Section 5.4 – Exclusion 
Criteria
Section 7.1.2 – Dosing and 
Administration
Appendix 3 – Surufatinib 
Dosing Nomogram
Added statements and an exclusion 
criterion applicable for Spain sites only, 
indicating that no subjects with BSA less 
≤0.6 or body weight ≤14 kg will be 
allowed to enroll in the study.
To add changes previously requested 
by Spain Health Authority and that 
were incorporated in prior Spanish
Addendum 1 to 2020-012-GLOB2 
Amendment 2.
Section 14 – References
Deleted publications no longer cited in 
protocol due to amendment.
To provide updated information.
Appendix 5 - Prohibited 
Concomitant Medications 
that Have a Known Risk of 
QT prolongation and/or 
Torsades de Pointes
List of prohibited concomitant medications 
with risk of QT prolongation and/or 
Torsades de Pointes has been updated.
To provide updated information.


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TABLE OF CONTENTS
STATEMENT OF COMPLIANCE...............................................................................................2 
SPONSOR’S APPROVAL............................................................................................................3 
INVESTIGATOR’S AGREEMENT.............................................................................................4 
DOCUMENT HISTORY...............................................................................................................5 
AMENDMENT SUMMARY........................................................................................................6 
TABLE OF CONTENTS.............................................................................................................10 
LIST OF TABLES.......................................................................................................................15 
LIST OF FIGURES .....................................................................................................................15 
LIST OF APPENDICES..............................................................................................................16 
LIST OF ABBREVIATIONS......................................................................................................17 
1 
SYNOPSIS.......................................................................................................................21 
1.1 
Study Schematic for 2020-012-GLOB2 .......................................................................24 
1.2 
Schedule of Events........................................................................................................24 
2 
INTRODUCTION ...........................................................................................................29 
2.1 
Background...................................................................................................................29 
2.1.1 
Target Indication and Population...............................................................................30 
2.1.2 
Description of Gemcitabine .......................................................................................30 
2.1.3 
Description of Surufatinib..........................................................................................31 
2.1.3.1 
Justification for Dosing Strategy ............................................................................31 
2.1.4 
Supportive Nonclinical Data......................................................................................31 
2.1.4.1 
Pharmacology .........................................................................................................31 
2.1.4.2 
Pharmacokinetics ....................................................................................................33 
2.1.4.3 
Toxicology..............................................................................................................34 
2.1.4.4 
Nonclinical Studies for Surufatinib in Combination with Gemcitabine.................35 
2.1.5 
Supportive Clinical Data............................................................................................36 
2.1.5.1 
Clinical Pharmacology and Pharmacokinetics........................................................36 
2.1.5.2 
Clinical Safety.........................................................................................................37 
2.1.5.3 
Clinical Efficacy .....................................................................................................37 
2.1.6 
Benefit/Risk Assessment ...........................................................................................38 
2.1.6.1 
Risk Assessment .....................................................................................................38 
2.1.6.2 
Benefit Assessment.................................................................................................45 


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2.1.6.3 
Overall Benefit/Risk Conclusion............................................................................45 
2.2 
Study Rationale.............................................................................................................45 
2.2.1 
Combination Therapy with Gemcitabine...................................................................45 
3 
OBJECTIVES AND ENDPOINTS.................................................................................48 
4 
STUDY DESIGN.............................................................................................................49 
4.1 
Dose Escalation.............................................................................................................49 
4.1.1 
Dose Finding Period ..................................................................................................49 
4.2 
Definition of Dose Limiting Toxicity...........................................................................51 
4.3 
Design Rationale...........................................................................................................53 
5 
POPULATION ................................................................................................................54 
5.1 
Recruitment...................................................................................................................54 
5.2 
Definitions.....................................................................................................................54 
5.3 
Inclusion Criteria ..........................................................................................................54 
5.4 
Exclusion Criteria .........................................................................................................57 
6 
STUDY CONDUCT........................................................................................................59 
6.1 
Study Procedures ..........................................................................................................59 
6.1.1 
Screening Period ........................................................................................................59 
6.1.1.1 
Informed Consent....................................................................................................59 
6.1.1.2 
Medical History ......................................................................................................59 
6.1.1.3 
Demographics .........................................................................................................59 
6.1.1.4 
Performance Score..................................................................................................60 
6.1.1.5 
Tumor Diagnosis and Treatment History ...............................................................60 
6.1.1.6 
Concomitant Medication and Procedures ...............................................................60 
6.1.2 
Safety Assessments....................................................................................................60 
6.1.2.1 
Physical Examination..............................................................................................60 
6.1.2.2 
Vital Signs...............................................................................................................60 
6.1.2.3 
Hematology.............................................................................................................60 
6.1.2.4 
Blood Chemistry, Liver Function Tests, and Kidney Function Tests.....................61 
6.1.2.5 
Coagulation.............................................................................................................61 
6.1.2.6 
Thyroid Function ....................................................................................................61 
6.1.2.7 
Urinalysis ................................................................................................................61 
6.1.2.8 
Pregnancy Test........................................................................................................61 


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6.1.2.9 
Electrocardiogram...................................................................................................61 
6.1.2.10 
Echocardiogram ......................................................................................................61 
6.1.2.11 
Knee X-Ray and Knee Magnetic Resonance Imaging ...........................................61 
6.1.3 
Efficacy Assessments.................................................................................................62 
6.1.4 
Pharmacokinetic Evaluations.....................................................................................62 
6.1.4.1 
Sampling Collection and Handling.........................................................................62 
6.1.4.2 
Analytical Procedures .............................................................................................62 
6.1.5 
Treatment Period........................................................................................................62 
6.1.6 
Safety Follow-up........................................................................................................64 
6.1.7 
End of Study ..............................................................................................................64 
6.2 
Discontinuation or Withdrawal.....................................................................................64 
6.2.1 
Individual Patients .....................................................................................................64 
6.2.1.1 
Treatment Interruption............................................................................................64 
6.2.1.2 
Permanent Discontinuation of Treatment ...............................................................64 
6.2.1.3 
Withdrawal from Study...........................................................................................65 
6.2.1.4 
Replacement of Patients..........................................................................................65 
6.2.1.5 
Patients Lost to Follow-up......................................................................................65 
6.3 
Study Termination ........................................................................................................66 
7 
STUDY INTERVENTIONS ...........................................................................................67 
7.1 
Surufatinib.....................................................................................................................67 
7.1.1 
Formulation, Storage, Preparation, and Handling .....................................................67 
7.1.2 
Dosing and Administration........................................................................................67 
7.2 
Gemcitabine..................................................................................................................68 
7.2.1 
Formulation, Storage, Preparation, and Handling .....................................................68 
7.2.2 
Dosing and Administration........................................................................................68 
7.3 
Dose Modifications.......................................................................................................68 
7.3.1 
Dose Modifications for Hematological Toxicity.......................................................70 
7.3.2 
Dose Modifications for Non-Hematological Toxicity...............................................71 
7.3.3 
Dose Modification of Surufatinib for Adverse Events of Special Interest ................72 
7.3.3.1 
Dose Modifications for Proteinuria ........................................................................72 
7.3.3.2 
Dose Modifications for Hypertension.....................................................................72 
7.3.3.3 
Dose Modifications for Hepatic Disorders .............................................................74 


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7.3.3.4 
Dose Modifications for Hemorrhage ......................................................................75 
7.3.3.5 
Dose Modifications for Thyroid Toxicity...............................................................75 
7.3.4 
Dose Modifications for Diarrhea ...............................................................................75 
7.3.5 
Dose Modifications for Thromboembolic Events......................................................75 
7.4 
Assessment and Verification of Compliance................................................................75 
7.5 
Prior and Concomitant Therapies .................................................................................75 
7.5.1 
Prohibited Therapies ..................................................................................................76 
7.5.2 
Permitted Therapies ...................................................................................................76 
7.5.3 
Drug-Drug Interactions..............................................................................................76 
7.6 
Drug Accountability......................................................................................................76 
8 
SAFETY MONITORING................................................................................................78 
8.1 
Definitions.....................................................................................................................78 
8.1.1 
Adverse Event............................................................................................................78 
8.1.2 
Serious Adverse Event...............................................................................................79 
8.1.3 
Causality or Relatedness............................................................................................79 
8.2 
Adverse Events of Gemcitabine....................................................................................80 
8.3 
Documenting Adverse Events.......................................................................................81 
8.3.1 
Timeframe for Collection ..........................................................................................81 
8.4 
Reporting Adverse Events ............................................................................................81 
8.4.1 
Expedited Reporting Period.......................................................................................81 
8.4.2 
All Serious Adverse Events and Protocol-Defined Adverse Events of Special Interest
....................................................................................................................................81 
8.4.2.1 
Drug-Induced Liver Injury......................................................................................82 
8.4.2.2 
Severe Hemorrhagic Events....................................................................................82 
8.5 
Adverse Events of Special Interest for Surufatinib.......................................................82 
8.6 
Clinical Laboratory Findings ........................................................................................82 
8.7 
Pregnancy......................................................................................................................83 
8.8 
Overdose or Misuse ......................................................................................................83 
9 
STATISTICAL ANALYSIS ...........................................................................................85 
9.1 
Hypothesis.....................................................................................................................85 
9.2 
Population .....................................................................................................................85 
9.2.1 
Sample Size Rationale ...............................................................................................85 
9.2.2 
Analysis Populations..................................................................................................85 


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9.3 
Statistical Analysis Methods.........................................................................................85 
9.3.1 
Disposition.................................................................................................................86 
9.3.2 
Demographics and Other Baseline Characteristics....................................................86 
9.3.3 
Prior and Concomitant Medications ..........................................................................86 
9.3.4 
Efficacy Analyses ......................................................................................................86 
9.3.4.1 
Objective Response Rate ........................................................................................86 
9.3.4.2 
Duration of Response..............................................................................................86 
9.3.4.3 
Disease Control Rate...............................................................................................87 
9.3.4.4 
Time to Response....................................................................................................87 
9.3.4.5 
Progression-Free Survival.......................................................................................87 
9.3.5 
Safety Analysis ..........................................................................................................87 
9.3.6 
Other Analysis ...........................................................................................................88 
9.3.6.1 
Taste and Palatability Survey..................................................................................88 
9.3.7 
Pharmacokinetics Analysis........................................................................................88 
9.4 
Timing of Analyses.......................................................................................................88 
10 
ETHICAL CONSIDERATIONS.....................................................................................89 
10.1 
Good Clinical Practice ..................................................................................................89 
10.2 
Ethics Review ...............................................................................................................89 
10.3 
Data Privacy..................................................................................................................89 
10.4 
Disclosure .....................................................................................................................90 
10.5 
Data Quality Assurance ................................................................................................90 
10.6 
Informed Consent..........................................................................................................90 
11 
OVERSIGHT...................................................................................................................92 
11.1 
Safety Review Committee ............................................................................................92 
11.2 
Quality Control and Assurance.....................................................................................92 
11.2.1 
Monitoring .................................................................................................................92 
11.2.2 
Audits.........................................................................................................................92 
11.2.3 
Records ......................................................................................................................93 
11.2.3.1 
Data Capture and Management...............................................................................93 
11.2.3.2 
Source Documentation............................................................................................93 
11.2.3.3 
Records Retention...................................................................................................94 
11.3 
Study Termination or Study Site Closure .....................................................................94 


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12 
PUBLICATION POLICY ...............................................................................................95 
13 
FINANCING AND INSURANCE..................................................................................96 
14 
REFERENCES ................................................................................................................97 
15 
APPENDICES ...............................................................................................................102 
LIST OF TABLES
Table 1 
Schedule of Events...............................................................................................25 
Table 2 
Schedule of Events for Pharmacokinetic Evaluation...........................................28 
Table 3 
Summary of Identified Risks of Surufatinib........................................................39 
Table 4 
Objectives and Endpoints ....................................................................................48 
Table 5 
Rolling 6 Dose Escalation Rules Based on DLT Evaluable Patients ..................50 
Table 6 
Description of Products........................................................................................67 
Table 7 
Surufatinib Dosing Nomogram............................................................................68 
Table 8 
Dose Modifications for Hematological Toxicity.................................................70 
Table 9 
Dose Modifications for Non-Hematological Toxicity.........................................71 
Table 10 
Dose Modification of Surufatinib for Proteinuria................................................72 
Table 11 
Dose Modification of Surufatinib for Hypertension............................................73 
Table 12 
Dose Modification of Surufatinib for Hepatic Disorders ....................................74 
Table 13 
Dose Modification of Surufatinib for Hemorrhage .............................................75 
Table 14 
Time Point Response: Patients with Target Lesions (with or without Non-Target 
Lesions)..............................................................................................................110 
Table 15 
Time Point Response: Patients with Non-Target Lesions Only ........................110 
Table 16 
Best Overall Response When Confirmation of Complete Response and Partial 
Response is Required.........................................................................................111 
Table 17 
Medications That Are Substrates, Inhibitors, or Inducers of CYP3A or Substrates 
of P-gp and BCRP..............................................................................................115 
LIST OF FIGURES
Figure 1 
Study Schematic...................................................................................................24 
Figure 2 
Tumor Volume in Fibrosarcoma HT-1080 Model...............................................36 
Figure 3 
Dosing Schematic ................................................................................................63 


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LIST OF APPENDICES
Appendix 1 
KARNOFSKY/LANSKEY PERFORMANCE STATUS SCALE...................103 
Appendix 2 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST Version 
1.1) .....................................................................................................................104 
Appendix 3 
SURUFATINIB DOSING NOMOGRAM........................................................114 
Appendix 4 
EXAMPLES OF MEDICATIONS THAT ARE SUBSTRATES, INHIBITORS, 
OR INDUCERS OF CYP3A OR SUBSTRATES OF P-GP OR BCRP...........115 
Appendix 5 
PROHIBITED CONCOMITANT MEDICATIONS THAT HAVE A KNOWN
RISK OF QT PROLONGATION AND/OR TORSADES DES POINTES......116 
Appendix 6 
CLINICAL EVALUATION OF POSSIBLE DRUG-INDUCED LIVER INJURY
............................................................................................................................119 
Appendix 7 
BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT 
PERCENTILE....................................................................................................121 
Appendix 8 
TOXICITY-SPECIFIC GRADING FOR LIVER FUNCTION TESTS ...........125 
Appendix 9 
THE TASTE AND PALATABILITY SURVEY..............................................126 
Appendix 10 AMENDMENT HISTORY ...............................................................................127 


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LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
AESI
Adverse event of special interest
AKI
Acute kidney injury
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AP
Anteroposterior
aPTT
Activated partial thromboplastin time
AR
Adverse reaction
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-24h
Area under the plasma concentration-time curve from time 0 to 
24 hours
AUC0-last
Area under the plasma concentration-time curve from time 0 to 
time of last measurable concentration
AUC0-t
Area under the plasma concentration-time curve from time 0 to 
time t
AUC0-tau
Area under the plasma concentration-time curve over the dosing 
interval
AUCss
Area under the plasma concentration-time curve at steady state
BCRP
Breast cancer resistance protein
BML
Below measurable limit
BOR
Best overall response
BP
Blood pressure
BSA
Body surface area
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CL/F
Apparent total clearance from plasma after oral administration
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CNS
Central nervous system
CR
Complete response
CRF
Case report form


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Abbreviation
Definition
CRO
Contract research organization
CSF-1R
Colony stimulating factor 1 receptor
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCR
Disease control rate
DILI
Drug-induced liver injury
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
epNET
Extra-pancreatic neuroendocrine tumor
EU
European Union
FDA
Food and Drug Administration
FDG-PET
18F-fluorodeoxyglucose positron emission tomography
FGFR-1
Fibroblast growth factor receptor 1
γ-GGT
Gamma-glutamyl transferase
GCP
Good Clinical Practice
GI
Gastrointestinal
hERG
Human ether-à-go-go-related gene
HR
Hazard ratio
HUVEC
Human umbilical vein endothelial cell
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IV
Intravenous


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Abbreviation
Definition
KDR
Kinase insert domain receptor
KM
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MTKI
Multi-tyrosine kinase inhibitors
MUGA
Multigated acquisition
NCI
National Cancer Institute
NE
Not evaluable
NET
Neuroendocrine tumors
NOAEL
No-Observed-Adverse-Effect Level
NR
Not reached
NRSTS
Non-rhabdomyosarcoma soft tissue sarcoma
ORR
Objective response rate
P/C
Protein/creatinine
PD
Pharmacodynamic(s)
PD
Progressive disease
PFS
Progression-free survival
PI
Principal Investigator
P-gp
P-glycoprotein
p-KDR
Kinase insert domain receptor phosphorylation
PK
Pharmacokinetic(s)
pNET
Pancreatic neuroendocrine tumor
PR
Partial response
PT
Preferred term 
PT
Prothrombin time
QD
Once daily
QTc
Corrected QT interval(s)
QTcF
Corrected QT interval by Fridericia
RECIST
Response Evaluation Criteria in Solid Tumors
RMS
Rhabdomyosarcoma
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
SAE
Serious adverse event


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Abbreviation
Definition
SAP
Statistical Analysis Plan
SAR
Serious adverse reaction
SD
Stable disease
SOC
System Organ Class
SOE
Schedule of events
SRC
Safety Review Committee
SSRI
Selective serotonin reuptake inhibitor
STS
Soft tissue sarcoma
T1/2
Half-life
T4
Free thyroxine
TAM
Tumor associated macrophage
TBIL
Total bilirubin
TEAE
Treatment-emergent adverse event
TGI
Tumor growth inhibition
TKI
Tyrosine kinase inhibitor
Tmax
Time to reach the maximum plasma concentration
TSH
Thyroid stimulating hormone
TTR
Time to response
UK
United Kingdom
ULN
Upper limit of normal
US
United States
Vd
Volume of distribution
VEGF
Vascular endothelial growth factor
VEGFR
Vascular endothelial growth factor receptor


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1
SYNOPSIS
Title
An Open-Label, Multicenter Phase 1/2 Study of Surufatinib in Combination 
with Gemcitabine in Pediatric, Adolescent, and Young Adult Patients with 
Recurrent or Refractory Solid Tumors
Short Title
A Study of Surufatinib in Combination with Gemcitabine in Pediatric,
Adolescent, and Young Adult Patients with Recurrent or Refractory Solid 
Tumors
Acronym
Not applicable
Phase
Phase 1/2
Study Status as of Protocol 
Amendment 3
As of 16 December 2022, enrollment to study 2020-012-GLOB2 was halted
based upon the strategic evaluation of the clinical development of surufatinib in 
the United States and Europe with HUTCHMED as the study Sponsor.  This 
change is not based on any concern for patient safety or efficacy relative to 
surufatinib treatment.  Currently enrolled patients who are deriving clinical 
benefit from treatment with surufatinib may continue to participate in the study 
as per the protocol.  There is no planned interruption in the supply of surufatinib 
to clinical trial sites with active patients. In addition, as no patients have enrolled 
in study Part 2 (dose expansion) as of the end of enrollment date, Part 2 is 
removed from the study design in this protocol Amendment 3. Part 1 (dose 
escalation) will continue as outlined in this protocol amendment. 
Rationale
Pediatric patients with recurrent or refractory solid tumors continue to 
experience dismal outcomes despite advances through much of pediatric 
oncology.  There is an unmet need for better treatments for pediatric patients 
with solid tumors. This study will be performed on pediatric patients with 
recurrent or refractory solid tumors who have no known curative therapy.
Although surufatinib monotherapy has shown clinical activity in adults with 
neuroendocrine tumors and in select adult cancer models, this study proposes 
that adding a chemotherapy agent in combination with surufatinib will provide 
added benefit for pediatric patients with refractory/recurrent solid tumors.  Many 
current pediatric early phase studies combine an investigational agent with an 
irinotecan/temozolomide backbone both for anti-tumor effect and because of the 
tolerability and non-overlapping toxicities of the irinotecan/temozolomide 
backbone.  However, irinotecan and temozolomide have shown limited effect in 
patients with osteosarcoma, a population of patients who may benefit most from 
a selective colony stimulating factor 1 receptor (CSF-1R) inhibitor such as 
surufatinib.  Gemcitabine is a pyrimidine antimetabolite that inhibits tumor 
growth by disrupting deoxyribonucleic acid replication.  Gemcitabine has been 
used as salvage chemotherapy alone and in combination in pediatric patients 
with relapsed/refractory sarcomas, particularly in patients with osteosarcoma 
but also in those with Ewing sarcoma or rhabdomyosarcoma (RMS).  In phase 
1 testing of gemcitabine in pediatric patients, no maximum tolerated dose 
(MTD) was reached, with only 1 in 6 patients experiencing Grade 4
myelosuppression when treated with 2100 mg/m2 of gemcitabine once weekly 
for 2 weeks in 28-day cycles.
Target Population
Pediatric, adolescent and young adult patients (age range ≥2 and <18 years of 
age for United States [US] sites, from birth to <18 years of age for European 
Union/United Kingdom [EU/UK] sites) with any recurrent or refractory solid 
tumors or lymphoma (not central nervous system) who have a known or 
expected dysfunction of vascular endothelial growth factor receptor-1, -2, and -
3; fibroblast growth factor receptor 1, or CSF-1R pathways.  Patients must 
have had histologic verification of malignancy at original diagnosis or relapse.


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Intervention
Surufatinib and gemcitabine will be administered as outlined in study summary.
Description of Sites
Approximately 30 study sites (~15 in the US, ~15 in EU/UK).
Objectives and Endpoints
Objective
Corresponding Endpoints
Primary 
x To determine MTD and/or recommended phase 2 
Dose (RP2D) of surufatinib, and to evaluate the 
safety and tolerability of surufatinib in combination 
with gemcitabine in pediatric patients with recurrent 
or refractory solid tumors or lymphoma
x
The incidence of dose limiting toxicities in each dose 
level
x
Safety, as assessed by:
o
The frequency and severity of adverse events
(AEs)
o
Physical examination findings
o
Vital signs
o
Laboratory test results
o
12-lead electrocardiogram (ECG)
Secondary
x To characterize the pharmacokinetics (PK) of 
surufatinib as a monotherapy and in combination 
with gemcitabine in pediatric patients with recurrent 
or refractory solid tumors or lymphoma
x Pharmacokinetic parameters for the dose escalation 
and
PK expansion cohorts:
maximum plasma 
concentration (Cmax), time to reach the maximum 
plasma concentration (Tmax), area under the plasma 
concentration-time curve (AUC), minimum plasma 
concentration (Cmin), effective half-life (t½), apparent 
total clearance from plasma after oral administration
(CL/F), and accumulation ratio
x To evaluate the anti-tumor activity of surufatinib in 
combination with gemcitabine in pediatric patients 
with recurrent/refractory solid tumors or lymphoma
x
Efficacy 
endpoints 
evaluated 
per 
RECIST 
version 1.1:
o
Objective response rate (ORR)
o
Disease control rate (DCR)
o
Time to response (TTR)
o
Duration of response (DoR)
o
Progression-free survival (PFS)
x
Acceptability and palatability of surufatinib oral 
suspension
x
The taste and palatability survey 
Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of surufatinib, thereby identifying the MTD 
and/or RP2D of surufatinib administered in combination with gemcitabine in pediatric patients with recurrent or 
refractory solid tumors or lymphoma.
The study will evaluate tolerability and safety of surufatinib administered in combination with gemcitabine, and 
provide confirmation of the recommended clinical dose of surufatinib in pediatric patients with recurrent or 
refractory solid tumors
The study will enroll 2 to 6 patients per dose level cohort (up to 4 cohorts) with recurrent or refractory solid tumors.
During cycle 1, surufatinib will be administered, orally, once daily (QD), as a single agent for 14 days followed by 
surufatinib daily in combination with gemcitabine intravenously on days 15 and 22 (cycle 1 duration=35 days) and 
days 1 and 8 of all subsequent cycles (cycle duration=21 days).
Assessment based on dose limiting toxicity (DLT) criteria will be performed in the first 35-day cycle (DLT 
Evaluation Period).  This study will utilize a rolling 6 design, with 3 dose escalation levels and 1 de-escalation 
level, if needed.
At the MTD/RP2D, a PK expansion cohort will be planned to ensure that up to 6 patients <12 years of age and 
6 patients ≥12 and <18 years of age have been evaluated at the MTD/RP2D.


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Patients can remain on treatment until completing cycle 17, or until progressive disease, unacceptable toxicity, or 
death; whichever comes first.
Follow-up on this study is required at 30 days after the last dose of protocol therapy.
Condition/Disease
Recurrent or refractory solid tumors or lymphoma
Study Duration
Estimated 36 months
Treatment Duration
Approximately 12 months (including 24 months enrollment).  Treatment 
duration is anticipated to be 6 to 12 months for individual patients.
Health 
Measurement/Observation
DLTs
Safety (AEs, physical examination, vital signs, laboratory test results, and ECG)
Efficacy (DCR, ORR)
Acceptability/palatability (the taste and palatability survey) 
Visit Frequency
Screening will occur within 28 days of study day 1.
Cycle 1: days 1, 8, 15, 22, and 29
Cycle 2 and onward: day 1, 8, and 15
Safety follow-up: 30 days after last dose
Number of Patients
Up to 36 patients in dose escalation cohorts.
Intervention Groups and 
Duration
Surufatinib starting dose will be 120 mg/m2 daily.  The first study cycle will be 
35 days. During cycle 1, surufatinib will be administered, orally, QD, as a single 
agent for 14 days followed by surufatinib daily in combination with gemcitabine 
(1000 mg/m2 weekly × 2 doses) intravenously on days 15 and 22.  Surufatinib 
dose can be decreased by 1 dose level or increased up to 2 dose levels from 
starting dose based on tolerability. Gemcitabine will not be escalated, and will 
be given on days 1 and 8 of all subsequent cycles. After cycle 1, cycle duration 
is 21 days.
Safety Review Committee
Yes


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1.1
Study Schematic for 2020-012-GLOB2
The study schematic is presented in Figure 1.
Figure 1
Study Schematic
PK=pharmacokinetic(s); RP2D=recommended phase 2 dose.
1.2
Schedule of Events
The schedule of events (SOE) is presented in Table 1.
The SOE for pharmacokinetic (PK)
evaluation  appears in Table 2. For detailed description of each event please reference Section 6.1.


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Table 1
Schedule of Events
Activity
Screening
Treatment Phase
Safety Follow-
up
Cycle 1 (35 days)
Subsequent Cycles 
(21 days per cycle)1
Day -28 
to Day 
‑2
Day -14 
to Day 
‑1
Day 
1
Day 8 
(±1d)
Day 15 
(±1d)
Day 22 
(±1d)
Day 29 
(±1d)
Day 1 
(±3d)
Day 8 
(±3d)
Day 15 
(±3d)
30 days after 
last dose (±7d)
Informed consent
X
Eligibility criteria 
review
X
Demographics
X
Medical history
X
Medication review
X
X
X
Pregnancy test2
X
X3
X
X
Complete physical 
exam4
X
Limited physical exam4
X
X
X
X
X
X
X
X
X
Performance score 
(Lansky or Karnofsky, 
or ECOG)
X
X
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
BP6
X
X
X
X
X
X
X
X
X
X
Height7
X
X
Weight7
X
X
Triplicate 12-lead 
ECG8
X
Day 1 of every even cycle (ie, 
cycles 2, 4, 6, 8, etc.)
X
Echocardiogram or 
MUGA
X
X
Chemistry panel9
X
X3
X
X
X
X
X
X
CBC with differential10
X
X3
X
X
X
X
X
X
X
X


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Table 1
Schedule of Events
Activity
Screening
Treatment Phase
Safety Follow-
up
Cycle 1 (35 days)
Subsequent Cycles 
(21 days per cycle)1
Day -28 
to Day 
‑2
Day -14 
to Day 
‑1
Day 
1
Day 8 
(±1d)
Day 15 
(±1d)
Day 22 
(±1d)
Day 29 
(±1d)
Day 1 
(±3d)
Day 8 
(±3d)
Day 15 
(±3d)
30 days after 
last dose (±7d)
Coagulation assay 
(aPTT, PT/INR)
X
X3
X
X
TSH, T4
X
X
Urinalysis11
X
X3
X
X
X
X
X
X
Tumor assessments
X
Day 1 of cycles 3, 5, 7, 9, 12, 15, end of cycle 17, and after every 3 cycles thereafter.
Bone marrow biopsies12
X
Day 1 of cycles 3, 5, 7, 9, 12 and 15, and end of cycle 1713
Knee X-ray
X
Every 6 months and end of treatment14
Pharmacokinetics
PK schedule per Table 2
AE reporting
Collected throughout time on study started at signing of informed consent
Patient diary
X
X
X
X
X
X
X
X
Taste and palatability 
survey15
X
X
Surufatinib dosing
Dosed daily at a dose according to the assigned dose level
Gemcitabine dosing
X
X
X
X
AE=adverse event; AP=anteroposterior; aPTT=activated partial thromboplastin time; BP=blood pressure; CBC=complete blood count; d=day; DLT=dose limiting 
toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; INR=International normalized ratio; MRI=magnetic resonance imaging; 
MUGA=multigated acquisition; PK=pharmacokinetics; PT=prothrombin time; QTcF=Corrected QT interval by Fridericia; T4=free thyroxine; TSH=thyroid 
stimulating hormone.
1.
Assessments may be obtained within 3 days prior to the start of subsequent cycles unless otherwise indicated.
2.
All female patients of childbearing potential must complete a serum pregnancy test at screening and at the safety follow-up visit, and a serum or urine pregnancy 
test on day 1 of every cycle starting at cycle 2.  Additional procedural details for pregnancy testing are available in Section 6.1.2.8.
3.
Laboratory tests need not be repeated at cycle 1 day 1 if therapy starts within 72 hours of obtaining laboratory test to assess eligibility.
4.
Complete physical examination refers to the examination of all body systems.  Limited physical examination includes vital signs, any change from baseline 
abnormalities, any new abnormalities, height, weight, and evaluation of patient-reported symptoms.
5.
Procedural details for vital signs are available in Section 6.1.2.2.
6.
Triplicate BP is required at baseline and at subsequent clinic visits if baseline BP is abnormal.  Wait for 1 to 3 minutes between BP readings.


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7.
Assessments can be done up to 7 days before scheduled visit.
8.
ECGs should be performed in triplicate at screening or if single read has a QTcF of ≥480 ms, and whenever feasible. Additional procedural details are provided 
in Section 6.1.2.9.
9.
Procedural details for blood chemistry are available in Section 6.1.2.4.
10.
If patient develops Grade 4 neutropenia, then CBC/differential count should be checked twice weekly (every 3 to 4 days) until recovery to Grade 3 or until
meeting the criteria for DLT.
11.
If urinalysis shows ≥ trace protein, then obtain urine P/C (protein/creatinine).  A 24-hour urine sample for quantitative protein should be collected, if possible,
for patients with ≥2+ proteinuria.
12.
If bone marrow disease clinically suspected.
13.
Only required if bone marrow biopsy at start of therapy was positive and until resolution.
14.
The X-ray of the right or left knee (tibial AP and lateral views) will be obtained for all patients at screening.  The follow-up X-rays (of the same knee obtained 
at screening) only need to be repeated in patients with open growth plates at study entry.  If abnormalities are detected on routine X-rays, an MRI scan of both 
knees should be performed.
15.
Parents of pediatric patients taking surufatinib oral suspension should complete the taste and palatability survey on day 1 and day 8 of cycle 1.
.


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Table 2
Schedule of Events for Pharmacokinetic Evaluation
Study 
Day
Surufatinib Administration and PK Samples
Time Relative to 
Surufatinib Dosing
Surufatinib Administration1
Surufatinib PK Samples,2,3
C1D1
Predose4
-
X
0 h
X
-
1 h
-
X
2 h
-
X
3 h
-
X
4 h
-
X
8 h
-
X
C1D2
Predose4
-
X
C1D8
Predose4
-
X
0 h
X
-
C1D15
Predose4
-
X
0 h
X
-
-
-
-
-
-
-
1 h
-
X
2 h
-
X
3 h
-
X
4 h
-
X
8 h
-
X
C1D16
Predose4
-
X5
C1D22
Predose4
-
X
0 h
X
-
-
-
-
C1D29
Predose4
-
X
0 h
X
-
Day 1 
of sub-
sequent 
cycles6
Predose4
-
X
or
X
0 h
X
≥3 h
-
CxDx=cycle x day x; eCRF=electronic case report form; h=hour(s); ; PK=pharmacokinetic(s).
1.
Study treatment must be taken at the investigative site under the supervision of the Investigator or designee and 
should not be taken at home on the morning of the visits. The date and time of the dose administered at the site 
and the dose prior to the visit must be recorded.
2.
The date and time of the PK samples must be recorded in the eCRF.
3.
Allowable sampling time deviation windows are ±5 minutes for 1 hour, ±10 minutes for 2 hours, 15 minutes for 
3 and 4 hours, and 30 minutes for 8 hours.
4.
Predose PK should be performed within 60 minutes before study treatment administration.
5.
The C1D16 predose PK may be omitted only if a predose PK sample on C1D15 is collected.
6.
On day 1 of subsequent cycles, 1 PK sample is to be obtained either at predose or at least 3 hours postdose.


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2
INTRODUCTION
2.1
Background
Relapsed and refractory solid tumors for which there are few effective treatment options are a 
significant source of morbidity and mortality in pediatric oncology. Surufatinib is a novel small 
molecule kinase inhibitor that modulates
the tumor microenvironment by inhibiting 
tumor-associated macrophages (TAMs) while also targeting tumor angiogenesis.  It selectively 
inhibits colony stimulating factor 1 receptor (CSF-1R), vascular endothelial growth factor receptor 
(VEGFR) 1, 2, and 3, and fibroblast growth factor receptor 1 (FGFR-1) (Xu 2019).  In human 
tumor xenograft models of cancer in adults (gastric cell carcinoma and renal cell carcinoma), it 
has potent anti-angiogenesis activity and improved kinase selectivity compared to earlier 
generations of small molecule tyrosine kinase inhibitors (TKIs) (Surufatinib Investigator’s 
Brochure [IB]).
Tumor associated macrophages in the tumor microenvironment are well described cells that affect 
the ability of many solid tumors to evade the host immune system, and high levels of TAMs have 
been associated with poor prognoses in a variety of solid tumors (Lewis 2006).  CSF-1R plays a 
critical role in signal transduction leading to the differentiation and persistence of macrophages 
and is a known mediator that promotes TAMs within the microenvironment.  CSF-1R modulates 
differentiation, proliferation, and survival via PI3K or the RAF/MEK/ERK pathways.  Regulation 
of cell adhesion and migration is modulated by the binding of CSF-1 to CSF-1R leading to 
phosphorylation of Focal Adhesion Kinase, which activates signaling, leading to cytoskeleton 
remodeling, adhesion, and migration.  The downstream effects of CSF-1/CSF-1R blockade 
produce an environment of decreased immune suppression and increased interferon response, 
impeding tumor growth (Osipov 2019). CSF-1R is expressed on a wide range of solid tumor cells, 
including osteosarcoma, and its inhibition suppresses osteosarcoma tumor cell line proliferation 
and growth in mice (Wen 2017).  CSF-1R inhibition sensitizes tumor cells to cytotoxic 
chemotherapy including cisplatin and trabectedin. 
CSF-1R is encoded by the c-fms proto-oncogene and is included as a relevant target in the National 
Cancer Institute (NCI)/Food and Drug Administration (FDA) Molecular Target List for the RACE 
for Children Act.  CSF-1R has 2 known ligands, CSF-1 and interleukin 34 (IL‑34).  CSF-1 is 
produced by fibroblasts, endothelial cells, monocytes, macrophages, osteoblasts, microglia, 
keratinocytes, bone marrow stroma, NK cells, B cells, and T cells.  Physiologic roles of CSF-1
include survival, proliferation, differentiation, and motility of cells in the monocyte lineage, as 
well a bone remodeling by osteoclasts (Rovida 2015, Achkova 2016). CSF-1R overexpression 
promotes proliferation, migration, and invasion of the nasopharyngeal carcinoma cell line 6-10B
(Chen 2018). In osteosarcoma cell lines, overexpression of CSF-1R enhances cell proliferation 
and accelerates cell growth, migration, and invasion.  Silencing of CSF-1R by ribonucleic acid 
(RNA) interference suppresses proliferation and osteosarcoma tumor growth in mice (Wen 2017).  
Xenograft mouse models using orthotopic osteosarcoma cell line and subcutaneous patient-derived 
xenografts, pexidartinib (kinase inhibitor targeting CSF-1R) treatment significantly inhibited local 
osteosarcoma tumor growth and lessened metastatic burden (Smeester 2020).  Additionally, in
murine neuroblastoma models, CSF-1R inhibition in combination with cyclophosphamide and 
topotecan inhibited tumor growth and improved mouse survival (Webb 2018).


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Small molecule and monoclonal antibody CSF-1R inhibitors are in clinical development both as 
monotherapy and in combination therapy (chemotherapy and/or immunotherapy) in adults with 
solid tumors and have demonstrated good tolerability (Cannarile 2017). Pexidartinib is approved 
for the treatment of tenovial giant cell tumor in the United States (US) and has also demonstrated 
clinical activity (response rate 5%) as a monotherapy in a phase 2 study for relapsed or refractory 
Hodgkin lymphoma (HL).  Although the efficacy of single agent PLX3397 in this study population 
was modest, the manageable safety profile and evidence of target inhibition may warrant further 
testing in combination therapy studies (Moskowitz 2012). JNJ-40346527, a selective inhibitor of 
CSF-1R tyrosine kinase, has shown clinical activity (1 patient with CR, 10 patients with stable 
disease [SD] of total 21 patients) in the phase 1 study for relapsed or refractory classical HL (von 
Treskow 2013). Lastly, in a phase 1 study of AMG 820, an investigational fully human CSF-1R 
antibody in adult patients with relapsed or refractory advanced solid tumors, AMG 820 was 
tolerated with manageable toxicities and clinical activity was observed (objective response rate 
[ORR] 4%; clinical benefit rate [CBR] 24% in 25 patients) (Papadopoulos 2017).
VEGF-mediated signaling plays a critical role in tumor growth by promoting angiogenesis, and 
high levels of VEGF expression are seen across a wide range of pediatric tumors, including 
neuroblastoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and rhabdomyosarcoma (RMS), and 
are associated with recurrence and poorer prognoses (Ghanem 2003, Eggert 2000, Gee 2005).
Additionally, solid tumors depend on vascular supply, and the inhibition of tyrosine kinases that 
promote tumor angiogenesis, including VEGFRs and FGFR-1, is a well described potential 
therapeutic target in patients in wide ranging solid malignancies.  Demonstration of clinical 
activity of multi-tyrosine kinase inhibitors (MTKI) such as regorafenib and cabozantinib have 
re-vitalized interest in MTKI, including those with VEGFR inhibition in solid tumors in children.
2.1.1
Target Indication and Population
As of 16 December 2022, enrollment to study 2020-012-GLOB2 was halted based upon the
strategic evaluation of the clinical development of surufatinib in the United States and Europe 
with HUTCHMED as the study Sponsor.  This change is not based on any concern for patient 
safety or efficacy relative to surufatinib treatment.  Currently enrolled patients who are deriving 
clinical benefit from treatment with surufatinib may continue to participate in the study as per the 
protocol.  There is no planned interruption in the supply of surufatinib to clinical trial sites with 
active patients. In addition, as no patients have enrolled in study Part 2 (dose expansion) as of the 
end of enrollment date, Part 2 is removed from the study design in this protocol Amendment 3.  
Part 1 (dose escalation) will continue as outlined in this protocol amendment. 
Although outcomes in pediatric cancer have improved significantly in recent years, the prognosis 
is still poor for pediatric patients with recurrent, refractory, or metastatic disease.  There remains 
a need for more effective therapies for these patients.  The study will include pediatric,
adolescent, and young adult patients ≥2 and <18 years of age (for US sites) and from birth to <18 
years of age (for European Union/United Kingdom [EU/UK] sites) who have recurrent or 
refractory solid tumors or lymphoma with no known curative therapy.
2.1.2
Description of Gemcitabine
Gemcitabine inhibits cell cycles progression and acts as a deoxyribonucleic acid (DNA) synthesis 
inhibitor.  Gemcitabine PK is linear and is described by a 2-compartment model.  Gemcitabine 
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long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly 
increased volume of distribution (Vd) with longer infusions. 
The inactive metabolite of 
gemcitabine is excreted in the urine with 92% to 98% of the gemcitabine dose excreted in the urine 
within 1 week of administration.
2.1.3
Description of Surufatinib
Surufatinib is a novel TKI that inhibits VEGFR 1, 2, and 3, as well as FGFR-1, which results in 
inhibition of angiogenesis.  In addition, surufatinib inhibits signaling via CSF-1R, which is thought 
to down-regulate TAMs, thus promoting anti-tumor immunity.
2.1.3.1
Justification for Dosing Strategy
The recommended phase 2 dose (RP2D) for surufatinib is 300 mg/day in adults. Surufatinib has 
not been studied in pediatric patients.  This study proposes to conduct a phase 1/2 study of 
surufatinib in combination with gemcitabine in pediatric patients with relapsed or refractory solid 
tumors or lymphoma with no known curative therapy. This dose finding study will use a rolling 
6 design (Simon 1989).
In adults receiving 200 to 350 mg per day of surufatinib, the T1/2 was 19.5 hours, and similar 
exposure accumulation was reached on days 14 and 28, indicating that a steady state was achieved 
on day 14 with the mean accumulation index of 1.8- to 2.7-fold. The starting dose of 120 mg/m2
once daily (QD) surufatinib in pediatric patients will be 70% of the adult RP2D (300 mg for a 
70 kg adult=175 mg/m2) and will be dosed based on body surface area (BSA). Gemcitabine will 
be administered intravenously at a dose of 1000 mg/m2 weekly × 2 doses, which has efficacy in 
pediatric sarcomas. Cycle 1 will aim to establish tolerability and safety and to obtain PK of 
surufatinib as a single agent and in combination with gemcitabine.
The proposed starting dose of 120 mg/m2 surufatinib in pediatric patients is further supported by 
a model-based approach. Based on population PK model analysis, a 120 mg/m2 dose is proposed 
for pediatric patients aged 2 to 5 years old and a 140 to 160 mg/m2 dose is proposed for pediatric 
patients aged 5 to 18 years old. These proposed dosing regimens are predicted to result in 
surufatinib area under the plasma concentration-time curve at steady state (AUCss) to fall within 
the target therapeutic exposure, derived from the 10th to 90th percentile of surufatinib AUCss after
300 mg QD dosing that demonstrated efficacy in patients with neuroendocrine tumors (NETs), in 
more than 98% of the pediatric patients.
2.1.4
Supportive Nonclinical Data
2.1.4.1
Pharmacology
Surufatinib (HMPL-012, also previously known as sulfatinib) is a small molecule oral kinase 
inhibitor with selective and potent inhibition of CSF-1R (half maximal inhibitory concentration 
[IC50] 4nM), VEGFR 1 (IC50 2nM), VEGFR 2 (IC50 24nM), VEGFR 3 (IC50 1nM), and FGFR-1
(IC50 15nM), with significantly weaker effect on other kinases such as PDGFR, c-KIT, and YES.
Consistent with its biochemical activity on kinase insert domain receptor (KDR) kinase inhibition,
surufatinib demonstrated strong inhibitory activity on 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 
those 
of 
PI3K/AKT, 


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RAS/RAF/MEK/ERK, and p38 were also inhibited in a dose-dependent manner. Furthermore, in 
functional assays using human umbilical vein endothelial cells (HUVECs), surufatinib inhibited
VEGF-dependent cell proliferation, with an IC50 of 16 nM, and inhibited 75% of HUVEC tube 
formation with at 0.3 μM. 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 has been 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 have been evaluated in vivo. 
Upon stimulation with VEGF (intravenous [IV],
0.5 μg/mouse), KDR phosphorylation (p-KDR) in the mouse lung tissue was significantly induced. 
Surufatinib administered orally completely inhibited VEGF-stimulated KDR phosphorylation for 
4 hours at 20 and 40 mg/kg and for 8 hours at 80 mg/kg, which suggest dose-dependent inhibition.
In this experiment, the drug exposure was determined. For instance, at 4 hours after oral 
administration of 20 mg/kg of surufatinib, the drug concentration in plasma reached 181 ng/mL 
(area under the plasma concentration-time curve [AUC] for 20 mg/kg was 2720 ng∙h/mL). These 
data provided PK/pharmacodynamic (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 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 demonstrated a good 
dose response in these studies. Among the 4 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 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 TGI.
The plasma concentrations of surufatinib were analyzed in BGC-823 tumor bearing mice at the 
end of the efficacy study after the last dose. 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 the
BGC-823 model (TGI=68%), and the corresponding minimum efficacious exposure, area under 
the plasma concentration-time curve from time 0 to 24 hours (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.
Safety Pharmacology:
In safety pharmacology studies, no adverse effects were observed on the cardiovascular and 
respiratory systems as evidenced by the results of a single dose study in anesthetized dogs (highest 


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dose 60 mg/kg) and the collected electrocardiograms (ECGs) in a 13-week dog repeat-dose toxicity 
study (highest dose 12 mg/kg/day). The absence of findings on the cardiovascular system in vivo
is in-line with the in vitro human ether-à-go-go-related gene (hERG) assay with an IC50 of 1.8 μM, 
which is 46-fold above the clinical maximum plasma concentration (Cmax) (free) at a dose of 
300 mg, indicating a low risk for corrected QT interval(s) (QTc) prolongation. No effect was 
found on the central nervous system (CNS) in mice at the highest dose tested (400 mg/kg) based 
on the Irwin’s behavior grading and pole-climbing tests. Collectively, the results showed that 
surufatinib had a low risk of adverse effects on the cardiovascular, respiratory and CNS.
2.1.4.2
Pharmacokinetics
After a single IV dose of 10 mg/kg surufatinib in rats, the plasma elimination T1/2 of surufatinib 
was measured as 2.8 hours, and plasma clearance and apparent Vd 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/kg or above, the bioavailability exceeded 50%. The low 
bioavailability observed at the low dose level might be associated with the efflux by P-glycoprotein
(P-gp) in intestinal epithelial cells.
After a single IV dose of 5 mg/kg in dogs, the plasma elimination T1/2 was 3.3 hours, and plasma 
clearance and apparent Vd 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 to
4.5 hours. In the dose range of 5 to 20 mg/kg, surufatinib exposure (Cmax and area under the plasma 
concentration-time curve from time 0 to time t [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%.
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 postdose, 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 
feces (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 
cytochrome P450 (CYP)3A4/5 (dehydrogenation, N-demethylation), CYP2C8 (dehydrogenation, 
N-demethylation), CYP2E1 (mono-oxidization), and flavin-containing monooxygenase.
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 
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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.
2.1.4.3
Toxicology
General Toxicology:  In single-dose toxicity studies in rats and dogs, no mortality occurred up to 
the highest dose tested at 2000 mg/kg, indicating a good tolerability following single oral dosing.
Repeated-dose toxicity studies were carried out for surufatinib in rats (1-month, 3-month, and 
6--month) and dogs (1-month, 3-month, and 9-month), respectively. The No-Observed-Adverse-
Effect Level (NOAEL) of surufatinib in the 13-week repeated-dose toxicity was 15 mg/kg/day and 
6 mg/kg/day, respectively, in rats and dogs. The toxicokinetic results indicated that the exposures 
of surufatinib in rats at the NOAEL dose were higher than the exposures at a clinical dose of 
300 mg in study 2015-012-00US1. In the repeated-dose toxicity studies, the main target organs 
were hepatobiliary system (increase of alkaline phosphatase [ALP], aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], total bilirubin [TBIL] and triglyceride, along with 
hepatocyte degeneration/necrosis, slight hyperplasia of bile duct), kidney (increase of urea 
nitrogen and creatinine, diffuse degeneration and swelling of the glomerular capillary endothelial 
cell, hyaline cast), immune system (decrease of lymphocyte in thymus, spleen, and mesenteric 
lymph node, splenic white pulp atrophy), hematopoietic system (bone marrow hematopoietic cell 
decrease), skeletal system effects (chondrocyte hyperplasia and hypertrophy of growth plate with 
osteodysplasia and broken teeth), pancreas (acinus atrophy), adrenals glands, and uterus atrophy, 
and corpus luteum necrosis. All effects were fully or partially reversible after a 4-week recovery 
period apart from the effects on the skeletal system (broken teeth). Taken together, it is worthwhile 
to note that at high doses surufatinib might cause kidney and gastrointestinal (GI) toxicities. In 
addition, with extended dosing at lower/tolerated doses, the lymphatic system might be affected. 
Therefore, during the 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.
Genetic Toxicology:  Surufatinib was not genotoxic based on the results of a standard panel of in 
vitro and in vivo genotoxicity studies comprised of an in vitro bacterial reverse mutation assay in 
Salmonella typhimurium (+/- S9), an in vitro chromosome aberration assay in Chinese hamster 
ovary cells (+/- S9), and an in vivo rat micronucleus test with inclusion of an alkaline comet assay.
Reproductive and development toxicology:  In the fertility and early embryonic development 
implantation study in rats with doses up to 45 mg/kg/day in males and up to 30 mg/kg/day in 
females, respectively, surufatinib at 30 mg/kg/day affected female reproductive function and 
embryo formation, and produced uterus damage. The NOAEL for male rat’s fertility and early 
embryonic development was established to be 45 mg/kg/day, and that for female rat’s fertility and 
early embryonic development was 10 mg/kg/day. In the embryo-fetal development study in rats 
at the top-dose of 15 mg/kg/day, mean maternal body weight gain decrease, an increase in post 
implantation loss, a reduction in gravid uterine weight, and reductions in adjusted mean fetal body 
weight were noted. Developmental toxicities observed at 15 mg/kg/day consisted of fetal external 
malformations, visceral malformations, skeletal malformations and skeletal growth retardation. 
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fetal development study in rabbits, the dose of 48 mg/kg/day interfered with embryo formation 
and induced growth retardation, the NOAEL of surufatinib for maternal effects was 48 mg/kg/day, 
and the NOAEL for embryo- fetal toxic effects was 24 mg/kg/day.
In a range-finding juvenile toxicity study, rats were dosed from postnatal (PND) 4 to up to PND 28.
Mortality occurred at 10 and 30 mg/kg/day, but not at 3 mg/kg/day. No effects were noted on 
incisor eruption, developed teeth, or femur length. In the definitive juvenile toxicity study with
surufatinib, rats were dosed from PND 10 to PND 70 at doses of 0.5, 1.5, or 3 mg/kg/day. No 
adverse findings were noted.
Phototoxicity: Surufatinib was not phototoxic based on the results of a phototoxicity study in 
guinea pigs.
2.1.4.4
Nonclinical Studies for Surufatinib in Combination with Gemcitabine
The combination of surufatinib with gemcitabine offers a unique combination of cellular signaling 
inhibition (immune modulation and angiogenesis) and inhibition of tumor replicative pathways 
(perturbed DNA replication) with additive or synergistic potential.  A xenograft model of nude 
mice subcutaneously injected with HT-1080 cells (human fibrosarcoma cell line) demonstrated 
additive to synergistic effects in TGI of surufatinib in combination with gemcitabine compared to 
either agent alone. In the anti-tumor efficacy study, surufatinib was administered 80 mg/kg/dose 
twice daily by oral gavage for consecutive 20 days, and gemcitabine was given once weekly at 3
and 10 mg/kg/dose by IV injection for 3 times.
The results (Figure 2) demonstrated that single agent treatment of surufatinib 80 mg/kg/dose and 
gemcitabine 10 mg/kg/dose led to TGI rates of 64.0% and 61.9%, respectively, while their 
combination generated a TGI of 90.2%. 
The statistical significance was observed when 
combination treatment was compared with either surufatinib or gemcitabine monotherapy on 
tumor volume changes (p<0.01). Based on these mechanisms of action, the combination of 
surufatinib with gemcitabine is hypothesized to improve the overall efficacy in patients versus 
monotherapy with either surufatinib or gemcitabine.
Surufatinib at a dose level of 80 mg/kg significantly improved anti-tumor activity of gemcitabine 
at 10 mg/kg. 
The enhanced anti-tumor effect by combination treatment might ascribe to 
simultaneous inhibition of different cell types as well as multiple pathways in tumor
microenvironments: gemcitabine killed tumor cells and surufatinib suppressed tumor angiogenesis 
and TAMs.
The TGIs of gemcitabine 3 and 10 mg/kg decreased from 54% and 84% at day 6 to 19% and 62% 
at day 20, respectively, suggesting a trend of emerging resistance to gemcitabine and consequently
also resulting in a gradually reduced anti-tumor efficacy by combination treatment.
The totality of the safety and efficacy data support the investigational use of surufatinib combined 
with gemcitabine in pediatric patients with relapsed/refractory disease.  These patients have little 
to no other treatment options and thus the overall benefit risk profile favors investigation of the 
potential benefits of the combination. Refer to the IB for further information regarding surufatinib 
nonclinical studies.


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Figure 2
Tumor Volume in Fibrosarcoma HT-1080 Model
BID=twice a day; IV=intravenous(ly); MPK=milligram per kilogram; PO=orally; SC=subcutaneously.
2.1.5
Supportive Clinical Data
2.1.5.1
Clinical Pharmacology and Pharmacokinetics
In Chinese patients with cancer, surufatinib was absorbed rapidly, with the concentration reaching 
maximum level after 1.0 to 2.0 hours of dosing.  Mean plasma T1/2 ranging from 14.9 to 20.2 hours 
was observed.  Following multiple doses of surufatinib QD, the plasma surufatinib concentration 
reached steady state 14 days after dosing, with exposure accumulating 1.2- to 2.4-fold at steady 
state compared to day 1 (2009-012-00CH1 and 2014-012-00CH1).  PK results from the US patient 
population (2015-012-00US1 [ongoing]) showed that surufatinib exposure, in general, increased 


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proportionally with an increasing dose from 50 to 400 mg QD.  There were no meaningful 
differences in surufatinib exposure between Chinese and US patients (Dasari 2020).
2.1.5.2
Clinical Safety
2.1.5.3
Clinical Efficacy
Surufatinib has demonstrated statistically significant and clinically meaningful efficacy in 
2 completed phase 3 randomized, double-blind, placebo-controlled studies in Chinese patients 
with advanced extra-pancreatic NET (SANET-ep) and patients with advanced pancreatic NET 
(SANET-p) and has shown promising anti-tumor activity in a US phase 1 study (2015-012-
00US1).  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; HR 0.334; p<0.0001).  Similarly, surufatinib-treated 
patients in the SANET-p study showed a statistically significant improvement in PFS compared 
with placebo-treated patients (median PFS of 10.9 months in surufatinib-treated patients versus 
3.7 months in placebo-treated patients; HR 0.491; p=0.0011).  In addition to the primary PFS 
endpoint, SANET-ep and SANET-p demonstrated meaningful improvements in other important 
efficacy measures such as ORR, disease control rate (DCR), duration of response (DoR), and time 
to response (TTR).
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In Study 2015-012-00US1, patients with biliary tract cancer, extra-pancreatic neuroendocrine 
tumor (epNET), pancreatic neuroendocrine tumor (pNET), and soft tissue sarcoma (STS) were 
enrolled.  Based on interim analysis for epNET and pNET cohorts, the PFS rate at 11 months for 
patients with epNETs (16 patients) was 51.1% (95% CI: 12.8, 80.3) and 57.4% (95% CI: 28.7, 
78.2) for patients with pNETs (16 patients).  The observed median PFS was 11.50 months (95% 
CI: 6.47, 11.50) and 15.18 months (95% CI: 5.19, Not reached [NR]) for patients with epNETs 
and pNETs, respectively.  An ORR of 6.3% was observed for patients with epNETs and 18.8% for 
patients with pNETs.  A disease control rate of 90.6% (95% CI: 75.0, 98.0) was observed for all 
NET patients (93.8% epNET; 87.5% pNET).  All patients had previously received everolimus 
and/or sunitinib (Paulson 2021).  Enrollment to the STS cohort is ongoing, and no analysis has 
been performed to date.
2.1.6
Benefit/Risk Assessment
2.1.6.1
Risk Assessment
Overall, nonclinical and clinical study results have demonstrated that surufatinib is safe and well 
tolerated.  Surufatinib is administered orally while gemcitabine will be administered intravenously. 
Due to the IV administration of gemcitabine, there is the potential risk for pain and local irritation 
at the infusion site. This will be evident clinically and can be treated symptomatically.  The 
collection of blood for PK sampling may require additional IV access.
Due to the risk of fetal and teratogenic adverse effects as seen in animal studies, pregnant or 
breastfeeding women will not be entered in this study.  Males or females of reproductive potential 
may not participate unless they have agreed to use 2 effective methods of birth control, including 
a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration 
of the study.  Abstinence is an acceptable method of birth control.  Both males and females with 
childbearing potential will be fully informed of the lack of reproductive toxicity data, and females 
of childbearing potential must have a negative pregnancy test prior to enrollment.  Legal guardians 
of all participating children will be informed of the lack of reproductive toxicity data.
Identified risks for surufatinib are hepatic disorder, hemorrhage, hypertension, AKI, proteinuria, 
leukopenia, anemia, thrombocytopenia, GI symptoms, and hypothyroidism/thyroid stimulating 
hormone increased.  Table 3 presents important and non-important identified risks.
Risks for gemcitabine are hypersensitivity, myelosuppression, pulmonary toxicity, hemolytic 
uremic syndrome, hepatic toxicity, exacerbation of radiation therapy toxicity, capillary leak 
syndrome, and posterior reversible encephalopathy syndrome.


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Table 3
Summary of Identified Risks of Surufatinib
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Table 3
Summary of Identified Risks of Surufatinib
CCI


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Table 3
Summary of Identified Risks of Surufatinib
CCI


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Table 3
Summary of Identified Risks of Surufatinib
CCI


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Table 3
Summary of Identified Risks of Surufatinib
CCI


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Table 3
Summary of Identified Risks of Surufatinib
AE=adverse event; AKI=acute kidney injury; ALT=alanine transaminase; AST=aspartate aminotransferase; BP=blood pressure; BUN=blood urea nitrogen; 
γ‑GGT=gamma-glutamyl transferase; MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SMQ=standardized MedDRA queries; 
TSH=thyroid stimulating hormone; VEGFR=vascular endothelial growth factor receptor.
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2.1.6.2
Benefit Assessment
Surufatinib may have the potential to provide benefit in the form of decreased tumor burden and/or 
a reduction in cancer-related symptoms in children, adolescents, and young adults with a variety 
of advanced solid malignancies who would otherwise have no known curative treatment options.
2.1.6.3
Overall Benefit/Risk Conclusion
The main risk to participants in this study is drug toxicity.  This protocol involves greater than 
minimal risk to children, adolescents, and young adults but presents the potential for direct benefit 
to individual patients.  Potential side effects of surufatinib and gemcitabine are outlined in the 
protocol and in the IB. Patients on this study may directly benefit from participation.  Patients will 
have been judged to be incurable with standard and alternative therapies, which they are eligible 
to receive.  The intent of this study is to determine a safe and tolerable dose and ultimately to 
produce a therapeutic tumor response, which would offer the potential for direct benefit to 
individual patients.
As described, the study design aims to minimize potential risks and although the potential benefits 
in patients are unknown at this time, nonclinical and clinical data demonstrate evidence of anti-
tumor activity.  Thus, the benefit/risk assessment for this first time in children study appears 
acceptable for patients for whom there is no alternative standard therapy.
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
2.2
Study Rationale
Pediatric patients with recurrent or refractory solid tumors continue to experience dismal outcomes 
despite advances through much of pediatric oncology.  There is an unmet need for better treatments 
for pediatric patients with solid tumors. This study will be performed on pediatric patients with 
recurrent or refractory solid tumors who have no known curative therapy.
Although surufatinib monotherapy has shown clinical activity in adults with NET and in select 
adult cancer models, this study proposes that adding a chemotherapy agent in combination with 
surufatinib will provide added benefit for pediatric patients with refractory/recurrent solid tumors.
Many current pediatric early phase studies combine an investigational agent with an 
irinotecan/temozolomide backbone both for anti-tumor effect and because of the tolerability and 
non-overlapping toxicities of the irinotecan/temozolomide backbone.  However, irinotecan and 
temozolomide have shown limited effect in patients with osteosarcoma, a population of patients 
who may benefit most from a CSF-1R inhibitor such as surufatinib.
2.2.1
Combination Therapy with Gemcitabine
Gemcitabine was chosen as the combination partner to surufatinib for pediatric development based 
upon 3 major factors: (1) well tolerated with a manageable toxicity profile, (2) minimal 
overlapping toxicities with surufatinib, and (3) demonstrated activity in a multitude of tumors. An 
acceptable toxicity profile is a critical characteristic in the proposed population of patients with 
relapsed/refractory pediatric malignancies, as these patients will have been heavily pre-treated 
with resultant lingering toxicities such as limited bone marrow reserve. The tolerability profile 


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permits gemcitabine to be co-administered with targeted agents such as surufatinib.  Gemcitabine 
has been combined with other TKIs, specifically antiangiogenic agents similar to surufatinib such 
as pazopanib, sunitinib, and axitinib, and shown to be both effective and safe (Duska 2020,
Michaelson 2015, Park 2019).
Gemcitabine alone, in combination with cytotoxic agents and in combination with targeted agents,
has demonstrated clinical benefit in patients with sarcoma.
Although gemcitabine has not been approved in the US or the EU/UK for the treatment of pediatric 
tumors, it is well known to be utilized in the treatment of a variety of pediatric malignancies 
including soft tissue and bone sarcomas (Pushpam 2020).  Several consensus guidelines for the 
treatment of sarcoma list gemcitabine (monotherapy or in combination) as treatment options: (1) 
The National Comprehensive Cancer Network (NCCN), (2) European Society for Medical 
Oncology – European Network for Rare Adult Solid Cancer (ESMO-EURACAN) Clinical 
Practice Guidelines, and (3) The Systemic Anti-Cancer Therapy (SACT) database for sarcoma in 
the United Kingdom (Dangoor 2016).
As a single agent, gemcitabine has modest activity in pediatric tumors.  In the pediatric phase 1 
study of gemcitabine involving 40 patients with disease refractory to conventional therapy: 
1 patient with a pancreatic tumor achieved a partial response (PR), 4 of 13 patients with osteogenic 
sarcoma had SD, and 1 of 4 patients with Ewings had SD for 17 months (Reid 2004).  Despite low 
rates of objective responses, in the context of disease refractory to standard of care agents, SD is 
an indicator of anti-tumor activity in this heavily pre-treated patient population.
More recently, gemcitabine has been studied in combination with other cytotoxic agents such as 
docetaxel resulting in slightly increased anti-tumor activity.  In a phase 2 study of gemcitabine and 
docetaxel in patients with recurrent Ewing sarcoma, osteosarcoma, or chondrosarcoma; PRs were 
observed in 1 of 14 patients with osteosarcoma, 2 of 14 patients with Ewing sarcoma, and 2 of 
25 patients with chondrosarcoma (Fox 2012).  The increased activity did however, come at a cost 
of increased toxicity.  Dose modifications for toxicity were required for 8 patients in cycles 1 and 
16 patients in subsequent cycles.  Furthermore, 7 patients withdrew due to toxicity.
This observation of enhanced anti-tumor activity for the combination of gemcitabine and docetaxel 
counter balanced by increased toxicity was confirmed in a phase 2 study conducted in adults with 
soft tissue sarcoma (Maki 2007).  Patients were randomized to either combination therapy with 
gemcitabine and docetaxel or gemcitabine monotherapy.  Objective responses (16% 
gemcitabine/docetaxel 
versus 
8% 
gemcitabine) 
and 
median 
PFS
(6.2 months 
gemcitabine/docetaxel versus 3.0 months gemcitabine) were both found to be superior for the 
combination.  However, significant toxicity was higher for the combination; the posterior 
probability of the combination having a shorter time to discontinuation for toxicity compared to 
gemcitabine alone was 0.999.  The Investigators concluded that gemcitabine/docetaxel yields 
superior anti-tumor activity but with increased toxicity.  Notably, this safety profile was observed 
in patients who received only 0 to 3 prior lines of therapy.  One would expect to see a worse 
tolerability profile of the combination in a more heavily pre-treated population, as is proposed in 
this initial pediatric study plan.
Gemcitabine has also been paired with targeted agents with encouraging results.  In a randomized 
phase 2 study in refractory soft tissue sarcoma, pazopanib + gemcitabine was shown to 
significantly improve PFS over pazopanib alone (HR 0.58; 95% CI 0.36, 0.92; p=0.02) (Schmoll
2021).  Similar results were reported in a population of 148 patients with recurrent ovarian cancer: 


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median PFS was 5.3 months for pazopanib + gemcitabine versus 2.9 months gemcitabine and 
overall response was also higher for the combination (20% versus 11%) (Duska 2020). The PFS 
benefit was most pronounced for the subpopulation with platinum refractory disease (5.32 versus
2.33 months; p<0.001), which is potentially applicable to pediatric patients who have been 
previously treated with platinum agents as part of standard of care. 
Furthermore, in a randomized phase 2 study of gemcitabine + pazopanib versus 
gemcitabine + docetaxel in patients with nonadipocytic soft tissue sarcoma, similar response rates 
as well as median PFS were observed for both arms (Somaiah 2021).  These data suggest 
gemcitabine combined with a targeted agent could potentially have similar efficacy as the 
combination of gemcitabine and docetaxel.  Of note, the combination of gemcitabine/pazopanib 
had a favorable safety profile: the rate of related Grade ≥3 AEs was 82% for the 
gemcitabine/docetaxel arm and 78% for the gemcitabine/pazopanib.
Gemcitabine is a pyrimidine antimetabolite that inhibits tumor growth by disrupting DNA 
replication.  Gemcitabine has been used as salvage chemotherapy alone and in combination in 
pediatric patients with relapsed/refractory sarcomas, particularly in patients with osteosarcoma but 
also in those with Ewing sarcoma or RMS (Mora 2009, Rapkin 2012).  In phase 1 testing of 
gemcitabine in pediatric patients, no maximum tolerated dose (MTD) was reached, with only 1 in 
6 patients experiencing Grade 4 myelosuppression when treated with 2100 mg/m2 of gemcitabine 
once weekly for 2 weeks in 28-day cycle (Reid 2004).  Gemcitabine has also been used safely in 
combination with nab-paclitaxel in pediatric patients with relapsed/refractory sarcomas at a dose 
of 1000 mg/m2 using a 2-week dosing interval (Metts 2018).  In another example of gemcitabine 
in combination therapy, a recent Children’s Oncology Group study (AHOD1221) combined 
gemcitabine with brentuximab and was well tolerated at a dose of 1000 mg/m2 on days 1 and 8
(Cole 2018). Complete response (CR) was observed in 24 (57%) of 42 evaluable patients as well 
as 13 patients with PR or SD within the first 4 cycles of treatment (Cole 2018).  Gemcitabine has 
also been combined with docetaxel and bevacizumab in relapsed and refractory pediatric sarcoma 
patients and shown good tolerability and encouraging anti-tumor activity: 2 of 3 patients had a PR
and the third patient had SD for >6 months (Higorani 2012). Lastly, gemcitabine combined with 
carboplatin and the CSF-1R inhibitor MCS110 is under active investigation in adults with triple 
negative breast cancer (NCT02435680) (Cannarile 2017).


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3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objectives
Endpoints
Primary
x
To determine MTD and/or RP2D 
of surufatinib, and to evaluate the 
safety and tolerability of 
surufatinib in combination with 
gemcitabine in pediatric patients 
with recurrent or refractory solid 
tumors or lymphoma
x
The incidence of dose limiting toxicities in 
each dose level
x
Safety, as assessed by:
o The frequency and severity of AEs
o Physical examination findings
o Vital signs
o Laboratory test results
o 12-lead ECG
Secondary
x
To characterize the PK of 
surufatinib as a monotherapy and 
in combination with gemcitabine 
in pediatric patients with 
recurrent or refractory solid 
tumors or lymphoma
x
Pharmacokinetic parameters for the dose 
escalation and PK expansion cohorts: 
Cmax, Tmax, AUC, Cmin, effective T1/2,
CL/F, and accumulation ratio
x
To evaluate the anti-tumor
activity of surufatinib in 
combination with gemcitabine in 
pediatric patients with 
recurrent/refractory solid tumors 
or lymphoma
x
Efficacy endpoints evaluated per RECIST 
version 1.1:
o ORR
o DCR
o TTR
o Duration of response (DoR)
o PFS
x
Acceptability and palatability of 
surufatinib oral suspension
x
The taste and palatability survey 
AE=adverse event; AUC=area under the plasma concentration-time curve; CL/F=apparent total clearance from 
plasma after oral administration; Cmax=maximum plasma concentration; Cmin=minimum plasma 
concentration; DCR=disease control rate; DoR=duration of response; ECG=electrocardiogram; 
MTD=maximum tolerated dose; ORR=objective response rate; PFS=progression-free survival; 
PK=pharmacokinetic(s); RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=Recommended 
Phase 2 Dose; T1/2=half-life; Tmax=time to reach the maximum plasma concentration; TTR=time to response.


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4
STUDY DESIGN
Design of the study is presented in the study schematic (Figure 1).
Overall Design
This is an open-label, multicenter, phase 1/2 study of surufatinib in combination with gemcitabine 
in pediatric, adolescent, and young adult patients with recurrent or refractory solid tumors.  This 
study design allows for dose escalation with intensive safety monitoring to ensure the safety of all 
patients.   This study will utilize a rolling 6 design, with 3 dose escalation levels and 1 de-escalation 
level, if needed.  The MTD and/or the RP2D will be designated in pediatrics.
4.1
Dose Escalation
This is a dose escalation study with sequential dose escalation of surufatinib in combination with 
gemcitabine.  Patients with any recurrent or refractory solid tumors or lymphoma, who have a 
known or expected dysfunction of VEGFR-1, -2, and -3; FGFR-1; or CSF-1R pathways may be 
enrolled.  The first study cycle will be 35 days.  During cycle 1, surufatinib will be administered, 
orally, QD, as a single agent for 14 days followed by surufatinib daily in combination with 
gemcitabine intravenously on days 15 and 22.  All subsequent cycles will be 21 days per cycle,
where surufatinib will be administered orally, QD, and gemcitabine administered intravenously on 
days 1 and 8.  The starting dose of surufatinib will be 120 mg/m2 daily, which is approximately 
70% of the adult single agent RP2D of 175 mg/m2 (300 mg/day normalized to standard adult BSA 
of 1.71 m2).  Gemcitabine (1000 mg/m2 weekly × 2 doses) will not be escalated and will be given 
on days 15 and 22 of cycle 1 and then on days 1 and 8 of all subsequent cycles.  Surufatinib will 
be given continuously on days 1 to 35 in cycle 1.  The first 14 days of cycle 1 serves to assess 
tolerability and toxicity of single agent surufatinib.
This study also includes a PK expansion cohort to be conducted at the presumed RP2D/MTD 
that is established in the dose escalation portion of the study. The PK expansion cohort will 
consist of up to 6 patients at each of the following 2 strata: patients <12 years of age and patients 
12 to <18 years of age based on age at the time of enrollment. Surufatinib PK profiles after the 
first dose and at steady state will be characterized in both dose escalation cohort and PK 
expansion cohort. Patients who are treated at the RP2D/MTD in dose escalation cohort will be 
counted in the PK expansion cohort. For Spain only: No subjects will be allowed on the study 
with a BSA ≤0.6 or body weight ≤14 kg.
4.1.1
Dose Finding Period
The dose finding period, which is the timeframe to define dose limiting toxicity (DLT), begins 
with the initial dose of surufatinib and ends on the last day of cycle 1. Should there be a delay 
(maximum 7 days delay) starting the subsequent cycle, dose finding will complete on the start date 
of the subsequent cycle.
Dose escalation and de-escalation rules:
The study will utilize the rolling 6 design (Skolnik 2008). Within a dose level cohort, up to 6
patients may be concurrently enrolled, accrual will only be suspended when awaiting data from 6
patients.  Dose level assignment will be determined based on the number of patients currently 
enrolled in the dose level, the number of DLTs observed, and the number of evaluable patients at 


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risk for developing a DLT.  Dose escalation/de-escalation rules are as follows, and in Table 5
below:
1. If 2 or more patients experience DLTs in dose level 1 then the dose will be considered not 
tolerated and there will be a de-escalation to dose level -1.
2. If 2 or more patients experience DLTs in dose levels 2 or 3 then the dose will be considered 
not tolerated and the prior dose level will be considered the MTD and will become the 
RP2D.
3. If 3 patients are enrolled in a dose cohort with no DLTs, then the next patient enrolled will 
be enrolled in the subsequent dose level.
4. If toxicity data is not yet available for 1 or more of the first 3 patients, then the next patient 
enrolled will be enrolled at the same dose level.
5. If a patient is not evaluable (NE) for toxicity, then they will be replaced in the same dose 
level with the next available patient.
6. The start of dosing in the subsequent cohort will not begin until the prior cohort has been 
evaluated and it has been determined that the MTD has not been exceeded.
7. There will be no intra-patient dose escalations.
8. The MTD/RP2D will be the dose level at which less than one-third of evaluable patients 
(dose escalation and PK expansion cohorts) experience a DLT in cycle 1.  If the MTD
determined in dose escalation cohort is considered not tolerable, additional patients will be 
enrolled to the PK expansion cohort at the next lower dose level.
Table 5
Rolling 6 Dose Escalation Rules Based on DLT Evaluable Patients
Total Number 
of Patients 
Enrolled at 
Dose Level
Number
of 
Patients 
with DLT
Number of 
Patients Without 
DLT
Number of Patients 
with Data Pending
Decision
2
0 or 1
0, 1, or 2
2, 1, or 0
Same dose level
2
2
0
0
De-escalatea
3
0
0, 1, or 2
3, 2, or 1
Same dose level
3
0
3
0
Escalateb
3
1
0, 1, or 2
2, 1, or 0
Same dose level
3
t2
0 or 1
1 or 0
De-escalatea
4
0
0, 1, 2, or 3
4, 3, 2, or 1
Same dose level
4
0
4
0
Escalateb
4
1
0, 1, 2, or 3
3, 2, 1, or 0
Same dose level
4
t2
0, 1, or 2
2, 1, or 0
De-escalatea
5
0
0, 1, 2, 3, or 4
5, 4, 3, 2, or 1
Same dose level
5
0
5
0
Escalateb
5
1
0, 1, 2, 3, or 4
4, 3, 2, 1, or 0
Same dose level
5
≥2
0, 1, 2, or 3
3, 2, 1, or 0
De-escalatea


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Table 5
Rolling 6 Dose Escalation Rules Based on DLT Evaluable Patients
Total Number 
of Patients 
Enrolled at 
Dose Level
Number
of 
Patients 
with DLT
Number of 
Patients Without 
DLT
Number of Patients 
with Data Pending
Decision
6
0
0, 1, 2, 3, or 4
6, 5, 4, 3, or 2
Suspend pending review
6
0
5 or 6
1 or 0
Escalateb
6
1
0, 1, 2, 3, or 4
5, 4, 3, 2, or 1
Suspend pending review
6
1
5
0
Escalateb
6
t2
0, 1, 2, 3, or 4
4, 3, 2, or 1
De-escalatea
DLT=dose limiting toxicity; MTD=maximum tolerated dose.
a
If 6 patients already enrolled at the next lower dose level, the MTD has been defined.
b
If the highest dose level has been reached, the recommended dose has been reached.
Safety monitoring and evaluation of dose escalation will be carried out by the Safety Review 
Committee (SRC). The SRC will determine whether it is safe to continue to the next predefined 
dose level, stay at the currently assigned dose level, or whether the dose should be de-escalated to 
a lower dose level and finally to determine the MTD/RP2D. Additional details are outlined in 
Section 11.1.
At the MTD/RP2D, a PK expansion cohort will be planned to ensure that up to 6 patients <12 years 
of age and 6 patients ≥12 and <18 years of age have been evaluated at the MTD/RP2D. This will 
allow the study to explore further the safety, tolerability, and PK at this dose.
4.2
Definition of Dose Limiting Toxicity
Dose limiting toxicity will be defined as any of the following events that are attributable to protocol 
therapy (at least possibly related).  Adverse events will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The NCI CTCAE provides 
descriptive terminology and a grading scale for each AE listed.
Any suspected or confirmed DLT is to be reported within 24 hours of learning of the event.  
Determination of a DLT will be made by the Investigator and the Sponsor’s monitor.  Patients 
who discontinue their study treatment for any reason other than DLT (eg, early disease 
progression) during cycle 1 and have not received at least 80% (28 of total 35 doses) of the 
prescribed oral surufatinib dose and both doses of gemcitabine prior to discontinuation will be 
replaced with another patient at the same dose level.
Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded 
from this definition.  The DLT monitoring and evaluation period for consideration of dose 
escalation/de-escalation will be the first cycle of treatment.  Should there be a delay (maximum 7 
days delay) starting the subsequent cycle, dose finding will complete on the start date of the 
subsequent cycle.  Toxicities with subsequent cycles will be monitored, and if a significant number 
of delayed toxicities are observed, the Sponsor will consider an amendment to include delayed 
toxicities in assessing the MTD.
Dose limiting hematological and non-hematological toxicity are defined differently.


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Non-Hematological DLT:
x
Any Grade 3 or greater non-hematological toxicity attributable to the protocol therapy with 
the specific exception of:

Grade 3 nausea, vomiting, or diarrhea recovering to ≤Grade 1 within 3 days after 
supportive therapy is administered

Grade 3 weight loss

Grade 3 or 4 fever <5 days in duration

Grade 3 infection <5 days in duration

Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, or hypomagnesemia 
responsive to oral supplementation within 7 days

Grade 3 proteinuria (urine P/C [protein/creatinine] ratio >1.9) unless confirmed with a 
second measurement within 72 hours

Grade 3 pruritus <5 days in duration

Grade 3 fatigue <5 days in duration
x
Grade 3 liver enzyme elevation including ALT/AST (up to 10 × the upper limit of normal 
(ULN) in the setting of normal bilirubin) that returns to Grade ≤1 or baseline within 7 days 
without holding study drug will NOT be considered a DLT

Grade 3 AST/ALT elevation >10 × ULN will be considered a DLT

Any Grade 3 AST/ALT duration of ≥8 days will be considered a DLT
x
Cases of Hy’s law (ALT or AST >3 x ULN along with TBIL >2 x ULN without evidence 
of cholestasis) will be considered a DLT if no other reason can be found to explain the 
observed injury (e.g., infection, malignancy, another drug capable of causing the liver 
injury, etc.)
x
Any Grade 2 non-hematological toxicity that persists for ≥7 days and is considered 
medically significant or intolerable by the patient that requires treatment interruption
x
Dose limiting hypertension (see Appendix 7)

Any Grade 4 hypertension

A systolic or diastolic blood pressure (BP) >5 mmHg above the 99th percentile (ie,
Grade 3) confirmed by repeated measurement on the same day is dose limiting if BP 
does not return to < ULN (Grade 1) within 14 days of initiation of antihypertensive 
medication.  For patients ≥18 years old, Grade 3 is defined as a diastolic BP 
≥100 mmHg or a systolic BP ≥160 mmHg
x
Grade 3 QTc prolongation >500 ms that persists despite correction of serum electrolyte 
abnormalities will be considered dose limiting
Hematological DLT:
x
In patients evaluable for hematological toxicity, DLT is defined as:

Grade 4 thrombocytopenia (platelets <25 000/mm3) for >7 days, or requiring a platelet 
transfusion on 2 separate days within a 7-day period regardless of association with 
bleeding

Grade 3 thrombocytopenia (platelets 25 000 – 50 000/mm3) with clinically significant 
bleeding 


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
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3) that lasts for 
>7 days

Cycle 1, days 15 and 22:
o Grade 4 neutropenia (ANC <500/mm3) that does not resolve to ANC ≥750/mm3
within 3 days will be considered dose limiting.

Myelosuppression that causes a delay of >7 days for start of cycle 2

Exception:
o
Grades 3 and 4 febrile neutropenia will not be considered a DLT.
DLT-Equivalent:
x
DLT-equivalent is defined as any AE meeting criteria for DLT that occurs outside the DLT 
evaluation period (cycle 1)
4.3
Design Rationale
The dose finding study is designed to provide safety and tolerability data of surufatinib in 
combination with gemcitabine in pediatric patients.  Cycle 1 will aim to evaluate the tolerability,
safety, and PK profile of surufatinib as a single agent and in combination with gemcitabine.  The 
maximum dose of surufatinib will not exceed 300 mg/day in any arm of the study as it is the RP2D 
for adults.
This study will utilize a rolling 6 design with 3 dose escalation levels and 1 de-escalation level, if 
needed.  Surufatinib starting dose will be 120 mg/m2 daily, which is approximately 70% of the 
adult single agent RP2D of 175 mg/m2 (300 mg/day normalized to standard adult BSA of 1.71 m2).  
Gemcitabine (1000 mg/m2 weekly × 2 doses) will not be escalated, and will be given on days 15 
and 22 of cycle 1, and then days 1 and 8 of all subsequent cycles.  Surufatinib will be given 
continuously on days 1 to 35 in cycle 1.  The first 14 days of cycle 1 serves to assess tolerability
and toxicity of single agent surufatinib. At MTD and/or RP2D, a PK expansion cohort will be 
planned to assure that up to 6 patients <12 years of age and 6 patients ≥12 and <18 years of age 
have been evaluated at the MTD/RP2D.
The rolling 6 design allows for reduction of the overall study duration by decreasing the number 
of times that enrollment is suspended for toxicity evaluation.   Toxicity will be assessed using the 
NCI CTCAE version 5.0, except for study sites in the US, for AST/ALT, grading in Appendix 8
will be used. Tumor assessments will be conducted according to Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1 criteria at screening, and throughout the study according the 
Schedule of Events outlined in Table 1. Confirmation of CR and PR is required at no less than 
4-week intervals between the date of initial response and the confirmation assessment date.


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5
POPULATION
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this study 
before starting study treatment.  Under no circumstances can there be exceptions to this rule. 
5.1
Recruitment
As of 16 December 2022, enrollment to study 2020-012-GLOB2 was halted based upon the 
strategic evaluation of the clinical development of surufatinib in the United States and Europe with
HUTCHMED as the study Sponsor. This change is not based on any concern for patient safety or 
efficacy relative to surufatinib treatment. Currently enrolled patients who are deriving clinical 
benefit from treatment with surufatinib may continue to participate in the study as per the protocol.  
There is no planned interruption in the supply of surufatinib to clinical trial sites with active 
patients. In addition, as no patients have enrolled in study Part 2 (dose expansion) as of the end of 
enrollment date, Part 2 is removed from the study design in this protocol Amendment 3.  Part 1 
will continue as outlined in this protocol amendment. 
This study will be offered to pediatric patients. Anticipated number of patients is as below:
x
Total: maximum 36 patients over approximately 2 years
x
Rolling 6 design with 3 planned dose escalation levels: 6×3=maximum 18 patients
x
One dose de-escalation if starting dose is intolerable: minimum 4 patients
x
PK expansion cohort up to 12 patients (6 patients <12 years of age and 6 patients ≥12 and 
<18 years of age)
x
15% unevaluable rate: 6 patients (maximum 36 patients)
5.2
Definitions
Patients officially enter the screening period following provision of informed consent either 
directly or via a legally authorized representative.
A screen failure is a consented patient who has been deemed ineligible on the basis of one or more 
eligibility criteria or who has withdrawn consent prior to treatment assignment. Screen failures 
may be rescreened no earlier than 7 days after the date of screen failure. Screen failures may be 
rescreened once.
An enrolled patient is one who has been deemed eligible and has been assigned an anticipated 
treatment start date.
5.3
Inclusion Criteria
To be included in this study, each individual must satisfy all of the following criteria:
1. Age: At time of study enrollment, patients must be
For US sites:
a.
≥2 and <18 years of age;
For EU/UK sites:
a.
From birth to <18 years of age;
2. Diagnosis:


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a.
Patients with any recurrent or refractory solid tumors or lymphoma (not CNS) that
have a known or expected dysfunction of VEGFR-1, -2, and -3; FGFR-1, or CSF-
1R pathways (based on literature) are eligible.  Patients must have had histologic 
verification of malignancy at original diagnosis or relapse.
3. Disease status: Patients must have measurable or evaluable disease 
4. Therapeutic options: Patient’s current disease state must be one for which there is no 
known curative therapy.
5. Performance level: Karnofsky ≥50 for patients ≥16 and <18 years of age and Lansky ≥50 
for patients <16 years of age (see Appendix 1), Eastern Cooperative Oncology Group 
(ECOG) ≤2 for patients ≥18 years of age. (Note: Patients who are unable to walk because 
of paralysis, but who are using a wheelchair, will be considered ambulatory for the purpose 
of assessing the performance score.)
6. Organ function requirements
Adequate organ and bone marrow function as defined below:
a.
ANC ≥750/mm3
b. Platelets ≥75000/mm3: patients must be transfusion independent and should not have 
received a platelet transfusion within 5 days of enrollment
c.
Hemoglobin ≥8.0 g/dL: patients may have received packed red blood cell transfusion
at any time prior to enrollment, but hemoglobin must remain ≥8.0 g/dL for at least 7 
days following transfusions
d. Serum creatinine based on age/sex as follows:
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1
1
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
≥16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating 
glomerular filtration rate (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and 
stature data published by the Centers for Disease Control and Prevention.
e.
Total bilirubin ≤1.5 × ULN for age.  For patients with primary liver malignancy or liver 
metastases or patients with documented/suspected Gilbert’s disease, TBIL ≤3 × ULN.
f.
In patients with no liver metastases: AST and ALT ≤3 × ULN (Please reference 
Appendix 8 for the ULN of AST and ALT for the study sites in the US.)
g. In patients with liver metastases: AST or ALT ≤5 × ULN.
h. Serum albumin ≥2 g/dL.
i.
Urine dipstick ≤1+ for protein or ≤30 mg/dL in urinalysis, unless quantitative protein 
is <1000 mg in a 24-hour urine sample or urine P/C ratio on spot urine testing is <0.5.


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j.
Adequate cardiac function as indicated by the following:
o
Shortening fraction of >27% by echocardiogram or left ventricle ejection fraction 
of ≥55% by radionuclide angiogram (multigated acquisitions, [MUGAs])
o
No clinically significant cardiac arrhythmias, stroke, or myocardial infarction 
within 6 months prior to enrollment
o
QTcF ≤480 ms
7. Patients with known bone marrow metastatic disease will be eligible for the study provided 
they meet the blood counts in the inclusion criteria (may receive transfusions provided that 
they are not known to be refractory to red cell or platelet transfusions).  These patients will 
not be evaluable for hematologic toxicity.  At least 5 of every cohort of 6 patients must be 
evaluable for hematologic toxicity for the dose escalation part of the study (cycle 1).  If 
dose limiting hematologic toxicity is observed, all subsequent patients enrolled at the same 
dose level must be evaluable for hematologic toxicity.
8. Adequate BP control which is defined as a BP <95th percentile (≤Grade 1) for age, height, 
and sex.  Please note that 3 serial BP readings should be obtained and averaged to determine 
baseline BP.  A patient’s condition may be controlled on no more than 1 antihypertensive 
medication and must be on a stable dose for at least 7 days prior to treatment initiation.
9. Prior therapy: Patients must have fully recovered from the acute toxic effects of all prior 
anticancer therapy and meet minimum durations from prior anticancer therapy prior to 
enrollment.
a.
Myelosuppressive therapy: the patient must not have received myelosuppressive 
chemotherapy within 3 weeks prior to the first dose of study treatment.
o
Exception: patients who have had vincristine need to have a washout of at least 
7 days prior to the first dose of study treatment.
b. Hematopoietic growth factors: at least 7 days must have elapsed since the completion 
of therapy with a growth factor; at least 14 days must have elapsed after receiving 
pegfilgrastim.
c.
Anticancer agents not known to be myelosuppressive (eg, not associated with reduced 
platelet or ANC): ≥7 days after the last dose of agent.
d. Antibodies: ≥21 days must have elapsed from infusion of the last dose of antibody and 
toxicity related to prior antibody therapy must be recovered to Grade ≤1.
e.
Radiotherapy: ≥2 weeks must have elapsed since local palliative radiation therapy 
(small port); ≥6 weeks must have elapsed since treatment with therapeutic doses of 
metaiodobenzylguanidine (MIBG); ≥3 months must have elapsed if prior craniospinal 
XRT was received, if ≥50% of pelvis was irradiated, or if total body irradiation (TBI) 
was received; ≥6 weeks must have elapsed if other substantial bone marrow irradiation 
was given.
f.
Stem cell rescue: ≥2 months must have elapsed since autologous transplant.
g. Patients must not have received prior exposure to surufatinib.
h. Patients may have received gemcitabine previously but must not have had radiographic 
progression of disease during prior gemcitabine chemotherapy.
10. Informed consent: Provision of signed and dated written informed consent (parent/legal 
guardian if patient <18 years of age) and assent (from patients aged >7 years) prior to any 
study-specific procedures, sampling, and analyses.


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11. Reproductive potential: Female patients must either be of nonreproductive potential or 
must have a negative serum pregnancy test upon study entry.
Female patients of 
childbearing potential and male patients with partners of childbearing potential agree to 
use a highly effective form(s) of contraception that results in a low failure rate (<1% per 
year) when used consistently and correctly, starting during the screening period, continuing 
throughout the entire study period, and for 6 months after taking the last dose of study drug. 
Such methods include oral, progestogen only, hormonal contraception (combined 
estrogen/progestogen should be avoided) or highly effective non-oral hormonal 
contraception (eg, Depo-Provera and Implanon) associated with inhibition of ovulation 
together with a barrier method (eg, diaphragm, always containing a spermicide), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, 
vasectomized partner, or sexual abstinence in line with the preferred and usual lifestyle of 
the subject. Oral and non-oral hormonal contraception should always be combined with 
an additional contraceptive method (ie, barrier method) because of a potential interaction 
with the study drug. The same criteria are applicable to male patients involved in this 
clinical study if they have a partner of childbirth potential, and male patients must always 
use a condom. 
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (ie, ≥12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not undergone 
surgical sterilization (removal of the ovaries and/or uterus).
5.4
Exclusion Criteria
If a patient meets any of the following criteria, he or she is ineligible for this study:
1. Pregnancy or breastfeeding: Pregnant or breastfeeding females will not be entered into this 
study due to risks of fetal and teratogenic AEs as seen in animal toxicity studies.  Pregnancy 
tests must be obtained in females who are postmenarchal. 
2. Concomitant medications
a.
Corticosteroids: patients receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible 
(if used to modify immune AEs related to prior therapy, ≥14 days must have elapsed 
since last dose of corticosteroid).
b. Investigational drugs: patients who are currently receiving another investigational drug 
are not eligible.
c.
Anticancer agents: patients who are currently receiving other anticancer agents are not 
eligible.
d. QTc agents: patients who are receiving drugs that prolong QTc (Appendix 5) within 
the last 7 days are not eligible.
e.
Patients may not be on clozapine, natalizumab, leflunomide, tofacitinib, or warfarin as 
these may interact with gemcitabine.
f.
Patients who are receiving medications that are strong inhibitors or inducers of 
CYP3A4 (Appendix 4)
3. Thyroid replacement therapy: Patients who require thyroid replacement therapy are not 
eligible if they have not been receiving a stable replacement dose for at least 3 weeks prior 
to study enrollment.
4. Patients who have uncontrolled infection are not eligible.


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5. Patients who have major surgery or significant traumatic injury within 28 days of the first 
dose of study treatment are not eligible.
a.
Central line placement or subcutaneous port placement is not considered major surgery.  
External central lines must be placed at least 3 days prior to enrollment and 
subcutaneous ports must be placed at least 7 days prior to enrollment.
6. Brain metastases and/or spinal cord compression untreated with surgery and/or 
radiotherapy and without clinical imaging evidence of SD for 14 days or longer; patients 
requiring steroids for CNS edema within 4 weeks prior to start of study treatment will be 
excluded.
7. Prothrombin Time (PT) >1.5 × ULN or international normalized ratio (INR) >1.5 or 
activated partial thromboplastin time (aPTT) >1.5 × ULN. 
8. Has a history of allergies to any ingredient of surufatinib or its capsule shell, including 
tartrazine (E 102). 
9. Has a history of allergies to the active ingredient of gemcitabine or to any of the excipients.
10. For Spain only: Has a BSA less ≤0.6 or body weight ≤14 kg.
 


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6
STUDY CONDUCT
The DLT evaluation period for each patient will be 35 days (first cycle), or until the start date of 
cycle 2 if the start of subsequent cycle is delayed.  Patients will be administered with surufatinib 
in combination with gemcitabine. Surufatinib will be administered daily.  Gemcitabine will be 
administered as an IV infusion on days 15 and 22 of cycle 1 then on days 1 and 8 of all subsequent 
cycles (21 days per cycle).  Patients will be allowed to continue treatment for a maximum of 17 
cycles if they meet criteria to continue treatment and are receiving clinical benefit in the opinion 
of the Investigator.
Tumor evaluation and safety assessments will continue through to the 
completion of treatment.
Patients can remain on treatment until completing cycle 17, or until progressive disease, 
unacceptable toxicity, or death; whichever comes first. If any patient completes 17 cycles and is 
still benefiting from study treatment, the Principal Investigator (PI) and Sponsor may discuss
options that allow the patient to continue to receive treatment.
6.1
Study Procedures
6.1.1
Screening Period
The screening period will last up to 28 days.  Informed consent must be signed prior to any study-
specific screening evaluations.
All clinical and laboratory assessments to determine eligibility must be performed within 14 days 
prior to enrollment unless otherwise indicated in the schedule of events.  The following laboratory
tests need not be repeated at cycle 1 day 1 if therapy starts within 72 hours of obtaining laboratory 
test to assess eligibility: complete blood count (CBC) with differential, bilirubin, ALT, and serum 
creatinine. 
Imaging studies must be obtained within 28 days prior to start of protocol therapy. Patients with 
bone marrow involvement must also have a bone marrow biopsy within 14 days prior to the start 
of protocol therapy.
6.1.1.1
Informed Consent
All patient must sign the informed consent form (ICF) prior to any study-related examinations or 
protocol procedures. Tumor assessments completed as standard of care prior to signing the 
informed consent, but within 28 days of first dose of study treatment, may be used as baseline 
scans.
6.1.1.2
Medical History
A complete medical history, including the patient’s medical history, disease history, and prior 
therapies for disease prior to signing of the ICF, should be recorded at screening. Comorbidities 
that began prior to signing the ICF should be recorded and followed as medical history.
6.1.1.3
Demographics
Demographic characteristics, including date of birth, sex, ethnic group/race, and any relevant 
lifestyle habits should be recorded at screening and in the applicable electronic case report form 
(eCRF) (as permitted by local regulations).


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6.1.1.4
Performance Score
The Lansky or Karnofsky Performance Score (see Appendix 1), or ECOG Performance Status will 
be used to assess patient’s functional impairment.
6.1.1.5
Tumor Diagnosis and Treatment History
Tumor diagnosis should include the date of primary diagnosis and its type, disease stage, the date 
of first metastasis, type of previous treatment, start and end dates, best overall response (BOR),
and date of PD.
The patient’s history of radiation therapy, including the start and end date/s and the site of radiation 
must be recorded. 
Surgical history, including operations and less-invasive diagnostic or 
therapeutic procedures (such as GI endoscopy, biopsy, etc.), the start and end date/s, and name of 
each procedure and operation site must also be recorded at screening and in the appropriate eCRF.
6.1.1.6
Concomitant Medication and Procedures
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient.  All concomitant medications within 28 days before first dose must be recorded in the 
applicable eCRF, including the generic name of the drug and daily dose, the reason/s for using the 
medication, as well as the start and stop dates of the medication.  Concomitant medications should 
be reviewed prior to each cycle during the study according to the schedule in Table 1.
6.1.2
Safety Assessments
The following procedures will be performed according to the schedule in Table 1. All assessments 
must occur within ±3 days (±1 day during cycle 1) from the scheduled date, unless otherwise noted.
6.1.2.1
Physical Examination
A complete physical examination includes patient height, weight, and general condition, as well 
as an examination of the head, heart, chest (including the lungs), abdomen, extremities, skin, 
lymph nodes, nervous system, and additional areas/systems as clinically indicated.
Limited 
physical examination includes vital signs, any change from baseline abnormalities, any new 
abnormalities, height, weight, and evaluation of patient-reported symptoms.
6.1.2.2
Vital Signs
Vital signs include systolic and diastolic BP, heart rate, respiration rate, and body temperature.  
For patients receiving antihypertensive medications with either a baseline history of hypertension 
or new onset of hypertension that develops on study, BP should be monitored per institutional 
standard practice. Blood pressure assessments will be conducted in triplicate and averaged to 
determine BP (BP reference Appendix 7).
6.1.2.3
Hematology
Hematology assessments include red blood cell count, hemoglobin, hematocrit, platelet count, and
white blood count with differential (absolute counts). 


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6.1.2.4
Blood Chemistry, Liver Function Tests, and Kidney Function Tests
The blood chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, magnesium, phosphorus, TBIL, direct bilirubin, ALT, AST, ALP, 
total protein, and albumin.
Patients with ALT or AST increase should followed up per Table 12.
6.1.2.5
Coagulation
Coagulation tests include PT, INR, and aPTT.
6.1.2.6
Thyroid Function
Thyroid function tests include serum free thyroxine (T4) and thyroid stimulating hormone (TSH).
6.1.2.7
Urinalysis
Urinalysis parameters include urine pH, protein, glucose, and blood; microscopic for white blood 
cells and red blood cell count.  If urinalysis shows ≥ trace protein, then obtain urine P/C.  A 24-hour 
urine sample for quantitative protein should be collected, if possible, for patients with ≥2+ 
proteinuria.
6.1.2.8
Pregnancy Test
All female patients of childbearing potential must complete a serum pregnancy test at screening 
and at the safety follow-up visit, and a serum or urine pregnancy test on day 1 of every cycle 
starting at cycle 2.  Serum pregnancy test should be repeated for women with suspected pregnancy.  
This is not applicable for postmenopausal female patients (ie, no menses for 12 months without an 
alternative medical cause), and the date of menopause should be recorded instead.  Pregnancy 
testing and contraception are not required for women with documented permanent sterilization (eg, 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy, or tubal ligation).
6.1.2.9
Electrocardiogram
Standard 12-lead ECGs will be performed after the patient has been resting for 5 to 10 minutes. 
Electrocardiograms should be performed in triplicate at screening or if single read has a corrected 
QT interval by Fridericia (QTcF) of ≥480 ms, and whenever feasible. Triplicate ECGs should be 
taken approximately 2 minutes apart. The combined QTcF values from these 3 ECGs will be 
averaged to provide a single value for each time point. Eligibility will be based on the average of 
the triplicate ECG conducted at screening.
6.1.2.10
Echocardiogram
Echocardiogram assessment parameters include shortening fraction and general assessment of 
cardiac function.  MUGAs assessment of left ventricular ejection fraction are permitted if 
echocardiograms cannot be performed.
6.1.2.11
Knee X-Ray and Knee Magnetic Resonance Imaging
The potential effect of surufatinib on bone development in children and adolescents with growing 
skeletons will be monitored by knee X-rays and knee MRI if clinically indicated.


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6.1.3
Efficacy Assessments
Tumor assessments will be performed at study visits as specified in Table 1.
All measurable and evaluable lesions should be assessed and documented using image-based 
evaluation.  All patients are to be evaluated utilizing contrast-enhanced CT scan of the chest, 
abdomen, and pelvis, or other acceptable cross-sectional imaging per RECIST version 1.1 (see 
Appendix 2).  Evaluations should include other areas of the body, as clinically indicated.  Disease 
status will be assessed by the Investigator or designated site staff using RECIST version 1.1.  The 
same imaging procedure used to define measurable lesions at baseline must be used throughout 
the study for each patient, unless medically contraindicated.  At the Investigator’s discretion, other 
methods of assessment of measurable disease as per RECIST version 1.1 may be used. 
Tumor assessments completed as standard of care prior to signing the informed consent, but within
28 days of first dose of study treatment, may be used as baseline scans.
6.1.4
Pharmacokinetic Evaluations
6.1.4.1
Sampling Collection and Handling
Blood samples will be collected for analysis of surufatinib plasma concentrations in all patients
according to the schedule in Table 2.
The actual dates and times of PK sampling should be 
recorded in appropriate eCRF.  In addition, the dates and times of the surufatinib dose administered 
on the day of PK collection and one day before PK collection must be recorded in the eCRF.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided to the sites.  Collection, handling, storage, and shipment 
of samples must be under the specified, and where applicable, controlled temperature conditions 
as indicated in the laboratory manual.
6.1.4.2
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of surufatinib using a validated, 
specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.
6.1.5
Treatment Period
Any patient that completes the screening period and meets all eligibility criteria will enter into 
the treatment period. Patients will be enrolled into a specific dose level or cohort, depending on 
when they enroll. The DLT evaluation period will last 1 cycle (35 days).  Patients who complete 
the DLT evaluation period may go on to receive up to a total of 17 cycles of therapy as long as 
they continue to undergo study required assessments and meet criteria to start subsequent cycles.




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6.1.6
Safety Follow-up
Follow-up on this study is required at 30 days from the last dose of protocol therapy for late onset 
AEs.  The post treatment follow-up will begin when the patient discontinues study treatment and 
all off-treatment assessments have been completed.  Patients should also be asked about 
concomitant medications at this follow-up.  Follow-up data will be submitted per the case report 
forms (CRFs).
6.1.7
End of Study
A patient will be considered to have completed the study once he or she has completed the last 
visit or the last scheduled procedure as outlined in Table 1.
The study will be considered completed once the last patient has completed the last visit or last 
scheduled procedure.
6.2
Discontinuation or Withdrawal
6.2.1
Individual Patients
6.2.1.1
Treatment Interruption
Treatment interruption and resumption parameters are defined in dose modifications Section 7.3.
6.2.1.2
Permanent Discontinuation of Treatment
The Investigator has the right to discontinue a patient from the study for any medical condition 
that the Investigator determines is in the best interest of the patient, reasons of noncompliance (eg, 
missed doses and visits), or pregnancy.
Any patient who discontinues treatment should be encouraged to return to the study site for an end 
of treatment visit and continue with the remaining study visits outlined in Table 1. The primary 
reason for discontinuation must be recorded on the appropriate eCRF.
Patients will be discontinued from protocol-defined therapy for any of the following reasons:
x
Patient determined to be ineligible

If the patient was found to be ineligible after starting treatment, follow-up should 
continue for 30 days from the last administration of study drug or until the toxicity 
resolves or returns to baseline, whichever is longer unless the patient commences a 
different anticancer therapy
x
Pregnancy or breastfeeding or intent to become pregnant or breastfeed
x
Any AE that meets criteria for discontinuation
x
Adverse event related to therapy that is Grade ≥3, with the exception of toxicities that do 
not meet criteria for discontinuation as defined in Section 4.2 describing DLTs
x
Dose interruption resulting in an interval between treatments of >21days
x
Patient noncompliance that, in the opinion of the Investigator, warrants withdrawal (eg, 
refusal to adhere to scheduled visits)
x
Initiation of alternative anticancer therapy including another investigational agent


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x
Progressive disease, unless in the opinion of the treating physician and agreement from the 
Sponsor, the patient is clinically benefiting from protocol therapy
x
Event (such as concurrent illness, significant drug toxicities, or complications) which, in
the opinion of the Investigator, is a contraindication to further dosing or in which 
discontinuation of the investigational product is judged by the Investigator to be in the best 
interest of the patient
x
Study terminated by sponsor
x
Withdrawal of consent or lost to follow-up
Patients who are permanently discontinued from further receipt of protocol treatment, regardless 
of the reason (withdrawal of consent, due to an AE, other), will be identified as having permanently 
discontinued treatment. Patients who are permanently discontinued from receiving protocol 
treatment because of toxicity will be followed for safety until the toxicities resolve or the 
completion of the 30-day follow-up period is completed.  Patients who are permanently 
discontinued from receiving protocol treatment because of disease progression will be followed 
for safety per Section 6.1.6.
Exceptions are if consent is withdrawn or the patient is lost to 
follow-up. Patients who decline to return to the site for evaluations will be offered follow-up by 
phone as an alternative.
Any patient who permanently discontinues protocol treatment will be removed from protocol.
6.2.1.3
Withdrawal from Study
Patients are at any time free to withdraw from the study, without prejudice to further treatment 
(withdrawal of parental/guardian consent and/or patient assent).  Such patients will always be 
asked about the reason(s) and the presence of any AEs.  If possible, they will be seen by an 
investigator and undergo the assessments and procedures scheduled for the post study assessment 
as in Table 1. Adverse events should be followed up for 30 days after study withdrawal as outlined 
in Section 8.3.
6.2.1.4
Replacement of Patients
Patients who discontinue their study treatment for any reason other than DLT (eg, early disease 
progression) during cycle 1 and have not received at least 80% (28 of total 35 doses) of the 
prescribed oral surufatinib dose and both doses of gemcitabine prior to discontinuation will be 
replaced with another patient at the same dose level.
6.2.1.5
Patients Lost to Follow-up
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
Before a participant is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods).  These 
contact attempts should be documented in the participant’s medical record.
Should the participant continue to be unreachable, he/she will be considered to be withdrawn from 
the study.


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6.3
Study Termination
The Sponsor, ethics committee, or regulatory authorities have the right to stop the study at any 
time. The reasons for stopping the study may include, but are not limited to, the following:
x
The incidence or severity of AEs in this or other studies indicates a potential health hazard 
to patients.
x
Patient enrollment is unsatisfactory.


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7
STUDY INTERVENTIONS
Study drug interventions are presented in Table 6.
Table 6
Description of Products
Product
Dose
Frequency
Route
Duration
Surufatinib
As per dosing table
QD
Oral
N/A
Gemcitabine
1000 mg/m2/dose
Cycle 1: Days 15 and 22
Cycles 2+: Days 1 and 8
Intravenous
90 minutes
QD=once daily.
7.1
Surufatinib
7.1.1
Formulation, Storage, Preparation, and Handling
Surufatinib is formulated with
as 
 hard gelatin capsules, in strengths of
25 and 50 mg of surufatinib per capsule.
The capsules are packaged in white high-density 
polyethylene (HDPE) bottles, which should be stored at temperatures between 10° to 30°C (50° to 
86°F) and protected from light and moisture. For additional details refer to the IB.
7.1.2
Dosing and Administration
If baseline (predose) 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 capsule(s) be taken with approximately 240 mL water and with
a meal. The administration time should be accurately recorded on the day of PK sampling. The 
dispersed suspensions in water can be prepared from the contents of both 25 and 50 mg capsules 
for pediatric patients that are unable to swallow the whole capsules. Instructions for administration 
of surufatinib capsules in suspension are provided in the pharmacy manual.
Palatability is a key characteristic for acceptability of oral drug formulations and compliance, 
especially in children.  The taste and palatability survey will be assessed in patients who have
taken surufatinib oral suspension (refer to Appendix 9).
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 vomiting occurs after dosing, the surufatinib dose should not be replaced. If patients miss a dose 
in the morning, a replacement dose can be taken if it is within 12 hours from the intended missed 
dose; otherwise, the patient should not make up the missed dose, but resume schedule the following 
day. The missed dose should be reported to investigators and recorded in the CRF.
Table 7 presents dose to be administered based on patient BSA to achieve the planned dose level 
(90, 120, 160, or 200 mg/m2). The table also provides the corresponding dose to be administered 
if a dose reduction is required for an individual patient (refer to Section 7.3).
CCI
CCI


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Table 7
Surufatinib Dosing Nomogram
90 mg/m2 (Dose Level -1)
120 mg/m2 (Dose Level 1)
BSA (m2)
Dose
(mg)
Dose 
Reduction 
(mg)
%
Reduction
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
0.4-0.64
50
25
50%
0.4-0.64
75
50
33%
0.65-0.9
75
50
33%
0.65-0.9
100
75
25%
0.91-1.17
100
75
25%
0.91-1.17
125
75
40%
1.18-1.36
125
75
40%
1.18-1.36
150
100
33%
1.37-1.85
150
100
33%
1.37-1.85
175
125
29%
1.86-2.07
175
125
29%
1.86-2.07
200
150
25%
≥2.08
200
150
25%
≥2.08
225
150
33%
160 mg/m2 (Dose Level 2)
200 mg/m2 (Dose Level 3)
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
BSA (m2)
Dose
(mg)
Dose 
Reduction 
(mg)
%
Reduction
0.4-0.64
100
75
25%
0.4-0.64
125
75
40%
0.65-0.9
125
75
40%
0.65-0.9
150
100
33%
0.91-1.17
175
125
29%
0.91-1.17
200
150
25%
1.18-1.36
200
150
25%
1.18-1.36
250
175
30%
1.37-1.85
250
175
30%
1.37-1.85
300
200
33%
1.86-2.07
300
200
33%
1.86-2.07
300
200
33%
侔2.08
300
200
33%
侔2.08
300
200
33%
BSA=body surface area.
For Spain only: No subjects will be allowed on the study with a BSA ≤0.6 or body weight ≤14 kg.
7.2
Gemcitabine
7.2.1
Formulation, Storage, Preparation, and Handling
Please reference prescription information or pharmacy manual for the detailed information of 
gemcitabine.
7.2.2
Dosing and Administration
Gemcitabine will be given at a dose of 1000 mg/m2/dose and infused intravenously over 
90 minutes.  Additional details regarding preparation and administration are found in the pharmacy 
manual or package insert.
7.3
Dose Modifications
x
For any concomitant conditions already apparent at baseline, the dose modifications will 
apply according to the corresponding shift in toxicity grade if the Investigator feels it is 
appropriate. For example, if a patient has Grade 1 asthenia at baseline that increases to 


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Grade 2 during treatment, this will be considered a shift of 1 grade and treated as Grade 1
toxicity for dose modification purposes.
x
No dose reductions or interruptions will be required for anemia (non-haemolytic) because 
it can be satisfactorily managed.
x
To recover from acute toxicity, unless otherwise indicated, the treatment can be delayed 
for up to 14 days. If a treatment delay longer than 14 days is required, the patient should 
be discontinued from the study treatment.
x
Where several toxicities with different grades or severity occur at the same time, the dose 
modifications should be according to the highest grade observed.
Dose modifications apply to surufatinib only, and only 1 dose reduction of surufatinib is permitted
(refer to Table 7). Once the dose is reduced, it cannot be increased.  There will be no dose 
modifications for gemcitabine, but the dose of gemcitabine may be held for toxicity. 


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7.3.1
Dose Modifications for Hematological Toxicity
Dose modifications for hematological toxicity are presented in Table 8.
Table 8
Dose Modifications for Hematological Toxicity
Time Period
Adverse Event
Action
Day 15 or 22 of Cycle 1
Day 8, Cycles 2+
Thrombocytopenia
Platelets 25 000 – 50 000/mm3
(Grade 3) without clinically 
significant bleeding
Recheck within 3 days and if improved to 
≥50 000/mm3, administer gemcitabine.
If no resolution within 3 days, hold 
gemcitabine and surufatinib and if improves 
to ≤Grade 2 within 7 days then resume 
surufatinib at reduced dose.
If patient has already had 1 dose reduction, 
then protocol therapy should be discontinued. 
Day 15 or 22 of Cycle 1
Day 8, Cycles 2+
Thrombocytopenia
Platelets 25 000 – 50 000/mm3
(Grade 3) with clinically 
significant bleeding, or
Platelets <25 000/mm3 (Grade 4)
lasting >7 days or requiring 
platelet transfusion on 2 separate 
days within a 7-day period
regardless of association with 
bleeding
Hold gemcitabine and surufatinib and if 
improves to ≤Grade 2 within 7 days then 
resume surufatinib at reduced dose.
If patient has already had 1 dose reduction, 
then protocol therapy should be discontinued. 
Day 15 or 22 of Cycle 1
Day 8, Cycles 2+
Neutropenia
ANC <500/mm3 (Grade 4)
Recheck within 3 days and if improved to 
≥750/mm3, administer gemcitabine.
If no resolution within 3 days, hold 
gemcitabine and surufatinib and if improves 
to ≥750/mm3 within 7 days then resume 
surufatinib at reduced dose.  Subsequent 
cycles should be administered with growth 
factor1 on day 9 after gemcitabine.
If patient has already had 1 dose reduction, 
then protocol therapy should be discontinued.
Toxicity occurring on 
days not specified above 
Thrombocytopenia
Platelets 25 000 – 50 000/mm3
(Grade 3) with clinically 
significant bleeding, or
Platelets <25 000/mm3 (Grade 4)
lasting >7 days or requiring 
platelet transfusion on 2 separate 
days within a 7-day period
regardless of association with 
bleeding
Hold surufatinib. 
If improves to ≤Grade 2 within 7 days without 
intervention, then resume surufatinib at 
reduced dose. 
If patient has already had a dose reduction, 
then protocol therapy should be discontinued.  
Toxicity occurring on 
days not specified above 
Neutropenia
ANC <500/mm3 (Grade 4)
If persists for >7 days, then hold surufatinib.
If improves to ≥750/mm3 within 7 days, then 
resume surufatinib at reduced dose.  
Subsequent cycles should be administered 
with growth factor on day 9 after gemcitabine.
If patient has already had one dose reduction, 
then protocol therapy should be discontinued.


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Table 8
Dose Modifications for Hematological Toxicity
Time Period
Adverse Event
Action
Toxicity occurring on 
days not specified above 
Myelosuppression that causes a 
delay of >7 day between treatment 
cycles
Discontinue surufatinib.
1
Myeloid growth factor support: use of neulasta is not allowed.  Granulocyte colony stimulating factor 
(G-CSF) may be administered at a dose of 5 μg/kg daily beginning on day 23 of cycle 1 or day 9 of cycles 2+ 
and continuing for a minimum of 7 days and until the post-nadir neutrophil count increases to ≥750/μL.
7.3.2
Dose Modifications for Non-Hematological Toxicity
Dose modifications for non-hematological toxicity are presented in Table 9.
x
Patients who have any non-hematological toxicity ≥Grade 3 may continue on protocol 
therapy if toxicity returns to ≤Grade 1/or baseline within 14 days of drug interruption, and 
should receive subsequent cycles at a reduced dose as described in Table 7.
x
If ≥Grade 3 non-hematological toxicity of same System Organ Class (SOC) recurs after 1
dose reduction, the patient must be removed from protocol therapy. 
x
Patients who have ≥Grade 3 non-hematological toxicities that does not resolve to ≤Grade 1
or baseline within 7 days after the planned start of the next treatment cycle must be removed 
from protocol therapy.
Dose modification for specific AEs proteinuria, hypertension, liver toxicities, and hemorrhage are 
presented in Section 7.3.3.
Table 9
Dose Modifications for Non-Hematological Toxicity
NCI CTCAE Version 5.0 Toxicity 
Grading
Action
Surufatinib
Gemcitabine
Grades 1 or 2
None
None
Grade 3
Expected manageable/reversible with 
dose reduction
Hold 
Hold 
Toxicity remains ≥Grade 3 >14 days
Discontinue
Discontinue
Toxicity lasts ≤14 days and resolves to 
≤Grade 1 or baseline
Reduce dose if not already 
reduced
Resume at the same dose
Reoccurrence of Grade 3/4 toxicity of 
same SOC
Discontinue or discuss with 
sponsor if the patient is 
clinically benefiting
Discontinue or discuss with 
sponsor if the patient is clinically 
benefiting
Not expected manageable/irreversible 
with dose reduction
Discontinue 
Discontinue
Grade 4 with the exception of febrile 
neutropenia
Discontinue 
Discontinue
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; SOC=System 
Organ Class.
Note: Patients who experience gastrointestinal perforation should permanently discontinue study drug. 


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7.3.3
Dose Modification of Surufatinib for Adverse Events of Special Interest
Dose modification of surufatinib for AEs of special interest (AESI) are provided in Table 10
(proteinuria), Table 11 (hypertension), Table 12 (hepatic disorders), and Table 13 (hemorrhage).  
AESIs of thyroid dysfunction and acute renal failure should also be monitored.
7.3.3.1
Dose Modifications for Proteinuria
Proteinuria has been reported with surufatinib in adult studies. 
o
If urinalysis shows ≥2+ protein, then obtain a 24-hour urine sample for protein or a random 
urine P/C ratio.
Table 10
Dose Modification of Surufatinib for Proteinuria
Grade and Definition
Dose Modification
Suggested Actions
Grade 1:
1+ proteinuria or urinary 
protein ≥ ULN -
<1.0 g/24 hours
None
Follow-up per planned schedule.
Grade 2:
Proteinuria 2+ or 3+ or urinary 
protein 1.0 g to 
<3.5 g/24 hours or urine P/C 
0.5-1.9
None
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
or urine P/C >1.9 (ie,
confirmed with a repeat urine 
P/C within 72 hours)
x
Hold surufatinib. 
x
If test results resolve to ≤Grade 2
in less than 14 days, resume 
surufatinib at reduced dose.
x
If surufatinib is held ≥14 days, 
permanently discontinue 
treatment.
Provide supportive treatment and 
increase the frequency of urine 
monitor weekly; consult 
nephrologist if necessary.
AE=adverse event; CTCAE=Common Terminology Criteria for Adverse Events; P/C=protein/creatinine; 
ULN=upper limit of normal.
Note: The CTCAE grade recorded for proteinuria is to be determined by the urine P/C or 24-hour urine 
collection; however, the start date of the AE will be recorded as the first instance of proteinuria (ie, urine 
dipstick).  Surufatinib treatment is to be discontinued if a patient develops nephrotic syndrome.
7.3.3.2
Dose Modifications for Hypertension
1. The ULN for BP is defined as a systolic or diastolic BP of 95th percentile for age, height, 
and gender for pediatric patients. For adolescent, the ULN is 130/80 mmHg. For adult
patients (≥18 years in this study), the ULN is 140/90 mmHg.
2. The NCI CTCAE version 5.0 will be used to determine the grade of hypertension for 
reporting purposes.
3. Elevated BP measurements are to be repeated on the same day to confirm the elevation. If 
confirmed, patients with elevated BP are to have BP measurements performed at least 
weekly until BP is < ULN.


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Table 11
Dose Modification of Surufatinib for Hypertension
Grade and Definition
Dose Modification and Management
Grade 1:
Prehypertension (systolic BP 120 to 
139 mmHg or diastolic BP 80 to 
89 mmHg)
or
Pediatric: Systolic/diastolic BP 
>90th percentile but<95th 
percentile;
Adolescent: BP ≥120/80 even if 
<95th percentile
None
Grade 2:
Stage 1 hypertension (systolic BP 
140 to 159 mmHg or diastolic BP 
90 to 99 mmHg) if previously 
within normal range, medical 
intervention indicated, recurrent or 
persistent (≥24 hours), symptomatic 
increase by >20 mmHg (diastolic) 
or to >140/90 mmHg , or 
monotherapy indicated
or
Pediatric and adolescent: Recurrent 
or persistent (≥24 hours) BP >
ULN; monotherapy indicated; 
systolic and/or diastolic BP 
between the 95th percentile and 
5 mmHg above the 99th percentile;
Adolescent: Systolic between 
130‑139 or diastolic between 80-89
even if <95th percentile
x
Initiate antihypertensive therapy if not previously started.
x
If previously on optimized antihypertensive medical management.
x
If BP ≥ ULN despite maximal antihypertensive therapy hold 
surufatinib.
o
Restart at the same dose if BP returns to < ULN within 
14 days of drug interruption after the initiation of an 
antihypertensive therapy or change in previous 
antihypertensive therapy.
o
If the BP remains ≥ ULN after restarting surufatinib then the 
drug should be held until BP < ULN. If BP returns to < ULN 
within 14 days of drug interruption, patient may resume 
surufatinib at a reduced dose.
o
If the BP remains ≥ ULN for >14 days in any situation, then 
the patient should be removed from protocol therapy. 
Grade 3:
Stage 2 hypertension (systolic 
pressure ≥160 mmHg or diastolic 
pressure ≥100 mmHg), medical 
intervention indicated, >1 drug or 
more intensive therapy than 
previously used indicated
or
Pediatric and adolescent:
Systolic and/or diastolic >5 mmHg 
above the 99th percentile
x
Initiate antihypertensive therapy if not previously started.
x
If previously on optimized antihypertensive medical management 
hold surufatinib.
o
If BP returns to < ULN within 14 days of drug interruption, 
the patient may resume treatment at a reduced dose.
o
If Grade 3 hypertension reoccurs, despite optimal medical 
management and a reduced dose of surufatinib, then 
discontinue surufatinib treatment.
o
If the BP remains ≥ ULN for >14 days in any situation, then 
the patient should be removed from protocol therapy.
Grade 4:
Life-threatening consequences 
(eg, malignant hypertension, 
transient or permanent neurologic 
deficit, and hypertensive crisis) or 
urgent intervention indicated
Discontinue surufatinib treatment.
BP=blood pressure; ULN=upper limit of normal.


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7.3.3.3
Dose Modifications for Hepatic Disorders
Table 12
Dose Modification of Surufatinib for Hepatic Disorders
Grade and Definition
Dose Adjustment
Suggested Actions
Grade 1:
ALT >1 to 3×ULN or 
AST >1 to 3×ULN
None
Follow-up per planned schedule.
Grade 2:
ALT >3 to 5×ULN or 
AST >3 to 5×ULN
Maintain the original dose, provide supportive 
care of complications of liver impairment, and 
observation for 1 week. 
Follow-up per planned schedule.
Discontinue study drug(s) if the 
biochemical criteria for Hy’s Law
have been met.1
Grade 3:
ALT >5 to 10×ULN 
or
AST >5 to 10×ULN
and
bilirubin ≤ ULN 
o
Continue surufatinib for 7 days
o
If ALT/AST improves to ≤5×ULN 
within 7 days, continue surufatinib 
at the same dose;
o
If ALT/AST remains >5 to 
10×ULN hold surufatinib for up to 
14 days;
o
If ALT/AST resolves or improves 
to ≤Grade 1/baseline between 8
and <21 days, resume surufatinib 
at a reduce dose (if possible);
o
If dose reduction not possible 
discontinue protocol therapy or 
discuss with sponsor if the patient 
is clinically benefiting.
Provide supportive care and 
increase the frequency of liver 
function monitoring to twice a 
week; consult expert if necessary.
Evaluate the biochemical criteria 
for Hy’s Law.1
Grade 3:
ALT >10 to 20×ULN 
or
AST >10 to 20×ULN
and
bilirubin ≤ ULN 
o
Hold surufatinib
o
If resolves or improves to ≤Grade
1/baseline within 7 days, resume 
surufatinib at a reduced dose;
o
If dose reduction not possible 
discontinue protocol therapy or 
discuss with sponsor if the patient 
is clinically benefiting.
Provide supportive care and 
increase the frequency of liver 
function monitoring to twice a 
week; consult expert if necessary.
Evaluate the biochemical criteria 
for Hy’s Law.1
Grade 4:
ALT >20×ULN or
AST >20×ULN
Discontinue surufatinib.
Urgent medical intervention 
indicated.
Discontinue study drug(s) if the 
biochemical criteria for Hy’s Law
have been met.1
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.
1
See Appendix 6 for important additional information.
2
For the study sites in the US, ALT ULN=45 U/L, AST ULN=50 U/L as referenced in Appendix 8.


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7.3.3.4
Dose Modifications for Hemorrhage
Table 13
Dose Modification of Surufatinib for Hemorrhage
Grade and Definition
Dose Modification
Suggested Actions
Grade 1
None
Follow-up per planned schedule.
Intolerable Grade 2
Hold surufatinib treatment.
Resume at a reduced dose if 
resolves to ≤Grade 1 within 
21 days.
Discontinue if lasting >21 days
Active management.
≥Grade 3
Discontinue surufatinib.
Immediate medical intervention to 
identify and treat the source of 
bleeding.
7.3.3.5
Dose Modifications for Thyroid Toxicity
Thyroid toxicity will be handled like any other non-hematological toxicity.  Patients with Grade 2
hypothyroidism adequately managed with thyroid hormone replacement may continue on protocol 
therapy.
7.3.4
Dose Modifications for Diarrhea
An anti-diarrheal agent may be prescribed at the onset of diarrhea and the patient should be 
instructed and education to initiate anti-diarrheal treatment with the onset of diarrhea.
7.3.5
Dose Modifications for Thromboembolic Events
If a thromboembolic event is confirmed, surufatinib should be held until therapeutic 
anticoagulation with heparins is established.  Surufatinib may be resumed at the same dose level 
in patients who are stable and have uncomplicated deep vein thrombosis (DVT) or pulmonary 
embolism (PE) and are deriving clinical benefit. 
7.4
Assessment and Verification of Compliance
Records of treatment compliance for each patient will be kept during the study. Clinical research 
associates will review treatment compliance during site visits and at the completion of study.  
Compliance will be monitored using the patient diary as well as the electronic medical record 
documentation of oral compliance with surufatinib, IV compliance with gemcitabine, and study 
assessment compliance.
7.5
Prior and Concomitant Therapies
Information on any treatment in the 4 weeks prior to starting study treatment and all concomitant 
treatments given during the study, with reasons for the treatment, will be recorded in the CRF.  If 
medically feasible, patients taking regular medication(s) should be maintained on this 
medications(s) throughout the study period.


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7.5.1
Prohibited Therapies
Concurrent anticancer therapy, including chemotherapy, radiation therapy, immunotherapy, 
immunomodulating agents (with the exception of corticosteroids), or biologic therapy may not be 
administered to patients receiving study treatment.  If these treatments are administered the patient 
will be removed from protocol therapy.
Patients may not be on clozapine, natalizumab, 
leflunomide, tofacitinib, or warfarin as these may interact with gemcitabine.
7.5.2
Permitted Therapies
Granulocyte colony stimulating factors should not be used prophylactically during the DLT 
evaluation period (cycle 1).  Use of prophylactic colony stimulating factors may be considered 
after cycle 1 if there is sustained myelosuppression in cycle 1 and after discussion with the PI.
Patients may receive treatment with corticosteroids (for nausea/emesis).
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen and
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care.
Other medication, which is considered necessary for the patient’s safety and well-being, may be 
given at the discretion of the Investigator and recorded in the appropriate sections of the eCRF.
Supportive care and other medications that are considered necessary for the patient’s well-being, 
may be given at the discretion of the Investigator.
This may include (but is not limited to) 
antibiotics, blood products, antiemetics, fluids, electrolytes, and general supportive care.
7.5.3
Drug-Drug Interactions
In vitro metabolism data indicate that CYP3A plays an important role in the metabolism of 
surufatinib.  The potential effects of medications that can affect the PK of surufatinib via the 
CYP3A pathway have not been tested in the clinic.  Therefore, medications that are 
strong/moderate inhibitors or strong/moderate inducers of CYP3A are prohibited and should not 
be administered 2 weeks or 5 half-lives (3 weeks for St John’s wort) before the study or 
concomitantly with surufatinib during the course of the study.  Examples of these medications are 
listed in Appendix 4.
In vitro, surufatinib is shown to have the potential to inhibit CYP3A, P-gp, and breast cancer 
resistance protein (BCRP) (refer to the IB).  Patients should avoid concomitant use of medications 
that are sensitive substrates or substrates with narrow therapeutic windows of CYP3A, P-gp, or 
BCRP where possible.  If used together, patients should be monitored more frequently for adverse 
reactions (ARs), and consider dose reduction of the CYP3A, P-gp, or BCRP substrate medication 
should occur.  Examples of the medications that are sensitive substrates and substrates with narrow 
therapeutic windows of CYP3A, P-gp, and BCRP are listed in Appendix 4.
7.6
Drug Accountability
All study drugs required for this study will be provided by HUTCHMED or a contract research 
organization (CRO). The recipient will acknowledge receipt of the study drug by returning the 
appropriate documentation form indicating shipment content and condition. Damaged supplies 
will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to, and disposed by the 
study site should be recorded by using the Drug Inventory Log. 


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Study drug will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to HUTCHMED or designated CRO 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. 


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8
SAFETY MONITORING
8.1
Definitions
8.1.1
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and which does not necessarily have to have a causal
relationship with this treatment.
All AEs will be assessed according to the NCI CTCAE 
version 5.0 for severity or intensity.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory findings), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study medication.
Any deterioration due to disease under study and associated symptoms or findings should not be 
regarded as an AE as long as the deterioration is clearly due to disease and can be anticipated.
AE examples include, but are not limited to:
a.
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increased in frequency and/or intensity of the condition.
b. Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. For all reports of overdose (whether 
accidental or intentional) with an associated AE, the AE term should reflect the 
clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology 
“accidental or intentional overdose without AE.”
c.
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgement of the investigator.
d.
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
e.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
f.
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event.
An AE does not include:
a.
Medical or surgical procedures (eg, pre-scheduled surgery, endoscopy, tooth 
extraction, transfusion).  The condition that leads to the procedure is an AE.
b. Anticipated day to day fluctuations of preexisting disease(s) or condition(s) presented 
or detected prior to or at the start of investigational therapy that do not worsen.
c.
Situations in which an untoward medical occurrence (eg, hospitalization for an 
elective surgery, social, and/or convenience admissions).
The term AE is used generally to include any AE whether serious or non-serious.


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8.1.2
Serious Adverse Event
An SAE is defined as any untoward medical occurrence that, at any dose during any study phase 
(ie, run-in, treatment, washout, follow-up), that results in any of the following outcomes:
x
Death
x
Immediately life-threatening situation (patient is at immediate risk of death at the time of 
the event)
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions
x
Congenital abnormality or birth defect in the offspring of a patient
x
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when based upon appropriate medical 
judgement may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse
8.1.3
Causality or Relatedness
The Investigator is required to provide an assessment of relationship of an AE and SAE to 
surufatinib and/or gemcitabine.  A number of factors should be considered in making this 
assessment including:
a.
The temporal relationship of the event to the administration of study drugs
b. Whether an alternative etiology has been identified
c.
Biological plausibility
d. Dechallenge (Positive dechallenge is a response observed for the reduction or 
disappearance of adverse drug reactions on withdrawal of a drug from a patient.)
e.
Rechallenge (Positive rechallenge: If the patient showed return of adverse effects 
after restart of a drug.)
The Investigator will assess causal relationship between investigational product and each AE, and 
answer “yes” or “noˮ 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 causal relationship will also be assessed for other medication and study procedure.  Note 
that for SAEs that could be associated with any study procedure the causal relationship is implied 
as ‘yes’.
The relationship to study drugs should be assessed using the following definitions:
a.
Not related: A clear-cut alternative explanation exists that the AE has an etiology 
other than study drugs (eg, preexisting condition, underlying disease, inter-current 
illness, or concomitant medication).
b. Related: There is a reasonable possibility that the product caused the treatment under 
investigation. In this definition, the phrase “a reasonable possibility” means that the 
relationship to study treatment cannot be ruled out. 
c.
Adverse reaction (AR): An AR is any AE caused by a drug.


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d. Suspected adverse reaction (SAR): An SAR is any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the AE. SAR implies a lesser degree of certainty about 
causality than AR.
e.
Unexpected: An event is considered unexpected if it is not listed in the IB, is not 
listed at the specificity or severity that has been observed. Unexpected also refers to 
events that are mentioned in the IB as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the particular drug under investigation.
f.
Gemcitabine has been approved for marketing in the US and in the EU/UK. The
health authority approved prescription drug labeling is used as the basis for 
determining whether an event is unexpected for reporting purposes.
Ambiguous cases should be considered as being a “reasonable possibility” of a causal relationship 
unless further evidence becomes available to refute this.  Causal relationship in cases where the 
disease under study has deteriorated due to lack of effect should be classified as no reasonable 
possibility.
8.2
Adverse Events of Gemcitabine
Toxicity profile of gemcitabine from package insert:
Common (>20% of patients)
Alopecia, rash maculopapular, constipation, diarrhea, nausea, vomiting, anemia, white blood 
cell decreased, neutrophil count decreased, platelet count decreased, ALP increased, ALT
increased, AST increased, bilirubin increased, infection1, peripheral motor neuropathy, 
peripheral sensory neuropathy, paresthesia, hematuria, proteinuria, dyspnea, fatigue, fever, pain 
Occasional (5% to 20% of patients)
Edema limbs, localized edema, hypotension, hyperglycemia, hypocalcemia, hypomagnesemia, 
anorexia, mucositis oral, pharyngeal mucositis, hemorrhage, bone pain, headache, somnolence, 
psychiatric disorders – other: mood disorders, serum creatinine increased, investigations – other: 
increased blood urea nitrogen, flu-like syndrome 
Rare (<5% of patients)
Cardiac disorders, other: arrhythmias, heart failure, myocardial infarction, vasculitis, bullous 
dermatitis, skin infection, infusion site reaction, radiation recall reaction, febrile neutropenia, 
hepatic failure, hepatobiliary disorders – other: sinusoidal obstruction syndrome, anaphylaxis, 
hearing impaired, arthralgia, myalgia, hemolytic uremic syndrome, AKI, blood and lymphatic 
system disorders – other: thrombotic microangiopathy, adult respiratory distress syndrome, 
bronchospasm, respiratory, thoracic and mediastinal disorders – other: interstitial lung disease, 
pulmonary edema, pulmonary fibrosis, respiratory failure 
Pregnancy/Lactation
Pregnancy Category D
Gemcitabine is embryotoxic causing fetal malformations (cleft palate and incomplete 
ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on 
a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery
and absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended 


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human dose on a mg/m2 basis). In mice, embryolethality was observed following doses of 
0.25 mg/kg/day (approximately 1/1300 the recommended human dose on a mg/m2 basis).  
Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and 
developmental delays.  It is not known whether gemcitabine or its metabolites are excreted in 
human milk.
8.3
Documenting Adverse Events
Adverse events will be collected throughout the study, from informed consent until 30 days after 
the last dose of protocol therapy (follow-up period).  The follow-up period is defined as 30 days 
after study treatment is discontinued.  SAEs occurring in the follow-up period should be reported 
to the regulatory authorities and Sponsor as delineated in Section 8.4.
8.3.1
Timeframe for Collection
Adverse events will be documented from the time of study enrollment through 30 days after the 
last day of study treatment. 
All AEs (irrespective of suspected causality) and SAEs must be followed until one of the following 
occurs:
x
Resolved or improved to baseline
x
Death
x
Start of new anticancer medication
x
Investigator confirms that no further improvement can be expected
x
Clinical or safety data will no longer be collected, or final database closure
8.4
Reporting Adverse Events
8.4.1
Expedited Reporting Period 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to
address potential new risks in a clinical study.  The Investigator must report such events (both 
initial and follow-up) to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event.
Serious adverse events (from informed consent to 30 days following the last dose of study 
treatment or initiating a new anti-tumor therapy) must report to the Sponsor within 24 hours after 
first learning of the event, regardless of relationship to study treatment.
8.4.2
All Serious Adverse Events and Protocol-Defined Adverse Events of Special 
Interest
Investigators will submit reports of all SAEs and protocol-defined events of special interest, 
regardless of attribution, to the Sponsor or the Sponsor’s designee via fax or email within 24 hours
of learning of the events.
For initial SAEs and protocol-defined events of special interest reports, investigators should record 
all case details that can be gathered within 24 hours on a SAE reporting form. Relevant follow-up 
information should be submitted to the Sponsor or the Sponsor’s designee as soon as it becomes 
available and/or upon request within 24 hours of the Investigator’s awareness of the events.


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Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and Independent Ethics Committee/Institutional Review Board (IEC/IRB).
8.4.2.1
Drug-Induced Liver Injury
Report all potential events of drug-induced liver injury (DILI), as defined below, regardless of 
whether it is a non-serious or serious AE to the Sponsor no more than 24 hours after learning of 
the event.
x
Serum AST or ALT >3 × ULN together with TBIL >2 × ULN.
This combination of lab abnormalities meets the biochemical criteria for Hy’s Law, which is 
associated with a markedly increased possibility of severe DILI, and may progress to liver 
transplantation or death. Some patients may present with symptoms such as: fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). If the 
biochemical criteria for Hy’s Law is met, surufatinib should be immediately discontinued, and 
patients need to be very closely monitored (bilirubin, ALP, AST, ALT measured 2 to 3 times 
weekly until the results return to baseline or normal), and other causes of liver injury evaluated 
(eg, new or worsening hepatobiliary metastases; non-malignant biliary obstruction; viral hepatitis 
A, B, or C; alcoholic or autoimmune hepatitis; preexisting or acute liver disease; ischemic liver 
injury; right-sided congestive heart failure; new or worsening liver metastases; or concomitant 
medication that could cause the observed injury).  Consultation with a gastroenterologist or 
hepatologist should be considered.
The findings described above must be reported to the Sponsor no more than 24 hours after 
awareness of the event.
8.4.2.2
Severe Hemorrhagic Events
When a hemorrhagic event meets NCI CTCAE ≥Grade 3 severity (regardless of whether it is 
serious or non-serious), the event should be reported to the Sponsor no more than 24 hours after 
first awareness of the event.
8.5
Adverse Events of Special Interest for Surufatinib
An 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.  AESI for surufatinib include:
x
Hepatic disorders
x
Proteinuria
x
Hypertension
x
Thyroid dysfunction
x
Hemorrhage
x
Acute renal failure
8.6
Clinical Laboratory Findings
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (eg, abnormalities that require study drug dose 


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modification, discontinuation of study drug, more frequent follow-up assessments, or further
diagnostic investigation).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, ALP and 
bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (eg, cholecystitis) needs to be 
recorded on the AE/SAE eCRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF.  If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE.  For example, an elevated serum potassium level of 7.0 mmol/L should be recorded as 
“hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or 
etiology changes. 
8.7
Pregnancy
If a patient becomes pregnant during the course of the study, protocol therapy should be 
discontinued immediately.
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth, or congenital abnormality) should be reported to the PI as well 
as the Sponsor using the appropriate forms and within 24 hours of knowledge of the event.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as SAEs.  
Elective abortions without complications should not be handled as AEs.
The outcome of a 
pregnancy should be followed up and documented even if the patient was withdrawn from the 
study.
If a pregnancy occurs during exposure to protocol therapy or in the 30 days after discontinuing 
investigational product, then investigators or other site personnel must inform the PI and the 
appropriate Sponsor representatives immediately, or no later than 24 hours of when he/she 
becomes aware of it.
The same timelines apply when outcome information is available.
8.8
Overdose or Misuse
There are no data on overdose in pediatrics since this is a first in pediatrics study of surufatinib 
alone or in combination with gemcitabine.  There is no definition of what constitutes an overdose.  
There is no known antidote.
Investigators should be advised that any patient who receives a higher dose than that intended 
should be monitored closely, managed with appropriate supportive care and followed up 
expectantly.
Such overdoses should be recorded as follows:


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x
An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms on the 
relevant AE/SAE modules in the CRF and on the overdose CRF module.
x
An overdose with no associated symptoms is only reported on the overdose CRF module.
If an overdose occurs in the course of the study, then investigators or other site personnel must 
inform the PI and the Sponsor representatives within 24 hours of when he/she becomes aware of 
it.


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9
STATISTICAL ANALYSIS
All statistical analysis will be performed under the direction of the Sponsor’s personnel. Details 
of the statistical analysis and data reporting will be provided in the Statistical Analysis Plan (SAP) 
document finalized prior to database lock.
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and the final analysis of the study will be conducted at the time of the analysis of the last cohort. 
9.1
Hypothesis
No formal hypothesis testing is planned for the study. 
9.2
Population
9.2.1
Sample Size Rationale
Up to 36 patients are to be enrolled in this study Three dose escalation levels will be explored 
using the rolling 6 design which will lead to maximum 18 evaluable patients. There is 1 additional 
dose level for dose de-escalation if starting dose is not tolerable. Then, up to 12 evaluable patients 
will be evaluated in the PK expansion cohort. Assuming a 15% unevaluable rate with respect to 
the DLT evaluation for dose escalation portion or PK assessment for PK expansion cohort, it is 
expected to have up to 36 patients in total for this study.
9.2.2
Analysis Populations
The following populations will be defined for this study:
x
DLT Evaluable Set (dose escalation phase): This population includes all patients enrolled 
in the dose escalation phase of the study who receive at least 80% (28 of 35 doses) of the 
prescribed oral surufatinib dose and both doses of gemcitabine during the DLT evaluation 
period or who discontinued treatment due to a DLT. 
x
Safety Analysis Set (All Treated Population): This population includes all patients who 
have received at least 1 dose of surufatinib or gemcitabine. Safety and efficacy data will 
be evaluated based on this population’s outcome. Patients in the safety analysis set 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 study treatment
received. 
x
Pharmacokinetic Analysis Set: This population will include all patients who received at 
least 1 dose of surufatinib and have at least one PK sample obtained and analyzed.
9.3
Statistical Analysis Methods
Data will be summarized by dose cohorts using descriptive statistics (continuous data) and/or 
contingency tables (categorical data) for demographic and baseline characteristics, efficacy 
measurements, safety measurements, and PK measurements.  Time to event variables will be 
summarized descriptively using the Kaplan-Meier (KM) method.  The quartiles including median
along with 80% and 95% CIs will be reported using the Brookmeyer and Crowley method (using 
the log-log transformation for CI) (Brookmeyer 1982).  Exact CIs for binomial proportions will be 
derived using the Clopper-Pearson method (Clopper 1934).  Analyses will be performed using 
SAS® (version 9.1 or higher). 


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9.3.1
Disposition
The number and percentage of patients who were enrolled in the study, treated, discontinued from 
study treatment (s), and discontinued from study will be presented for all enrolled patients.  The 
primary reason for treatment discontinuation and study discontinuation will be summarized 
according to the categories in the eCRF.  Important protocol deviations will be summarized and 
listed by category.
9.3.2
Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized for the safety analysis set 
using descriptive statistics.  A summary of baseline patient and disease characteristics, diagnosis, 
medical history, and prior therapies will be reported using descriptive statistics.
Other patient characteristics will be summarized as deemed appropriate.
9.3.3
Prior and Concomitant Medications
Prior medications will be defined as medications that stopped before the day of first dose of 
study treatment (s). Concomitant medications will be defined as medications that 1) started 
before the first dose of study treatment (s) and were continuing at the time of the first dose of 
study treatment (s), or 2) started on or after the date of the first dose of study treatment (s) up to 
30 days after the last treatment. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary drug codes and will be further coded to the appropriate 
Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior and 
concomitant medications will be summarized and listed by drug and drug class. A listing of 
prior and concomitant medications will be provided.
9.3.4
Efficacy Analyses
9.3.4.1
Objective Response Rate
Objective response rate is defined as the proportion of patients with a BOR of CR or PR as 
determined by the Investigator using RECIST version 1.1.  BOR is defined as the best response 
recorded from the start of study drug (s) until documented RECIST version 1.1 progression or the 
start date of new anticancer therapy, whichever comes first.  Both confirmed and unconfirmed 
responses will be evaluated.  To be assigned a status of confirmed PR or CR, the response must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are 
first met. 
The ORR and the corresponding 2--sided Clopper-Pearson 80% CI will be presented.
9.3.4.2
Duration of Response
Duration of response is defined as the time from the first occurrence of PR or CR, whichever 
comes first until disease progression or death.  Duration of response will be summarized separately 
for both confirmed and unconfirmed responders using Kaplan-Meier methodology.


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9.3.4.3
Disease Control Rate
Disease control rate is defined as the proportion of patients with a BOR of CR, PR, or SD as 
determined by the Investigator using RECIST version 1.1.  The DCR and the corresponding 
2--sided Clopper-Pearson 80% CI will be presented.
9.3.4.4
Time to Response
Time to response is defined as the time (months) from start of study drug until the date of first 
occurrence of PR or CR.  Time to response will be summarized for responders using Kaplan-Meier
methodology.
9.3.4.5
Progression-Free Survival
Progression-free Survival is defined as the time (months) from the start of study treatment (s) until 
the first radiographic documentation of objective progression as assessed by the investigator using 
RECIST Version 1.1 or death from any cause.  PFS assessed by the investigators per RECIST v1.1 
will be estimated using the Kaplan-Meier method.  The Kaplan-Meier estimates of PFS will be 
plotted over time. The corresponding quartiles (including the median), if estimable, will also be 
estimated using Kaplan-Meier method. Two-sided 95% CIs of median, if estimable, will be 
constructed with generalized Brookmeyer and Crowley method (Brookmeyer 1982).
9.3.5
Safety Analysis
The summary of the exposure to study treatments (surufatinib and gemcitabine), AEs including 
DLTs, AEs leading to drug modification or discontinuation, changes in laboratory results, changes 
in vital signs, etc, will be presented.  
The severity of all AEs will be graded according to NCI CTCAE version 5.0, and the AE verbatim 
term will be coded by the Medical Dictionary for Regulatory Activities (MedDRA).
TEAEs are defined as AEs that started or worsened in severity on or after the first dose of study 
drug and no later than 30 days after the date of last study drug administration. 
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in patient data listings.  The number and 
frequency of patients experiencing AEs will be summarized according to SOC and preferred term 
(PT).  If a patient reports a TEAE more than once within that SOC/PT, the AE with the highest 
severity will be used in the corresponding severity summaries.
The following safety summaries will be produced:
x
Overview of AEs
x
Summary of DLTs 
x
Summary of DLT-equivalent (DLTs which occur outside the DLT evaluation window)
x
Summary of TEAEs, including severity and relationship to study drug
x
Summary of AESIs for surufatinib, including severity and relationship to study drug
x
Summary of serious TEAEs
x
Summary of TEAEs leading to dose interruption, dose reduction, or termination of study 
drug
The above summaries will be repeated for TEAEs related to study drug.


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Drug exposure, including number of cycles received, total duration of exposure, cumulative dose 
received (mg), dose intensity, and relative dose intensity of surufatinib and gemcitabine will be 
summarized.  The number and percentage of patients requiring dose interruption, dose delay, dose 
reduction, and treatment discontinuation because of AEs will be summarized.  The reasons for 
dose modifications will also be summarized for each drug.
For laboratory tests that are graded by NCI CTCAE version 5.0 or higher, results will be 
summarized by grade.  Treatment-emergent changes as defined by worsening of at least one grade 
from baseline will be summarized by the maximum post-baseline grade.  A shift-table 
summarizing shifts from baseline to maximum post-baseline grade will be presented.
The changes in vital signs and ECOG PS scores from baseline will be summarized.  Changes in 
12-lead ECG (eg, changes in QTcF) will be summarized.
9.3.6
Other Analysis
9.3.6.1
Taste and Palatability Survey
Data for the evaluation of taste of surufatinib oral suspension will be summarized on a scale of 1 
(very bad) through 5 (very nice) .
9.3.7
Pharmacokinetics Analysis
Evaluation on PK will be performed on the PK analysis set.  Concentration data of surufatinib in 
plasma will be tabulated and summarized using descriptive statistics (number of patients [n]; 
arithmetic mean with standard deviation; coefficient of variation [CV]; and median, minimum, 
and maximum) as appropriate.
PK parameters of surufatinib to be determined using a noncompartmental approach include, but 
are not limited to Cmax, effective T1/2, time to reach the maximum plasma concentration (Tmax),
area under the plasma concentration-time curve (AUC), minimum plasma concentration (Cmin),
apparent total clearance from plasma after oral administration (CL/F) at steady state, and 
accumulation ratio.  Additional PK parameters may be included if deemed appropriate.  PK 
analysis will be performed using actual blood collection times relative to dosing times recorded in 
the raw data.  If an actual blood collection time or a dosing time is missing, the nominal time may 
be used.  Details of the PK analysis, including data handling rules and software used to perform 
the PK analysis, will be provided in the PK SAP.
9.4
Timing of Analyses
Safety and PK data will be reviewed by dose level during the dose escalation phase of the study.  
The purpose of these reviews is to evaluate safety and tolerability for each dose escalation and 
determine if a DLT has been observed.


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10
ETHICAL CONSIDERATIONS
10.1
Good Clinical Practice
The study will be conducted in accordance with the protocol, consensus, and ethical principles 
derived from international guidelines, including the Declaration of Helsinki and Council for 
International Organizations of Medical Sciences International Ethical Guidelines, applicable ICH 
GCP guidelines, and applicable regulations and guidelines governing clinical study conduct.
10.2
Ethics Review
The IEC/IRB must review the protocol and amendments, IB, ICF, study-relevant materials (such 
as advertisements for patient recruitment), and any other essential documents.  IEC/IRB approval 
is to be obtained prior to the start of the study at the Investigator’s site.
All amendments are to be reviewed and approved by the IEC/IRB and applicable regulatory 
authorities (as required) and documented.  All SAEs or other significant safety findings should be 
reported to the Sponsor, the IEC/IRB, and applicable regulatory authorities as required.  During 
the study, protocol deviations that may increase a patient’s risk should be reported to the IEC/IRB 
in a timely manner.
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants.
The Investigator will be responsible for the following:
x
Providing written summaries of the status of the study to the IEC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IEC/IRB
x
Notifying the IEC/IRB of SAEs or other significant safety findings as required by IEC/IRB 
procedures
x
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IEC/IRB, European regulation 536/2014 for clinical studies 
(if applicable), European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations
10.3
Data Privacy
All information about the study drug (such as patent application, formulation, manufacturing 
process, and basic study information) is considered confidential as long as it is unpublished.
All information obtained in the study is considered confidential.  The Sponsor will open the 
information to investigational personnel and any other regulatory authority when necessary.  To 
ensure the completeness of the study analysis data, investigational personnel are accountable for 
providing all results and data to the Sponsor.
Investigators must guarantee the privacy of patients by not disclosing patient-related information 
to third parties without authorization. eCRFs and other documents submitted to the Sponsor should 
not contain the patient’s name.


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x
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information that would make the patient identifiable will not be transferred.
x
Patients are identified only by unique identifier.  Investigators may retain the identification 
forms, which include patient numbers, names, and addresses. Informed consent forms and 
other documents should be documented properly and should not be given to the Sponsor.
x
The patient must be informed that his or her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the patient, who will be required to give consent for his or her data to be used 
as described in the informed consent.
x
The patient must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC/IRB members, and by inspectors from regulatory authorities.
10.4
Disclosure
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.
10.5
Data Quality Assurance
x
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.
x
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 eCRF.
x
Guidance on completion of CRFs will be provided in the eCRF Completion Guidelines.
x
The Investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source data documents.
x
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
x
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
x
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations [CROs]).
10.6
Informed Consent
x
Investigators or designees must obtain the signed ICF from patients prior to conducting 
any study-related procedures.


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x
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.
x
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 local regulations, ICH guidelines, and the IEC/IRB or study 
site.
x
Patients must be informed that they may withdraw consent to participate in the study 
without any limitations.  If the patient cannot sign the ICF, a legally acceptable 
representative of the patient must sign the ICF.
x
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.
x
Informed consent should be recorded on the eCRF.
x
If the benefit/risk assessment changes after the safety analysis, the ICF needs to be 
reviewed and updated, and all updated information should be provided to patients 
(including patients who have already received the study drug).
x
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.


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11
OVERSIGHT
11.1
Safety Review Committee
The SRC will be established under a charter to conduct safety data reviews during the study.  The 
SRC will be comprised of sponsor and CRO medical team members and the site investigators.  The 
SRC will determine whether it is safe to continue to the next predefined dose level, stay at the 
currently assigned dose level, or whether the dose should be de-escalated to a lower dose level and 
finally to determine the MTD/RP2D. 
11.2
Quality Control and Assurance
The clinical study will be executed and reported following GCPs, all applicable regulatory 
requirements and applicable standard operating procedures, including quality control of 
documents.
The Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates study-related duties and functions conducted at the study site.  The Sponsor and 
Investigator will ensure that any individual or party who performs study-related duties or functions 
on behalf of the Sponsor/Investigator is qualified to perform the study-related duties or functions.
The overall procedures for quality assurance of clinical study data are described in the Sponsor or 
designee’s standard operational procedures.  The planned quality assurance and quality control 
procedures for the study are described in the following sections.
11.2.1
Monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, the Sponsor’s 
personnel (or designated CRO) will review the protocol and eCRFs with the Investigators and their 
staff. During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence of the protocol to GCP, and 
the progress of enrollment and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel including the Investigator must be 
available to assist the field monitor during these visits.
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. The Sponsor’s monitoring standards require full verification
of the informed consent, adherence to the inclusion/exclusion criteria, and documentation of SAEs. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan.
11.2.2
Audits
Authorized representatives of the Sponsor, a regulatory/competent authority, and/or an IEC/IRB
representative may visit the site to perform audits or inspections, including source data verification.  
Should this occur, the Investigator is responsible for the following:
x
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
x
Providing access to all necessary facilities, study data, and documents for the inspection or 
audit


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x
Communicating any information arising from inspection by the regulatory authorities to 
the Sponsor immediately
x
Taking all appropriate measures requested by the Sponsor to resolve the problems found 
during the audit or inspection
x
Documents patient to audit or inspection including but not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IEC/IRB files, documentation of 
certification and quality control of supporting laboratories, and records relevant to the study 
maintained in any supporting pharmacy facilities.  Conditions of study material storage are 
also patient to inspection.  In addition, representatives of the Sponsor may observe the 
conduct of any aspect of the clinical study or its supporting activities both within and 
outside of the Investigator’s institution.
In all instances, the confidentiality of the data must be respected.
11.2.3
Records
11.2.3.1
Data Capture and Management
The term eCRF refers to the electronic data capture (EDC) system.
The EDC system is the 
database where pertinent study data are collected.  For all patients, including screen failures, data 
will be collected on source documents first.  The PI 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 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 PI has final responsibility for the accuracy and authenticity of all clinical and 
laboratory data entered in the EDC.  Patient source documents are the Investigator’s/physician’s
patient records maintained at the study site.  In cases where the source documents are the hospital 
or the physician’s chart, the information collected in the EDC must match those charts.
The completed pages of the EDC system are the sole property of the Sponsor and should not be 
made available in any form to third parties without written permission from the Sponsor, except 
for authorized representatives of the Sponsor or appropriate regulatory authorities.
11.2.3.2
Source Documentation
x
The Investigator/institution should maintain accurate source documents and study records 
for all patients that support the information entered in the eCRF.
x
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete.  Changes to source data should be traceable and not obscure the original entry.
x
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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11.2.3.3
Records Retention
Records and documents, including signed ICFs, source documents, study drug documents, 
monitoring visit records, regulatory documents, and all other correspondence and documents 
pertaining to the conduct of this study must be retained by the Investigator for at least 5 years after 
study completion, unless local regulations or institutional policies require a longer retention period.
If the documents cannot be stored properly at the investigational site, the documents can be 
transferred by the Investigator and sponsor to an approved storage facility. The documents must 
be sealed for storage and easily found for review in the case of a regulatory authority audit.  No 
records may be transferred to another location or party without written notification to the sponsor.
No records may be destroyed during the retention period following study completion or 
discontinuation without the written approval of the Sponsor.  Records must be destroyed in a 
manner that ensures confidentiality. 
11.3
Study Termination or Study Site Closure
The Sponsor and the Investigator have the right to close out a study 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:
x
The Investigator has received all items and information necessary to perform the study, but 
has not enrolled any patient within a reasonable period of time
x
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
x
The total number of patients 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 IEC/IRB, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements.  The 
Investigator shall promptly inform the patient and should assure appropriate patient therapy and/or 
follow-up.


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


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


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15
APPENDICES


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APPENDIX 1 
KARNOFSKY/LANSKEY PERFORMANCE STATUS SCALE  


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APPENDIX 2 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1)  
Selected sections from the RECIST version 1.1, are presented below.
1. Measurability of Tumor at Baseline
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below.
1.1.1 Measurable Tumor Lesions
Tumor lesions must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size as follows:
x
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 5 mm)
x
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable)
x
20 mm by chest X-ray
x
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be t15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and follow-up, only the 
short axis will be measured and followed.
1.1.2 Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis t10 but 15 mm) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural 
or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques.
1.1.3 Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below.
Bone Lesions:
x
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques can 
be used to confirm the presence or disappearance of bone lesions.
x
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI scan can 
be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
x
Blastic bone lesions are non-measurable.


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Cystic Lesions:
x
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.
x
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Lesions with Prior Local Treatment:
x
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Study protocols should detail the conditions under which such 
lesions would be considered measurable.
1.2 Specifications by Methods of Measurements
1.2.1 Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment.
1.2.2 Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
and t10 mm in diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.
Chest X-Ray.  Chest CT scan is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT scan is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung.
CT, MRI.  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT scan slice thickness is 5 mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV contrast 
because of allergy or renal insufficiency, the decision as to whether a non-contrast CT scan or MRI 
(without IV contrast) will be used to evaluate the patient at baseline and during the study should 
be guided by the tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT scan is done, the 
decision as to whether non-contrast CT scan or MRI (enhanced or non-enhanced) will be 


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performed should also be based on the tumor type and the anatomic location of the disease, and 
should be optimized to allow for comparison with the prior studies if possible. Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. Care must be 
taken in measurement of target lesions on a different modality and interpretation of non-target 
disease or new lesions, since the same lesion may appear to have a different size using a new 
modality.
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of these 
techniques for objective tumor evaluation cannot generally be advised.
2. Tumor Response Evaluation
2.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Measurable disease 
is defined by the presence of at least 1 measurable lesion, as detailed above.
2.2 Baseline Documentation of Target and Non-Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline.  This means that, for 
instances in which patients have only 1 or 2 organ sites involved, a maximum of 2 lesions (1 site) 
and 4 lesions (2 sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is !10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition should lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion that can be measured 
reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor.  As noted above, pathological nodes that are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
t15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For example, 
an abdominal node that is reported as being 20 mm u 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis t10 mm but 15 mm) should 
be considered non-target lesions.  Nodes that have a short axis of 10 mm are considered 
non-pathological and should not be recorded or followed.


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum.  The baseline 
sum of diameters will be used as a reference to characterize further any objective tumor regression 
in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the electronic Case Report Form (eCRF) (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).
2.3 Response Criteria
2.3.1 Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor response for 
target lesions.
x
Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to 10 mm.
x
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum of diameters
x
Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (nadir), including baseline. In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. The appearance of 1 or more new lesions is also considered progression.
x
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum on study.
2.3.2 Special Notes on the Assessment of Target Lesions
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to 10 mm on study.  This means that when lymph nodes are included as target 
lesions, the sum of lesions may not be 0 even if CR criteria are met, since a normal lymph node is 
defined as having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure. During the study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the eCRF, as follows:
x
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned and below measurable 
limit (BML) should be ticked. (BML is equivalent to a “less than” sign.) (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size 


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when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well and BML should 
also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance should be 
the maximum longest diameter for the coalesced lesion.
2.3.3 Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
x
CR: Disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (10 mm short axis).
x
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits.
x
PD: Unequivocal progression of existing non-target lesions. The appearance of one or 
more new lesions is also considered progression.
2.3.4 Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.
In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease. This circumstance arises in some phase 3
studies when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease, that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion).  


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Examples include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as “sufficient 
to require a change in therapy.”  If unequivocal progression is seen, the patient should be 
considered to have had overall PD at that point.  While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial.
2.3.5 New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought
to represent something other than tumor (for example, some “new” bone lesions may be simply 
healing or flare of preexisting lesions).  This is particularly important when the patient’s baseline 
lesions show PR or CR.  For example, necrosis of a liver lesion may be reported on a CT scan 
report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan.
18F-Fluorodeoxyglucose Positron Emission Tomography
While 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) response assessments 
need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly, possible “new” disease).  
New lesions on the basis of FDG-PET imaging can be identiﬁed according to the following 
algorithm:
A negative FDG-PET scan at baseline with a positive FDG-PET scan during the study is a sign of 
PD based on a new lesion.
In the case of no FDG-PET scan at baseline and a positive FDG-PET scan during the study:
x
If the positive FDG-PET scan during the study corresponds to a new site of disease 
conﬁrmed by CT scan, this will be considered PD.
x
If the positive FDG-PET scan during the study is not conﬁrmed as a new site of disease on 
CT scan, additional follow-up CT scans are needed to determine whether there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).
x
If the positive FDG-PET scan during the study corresponds to a preexisting site of disease 
on CT scan that is not progressing on the basis of the anatomic images, this will not be 
considered PD.


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2.4 Evaluation of Response
2.4.1 Time Point Response (Overall Response)
It is assumed that at each protocol specified time point, a response assessment occurs.  Table 14
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only Table 15 is to be used.
Table 14
Time Point Response: Patients with Target Lesions (with or without Non-
Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease; PR partial response; SD stable disease.
Table 15
Time Point Response: Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CR complete response; NE not evaluable; PD progressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some studies; thus, assigning “stable disease” when no 
lesions can be measured is not advised.
2.4.2 Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is NE at that 
time point.  If only a subset of lesion measurements are made at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response.  
This would be most likely to happen in the case of PD.  For example, if a patient had a baseline 
sum of 50 mm with 3 measured lesions and, during the study, only 2 lesions were assessed, but 


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those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is NE.  Similarly, if one or more non-target 
lesions are not assessed, the response for non-target lesions should be “unable to assess” except 
where there is clear progression.  Overall response would be “unable to assess” if either the target 
response or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being NE at that time point.
2.4.3 Best Overall Response: All Time Points
The BOR is determined once all the data for the patient is known.  Best response determination in 
studies where confirmation of CR or PR is not required: Best response in these studies is defined 
as the best response across all time points (for example, a patient who has SD at first assessment, 
PR at second assessment, and PD on last assessment has a BOR of PR).  When SD is believed to 
be best response, it must also meet the protocol specified minimum time from baseline.  If the 
minimum time is not met when SD is otherwise the best time point response, the patient’s best 
response depends on the subsequent assessments.  For example, a patient who has SD at first 
assessment, PD at second, and does not meet minimum duration for SD, will have a best response 
of PD.  The same patient lost to follow-up after the first SD assessment would be considered NE.
Best response determination in studies where confirmation of CR or PR is required: Complete 
response or PR may be claimed only if the criteria for each are met at a subsequent time point as 
specified in the protocol (generally 4 weeks later).  In this circumstance, the BOR can be 
interpreted as in Table 16.
Table 16
Best Overall Response When Confirmation of Complete Response and 
Partial Response is Required
Overall Response
First Time Point
Overall Response
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SDɾPD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise, NE


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NE
NE
NE
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, and NE=not evaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR).  Best response would depend on whether minimum duration for SD was met.  However, sometimes 
‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR, not CR at the first time point.  Under these circumstances, the original CR should be changed 
to PR and the best response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may not 
have a total sum of “zero” on the eCRF.
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy.  The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Table 14 and 
Table 15.
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected.
In studies for which patients with advanced disease are eligible (ie, primary disease still or partially 
present), the primary tumor should also be captured as a target or non-target lesion, as appropriate.  
This is to avoid an incorrect assessment of CR if the primary tumor is still present but not evaluated 
as a target or non-target lesion.
2.5 Frequency of Tumor Re-evaluation
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment.  However, in the context of phase 2 studies where the beneficial 
effect of therapy is not known, follow-up every 6 to 8 weeks (timed to coincide with the end of a 
cycle) is reasonable.  Smaller or greater time intervals than these could be justified in specific 
regimens or circumstances.  The protocol should specify which organ sites are to be evaluated at 
baseline (usually those most likely to be involved with metastatic disease for the tumor type under 
study) and how often evaluations are repeated.  Normally, all target and non-target sites are 
evaluated at each assessment.  In selected circumstances certain non-target organs may be 
evaluated less frequently.  For example, bone scans may need to be repeated only when CR is
identified in target disease or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death).  If ‘time to an event’ 
(eg, time to progression, disease-free survival, PFS) is the main endpoint of the study, then routine 
scheduled re-evaluation of protocol specified sites of disease is warranted.  In randomized 


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comparative studies in particular, the scheduled assessments should be performed as identified on 
a calendar schedule (for example: every 6 to 8 weeks on treatment or every 3 to 4 months after 
treatment) and should not be affected by delays in therapy, drug holidays or any other events that 
might lead to imbalance in a treatment arm in the timing of disease assessment.
2.6 Confirmatory Measurement/Duration of Response
2.6.1. Confirmation
In non-randomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies (see the paper by Bogaerts et al. in this Special 
Issue 10).  However, in all other circumstances, for example in randomized studies (phase 2 or 3) 
or in studies where SD or progression are the primary endpoints, confirmation of response is not 
required since it will not add value to the interpretation of study results.  However, elimination of 
the requirement for response confirmation may increase the importance of central review to protect 
against bias, in particular in studies that are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the study protocol.
2.6.2. Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
2.6.3. Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases.  If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance in 
a particular study, the protocol should specify the minimal time interval required between 2
measurements for determination of SD.
Note: The DoR and SD as well as the PFS are influenced by the frequency of follow-up after 
baseline evaluation.  It is not in the scope of this guideline to define a standard follow-up 
frequency.  The frequency should take into account many parameters including disease types and 
stages, treatment periodicity and standard practice.  However, these limitations of the precision of 
the measured endpoint should be taken into account if comparisons between studies are to be made.


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APPENDIX 3 
SURUFATINIB DOSING NOMOGRAM  
Surufatinib Dosing Nomogram
90 mg/m2 (Dose Level -1)
120 mg/m2 (Dose Level 1)
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
0.4-0.64
50
25
50%
0.4-0.64
75
50
33%
0.65-0.9
75
50
33%
0.65-0.9
100
75
25%
0.91-1.17
100
75
25%
0.91-1.17
125
75
40%
1.18-1.36
125
75
40%
1.18-1.36
150
100
33%
1.37-1.85
150
100
33%
1.37-1.85
175
125
29%
1.86-2.07
175
125
29%
1.86-2.07
200
150
25%
≥2.08
200
150
25%
≥2.08
225
150
33%
160 mg/m2 (Dose Level 2)
200 mg/m2 (Dose Level 3)
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
BSA (m2)
Dose 
(mg)
Dose 
Reduction 
(mg)
%
Reduction
0.4-0.64
100
75
25%
0.4-0.64
125
75
40%
0.65-0.9
125
75
40%
0.65-0.9
150
100
33%
0.91-1.17
175
125
29%
0.91-1.17
200
150
25%
1.18-1.36
200
150
25%
1.18-1.36
250
175
30%
1.37-1.85
250
175
30%
1.37-1.85
300
200
33%
1.86-2.07
300
200
33%
1.86-2.07
300
200
33%
侔2.08
300
200
33%
侔2.08
300
200
33%
BSA=body surface area.
For Spain only: No subjects will be allowed on the study with a BSA ≤0.6 or body weight ≤14 kg.
Note: This table also appears in main text as Table 7.


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APPENDIX 9 
THE TASTE AND PALATABILITY SURVEY  
Please rate how your child reacted to the taste of the surufatinib oral suspension. Select one 
below.
x
Very nice (Smiley-Face Scale 5)
x
Nice (Smiley-Face Scale 4)
x
Not nice, not bad (Smiley-Face Scale 3)
x
Bad (Smiley-Face Scale 2)
x
Very bad (Smiley-Face Scale 1)
Smiley-Face Scale
Source: Diane 2017.


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SAP_001.pdf: 
 
 
 
HUTCHMED Limited 
Study Protocol: 2020-012-GLOB2 
 
SAP Version 1.0 
 
CONFIDENTIAL 
Page 1 of 38 
Date: 23 May 2023 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
AN OPEN-LABEL, MULTICENTER PHASE 1/2 STUDY OF SURUFATINIB IN 
COMBINATION WITH GEMCITABINE IN PEDIATRIC, ADOLESCENT, AND YOUNG 
ADULT PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS 
 
 
 
Protocol Number: 
2020-012-GLOB2 
 
 
Name of Test Drug: 
Surufatinib (HMPL-012) 
Gemcitabine 
 
 
Phase: 
Phase 1/2 
 
 
 
Sponsor Name: 
HUTCHMED Limited 
 
Building 4, 720 Cailun Road,  
 
China (Shanghai) Pilot Free Trade Zone 
Shanghai, China 201203 
 
 
Analysis Plan Version 
Version 1.0 
 
 
Effective Date 
23 May 2023 
 
 
 
 
Compliance: The study described in this report was performed according to the principle of Good Clinical Practice 
(GCP).  
Confidentiality Statement 
The information contained in this Statistical Analysis Plan (SAP) is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of HUTCHMED Limited or its 
subsidiaries. 
 






 
 
 
HUTCHMED Limited 
Study Protocol: 2020-012-GLOB2 
 
SAP Version 1.0 
 
CONFIDENTIAL 
Page 4 of 38 
Date: 23 May 2023 
 
 
 
 
TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY DETAILS .....................................................................................................11 
2.1. 
Study Objectives .........................................................................................................11 
2.2. 
Study Design ...............................................................................................................11 
2.2.1. 
Dose Escalation ..........................................................................................................12 
2.2.2. 
Dose Finding ...............................................................................................................12 
2.3. 
Determination of Sample Size ....................................................................................13 
2.3.1. 
Dose Escalation ..........................................................................................................13 
3. 
ANALYSIS SETS ......................................................................................................14 
3.1. 
Definition of Analysis Sets .........................................................................................14 
3.1.1. 
Safety Analysis Set (All Treated Population) .............................................................14 
3.1.2. 
DLT-Evaluable Analysis Set (DEAS) ........................................................................14 
3.1.3. 
Pharmacokinetics (PK) Analysis Set ..........................................................................14 
3.2. 
Protocol Deviation ......................................................................................................14 
4. 
ENDPOINTS ..............................................................................................................15 
4.1. 
General Principles for Derived and Transformed Data ..............................................15 
4.1.1. 
Reference Start Date and End Date and Study Day ...................................................15 
4.1.2. 
Baseline and Change from Baseline ...........................................................................15 
4.1.3. 
Treatment Period ........................................................................................................15 
4.2. 
Primary Endpoints ......................................................................................................16 
4.3. 
Secondary Endpoints ..................................................................................................16 
4.3.1. 
Pharmacokinetic Evaluations ......................................................................................16 
4.3.2. 
Efficacy Endpoints ......................................................................................................16 
4.3.3. 
Taste and Palpability ...................................................................................................18 


 
 
 
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4.4. 
Exposure Endpoints ....................................................................................................18 
4.5. 
Safety Endpoints .........................................................................................................19 
4.5.1. 
Dose Limiting Toxicities ............................................................................................20 
4.5.2. 
Adverse Events (AEs) .................................................................................................20 
4.5.3. 
Laboratory ...................................................................................................................20 
4.5.4. 
Electrocardiogram (ECG) ...........................................................................................22 
4.5.5. 
Vital Signs ..................................................................................................................23 
4.5.6. 
Performance Status .....................................................................................................23 
4.5.7. 
Echocardiogram ..........................................................................................................23 
4.5.8. 
Physical Examination .................................................................................................23 
4.5.9. 
Knee X-Ray/MRI ........................................................................................................24 
4.6. 
Other Endpoints ..........................................................................................................24 
4.6.1. 
PK Endpoints ..............................................................................................................24 
4.6.2. 
Taste and Palatability ..................................................................................................24 
5. 
ANALYSIS METHODS ............................................................................................25 
5.1. 
General Principles .......................................................................................................25 
5.1.1. 
General Methodology .................................................................................................25 
5.1.2. 
Handling Missing Data ...............................................................................................26 
5.1.2.1. 
Adverse Events Start/End Date ..................................................................................26 
5.1.2.2. 
Concomitant Medication/Procedure/Surgery Start/End Date .....................................27 
5.1.3. 
Visit Windowing .........................................................................................................27 
5.1.4. 
Adjustment of Covariates ...........................................................................................27 
5.2. 
Analysis Methods .......................................................................................................27 
5.2.1. 
Subject Disposition .....................................................................................................27 
5.2.2. 
Protocol Deviation ......................................................................................................28 
5.2.3. 
Demographic and Other Baseline Characteristics ......................................................28 
5.2.4. 
Disease History ...........................................................................................................28 
5.2.5. 
Medical History ..........................................................................................................28 
5.2.6. 
Prior Anti-cancer Medication/Radiotherapy/Procedure or Surgery (including 
subsequent) .................................................................................................................29 


 
 
 
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5.2.6.1. 
Prior Anti-cancer Medication .....................................................................................29 
5.2.6.2. 
Prior Anti-cancer Radiotherapy ..................................................................................29 
5.2.6.3. 
Prior and Subsequent Procedure or Surgery ...............................................................29 
5.2.7. 
Prior and Concomitant Medications ...........................................................................30 
5.2.8. 
Efficacy Analyses .......................................................................................................30 
5.2.8.1. 
Primary Efficacy Analyses .........................................................................................30 
5.2.8.2. 
Sensitivity Analysis for Primary Efficacy Endpoint ..................................................30 
5.2.8.3. 
Multiplicity Control ....................................................................................................30 
5.2.8.4. 
Secondary Efficacy Analyses .....................................................................................30 
5.2.9. 
Exposure of Study Drug .............................................................................................30 
5.2.10. 
Safety Analyses ..........................................................................................................31 
5.2.10.1. 
Dose Limiting Toxicity (DLT) ...................................................................................31 
5.2.10.2. 
Adverse Events ...........................................................................................................31 
5.2.10.3. 
Death ...........................................................................................................................32 
5.2.10.4. 
Laboratory Evaluations ...............................................................................................32 
5.2.10.5. 
Electrocardiogram .......................................................................................................32 
5.2.10.6. 
Vital Signs ..................................................................................................................32 
5.2.10.7. 
Performance Status .....................................................................................................33 
5.2.10.8. 
Echocardiogram ..........................................................................................................33 
5.2.10.9. 
Physical Examination .................................................................................................33 
5.3. 
Subgroup Analyses .....................................................................................................33 
5.4. 
Other Analyses ............................................................................................................33 
5.4.1. 
Taste and Palatability ..................................................................................................33 
6. 
PLANNED ANALYSIS .............................................................................................34 
6.1. 
Safety Review Committee ..........................................................................................34 
6.2. 
Final Analysis .............................................................................................................34 
7. 
CHANGE FROM THE PROTOCOL ........................................................................35 
REFERENCE .................................................................................................................................36 
APPENDIX 1 PT LIST FOR AESI ............................................................................................37 


 
 
 
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List of Tables 
Table 1 Objectives and Endpoints .................................................................................................11 
Table 2 Censoring Rules for PFS...................................................................................................18 
Table 3 Laboratory Assessment .....................................................................................................21 
Table 4 Potentially Clinically Significant Criteria for Vital Signs ................................................23 
Table 5 Treatment Display in TLFs ...............................................................................................25 
 
List of Figures 
Figure 1 Study Schematic ..............................................................................................................13 
 


 
 
 
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Date: 23 May 2023 
 
 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Plasma Concentration-Time Curve 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BP 
Blood Pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CFB 
Change From Baseline 
CI 
Confidence Interval 
CL/F 
Apparent Total Clearance from Plasma After Oral Administration 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate 
DEAS 
DLT-Evaluable Analysis Set 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IL-34 
Interleukin 34 


 
 
 
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Abbreviation 
Term 
INR 
International Normalized Ratio 
LLoQ 
Lower Limit of Quantification 
MCHC 
Mean Corpuscular Haemoglobin 
MCV 
Mean Corpuscular Volume 
MTD 
Maximum Tolerated Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
OC 
Observed Case 
PE 
Physical Examination 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance Status 
PT 
Preferred Term 
PrT 
Prothrombin time 
QTcF 
Corrected QT Interval by Fridericia 
RBC 
Red Blood Cells Platelet Count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SI 
International System of Units 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 
T1/2 
Half-life 
Tmax 
Time to reach the maximum plasma concentration 
TPR 
Time Point Responses 
TTR 
Time To Response 
ULN 
Upper Limit of Normal 
ULoQ 
Upper Limit of Quantification 
WHO-DD 
World Health Organization Drug Dictionary 


 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses and data 
presentations for study 2020-012-GLOB2. The SAP is based on the Protocol amendment 3, 
dated 24 January 2023. The SAP for pharmacokinetic will be prepared separately. 
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan. Planned tables, figures, and listings are specified. All decisions 
regarding final analyses, as defined in this SAP document, have been made prior to locking the 
database. Any deviations from these guidelines will be documented in the clinical study report 
(CSR). 


 
 
 
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2. STUDY DETAILS 
Table 1 describe the primary and secondary objectives of this study. 
2.1. Study Objectives 
Table 1 Objectives and Endpoints  
 
Objectives 
Endpoints 
Primary 
x To determine maximum tolerated 
dose (MTD) and/or recommended 
phase 2 Dose (RP2D) of surufatinib, 
and to evaluate the safety and 
tolerability of surufatinib in 
combination with gemcitabine in 
pediatric subjects with recurrent or 
refractory solid tumors or lymphoma 
x The incidence of Dose Limiting Toxicities (DLT) 
in each dose level 
x Safety, as assessed by: 
o The frequency and severity of Adverse Events 
(AEs) 
o Physical examination findings 
o Vital signs 
o Laboratory test results 
o 12-lead electrocardiogram (ECG) 
Secondary 
x To characterize the pharmacokinetics 
(PK) of surufatinib as a monotherapy 
and in combination with gemcitabine 
in pediatric subjects with recurrent or 
refractory solid tumors or lymphoma 
 
x PK parameters for the dose escalation and PK 
expansion cohorts: maximum plasma 
concentration (Cmax), time to reach the maximum 
plasma concentration (Tmax), area under the 
plasma concentration-time curve (AUC), 
minimum plasma concentration (Cmin), effective 
half-life (T½), apparent total clearance from 
plasma after oral administration (CL/F), and 
accumulation ratio 
 
 
x To evaluate the anti-tumor activity of 
surufatinib in combination with 
gemcitabine in pediatric patients with 
recurrent/refractory solid tumors or 
lymphoma 
x Efficacy will be assesses based on tumor response 
per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1: 
o Objective response rate (ORR) 
o Disease control rate (DCR) 
o Time to response (TTR) 
o Duration of response (DoR) 
o Progression-free survival (PFS) 
x Acceptability and palatability of 
surufatinib oral suspension 
x The taste and palatability survey  
2.2. Study Design 
This is an open-label, multicenter, uncontrolled, Phase 1/2 study of surufatinib in combination 
with gemcitabine in pediatric, adolescent, and young adult subjects with recurrent or refractory 
solid tumors.  This study design allows for dose escalation with intensive safety monitoring to 
ensure the safety of all subjects. 


 
 
 
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This study will utilize a rolling 6 design, with 3 dose escalation levels and 1 de-escalation level, 
if needed. The MTD and/or the RP2D will be designated in pediatrics. 
The study duration is estimated to be approximately 36 months. 
2.2.1. 
Dose Escalation 
Dose escalation will be performed with sequential doses of surufatinib in combination with 
gemcitabine (Figure 1). 
The first study cycle will be 35 days.  During Cycle 1, surufatinib will be administered as a 
single agent for 14 days followed by surufatinib daily in combination with gemcitabine on days 
15 and 22. All subsequent cycles will be 21 days per cycle, where surufatinib will continue to be 
administered daily and gemcitabine will be administered on days 1 and 8. The starting dose of 
surufatinib will be 120 mg/m2 daily.  Gemcitabine (1000 mg/m2 weekly × 2 doses) will not be 
escalated and will be given on days 15 and 22 of Cycle 1 and then on days 1 and 8 of all 
subsequent cycles. Surufatinib will be given continuously on days 1 to 35 in Cycle 1. The first 14 
days of Cycle 1 serves to assess tolerability and toxicity of single agent surufatinib.   
A PK expansion cohort will be conducted at the presumed RP2D/MTD and will consist of up to 
6 subjects in each of the following 2 strata: subjects <12 years of age and subjects 12 to <18 
years of age based on age at the time of enrollment. Surufatinib PK profiles after the first dose 
and at steady state will be characterized in both dose escalation cohort and PK expansion cohort. 
Subjects who are treated at the RP2D/MTD in dose escalation cohort will be counted in the PK 
expansion cohort. 
To evaluate safety and tolerability for each dose escalation and determine if a DLT has been 
observed, safety and PK data will be reviewed by dose level. 
The schedule of events can be found in Table 1 of the protocol.  
2.2.2. 
Dose Finding 
The dose finding period is the timeframe to define dose limiting toxicity (DLT) and begins with 
the initial dose of surufatinib and ends on the last day of Cycle 1. Should there be a delay 
(maximum 7 days delay) starting the subsequent cycle, dose finding will complete on the start 
date of the subsequent cycle. 
Full details of the dose escalation and de-escalation rules can be found in Section 4.1.1 of the 
Protocol. 


 
 
 
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Figure 1 Study Schematic 
 
2.3. Determination of Sample Size 
Up to 36 subjects are to be enrolled in this study.  
2.3.1. 
Dose Escalation 
Three dose escalation levels will be explored using the rolling 6 design which will lead to 
maximum 18 evaluable subjects. There is 1 additional dose level for dose de-escalation if starting 
dose is not tolerable. Then, up to 12 evaluable subjects will be evaluated in the PK expansion 
cohort.  Assuming a 15% unevaluable rate with respect to the DLT evaluation for dose escalation 
portion or PK assessment for PK expansion cohort, it is expected to have up to 36 subjects in total.  


 
 
 
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3. ANALYSIS SETS 
3.1. Definition of Analysis Sets  
Data analyses will be based on the analysis sets defined below. Analysis sets, including 
exclusions based on major deviations, will be reviewed and approved by the Sponsor prior to the 
study database lock. 
3.1.1. 
Safety Analysis Set (All Treated Population) 
The Safety Analysis Set includes all subjects who receive at least 1 dose of surufatinib or 
gemcitabine. Safety data and efficacy will be evaluated based on this population’s outcome.  
Subjects in the Safety Analysis Set will be analyzed by their actual dose initially received. If 
subjects have dose reduction during the study, all data will be summarized/analyzed based on the 
initial dose of subject drug received. For outputs relating to efficacy, the analysis set will be 
referred to as the All Treated Population. 
3.1.2. 
DLT-Evaluable Analysis Set (DEAS) 
The DLT-evaluable analysis set includes all subjects enrolled in the dose escalation phase of the 
study who receive at least 80% (28 of 35 doses) of the prescribed oral surufatinib dose and both 
doses of gemcitabine during the DLT evaluation period or who discontinued treatment due to a 
DLT.  
3.1.3. 
Pharmacokinetics (PK) Analysis Set 
This population will include all patients who received at least 1 dose of surufatinib and have at 
least one PK sample obtained and analyzed. The PK Analysis Set will not be used for any 
analyses described in this SAP. A PK analyses plan will be described in a separate document.  
3.2. Protocol Deviation  
Certain protocol deviations are major in that they may affect the ability to assess the safety and 
efficacy of study drug.  
If a subject is enrolled, but fails to receive treatment, the reason for not receiving treatment will 
be noted in the CSR. Any such subjects who are not treated will be excluded from the Safety 
Analysis Set but will be included in the subject listings for the CSR. 
All major protocol deviations will be reviewed in a data review meeting to classify protocol 
deviations as minor or major, and to discuss the potential impact on statistical analysis. 


 
 
 
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4. ENDPOINTS 
4.1. General Principles for Derived and Transformed Data 
4.1.1. 
Reference Start Date and End Date and Study Day 
Generally, reference start date is defined as the first date when a non-zero dose of subject drug 
was administrated (i.e., date of first non-zero dose of any drug, whichever occurs first). Day 1 is 
the day of the first dose of study drug in Cycle 1. 
Study day will be calculated from the reference start date, and it will be used to show start/stop 
day of assessments and events relative to the first administration of study drug. 
If the date of the event is on or after the reference start date, Study day = (date of event – 
reference start date) + 1. 
If the date of the event is prior to the reference start date, Study day = (date of event – reference 
start date). 
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings. 
4.1.2. 
Baseline and Change from Baseline 
Baseline is defined as the last non-missing assessment prior to the first administration of subject 
drug (i.e., date of first non-zero dose of any drug, whichever occurs first), including scheduled 
and unscheduled visits, unless otherwise specified.  In the case where the last non-missing 
assessment and the first administration date coincides without time information, that 
measurement will be considered pre-dose. For quantitative measurements,  
 change from baseline (CFB) will be calculated as: CFB = Assessment value at visit X – 
Baseline value;  
 percentage CFB (% CFB) will be calculated as % CFB = (Assessment value at each visit X – 
Baseline value)/Baseline value × 100. 
4.1.3. 
Treatment Period 
All enrolled subjects enter into the treatment period. Subjects may receive up to 17 cycles of 
therapy as long as they continue to undergo study required assessments and meet criteria to start 
subsequent cycles. 
Unless otherwise specified, the treatment period for analysis purposes is defined as the period 
from first administration date to 30 days + 7 days after last administration date of treatment. For 
safety data, only the assessments/events collected during the treatment period will be evaluated. 
The worst post-baseline is defined as the worst assessment/event during the treatment period 
including both scheduled and non-scheduled visits. 


 
 
 
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Follow-up on this study is required at 30 days from the last dose of protocol therapy for late 
onset AEs and survival. The post-treatment follow-up will begin when the subject discontinues 
study treatment and all off-treatment assessments have been completed. 
The severity of AEs and laboratory results depends on Common Terminology Criteria for 
Adverse Events (CTCAE) grade. The worst post baseline value is defined as the highest CTCAE 
grade during on treatment period. 
The worst post-baseline abnormality is defined as Abnormal, Clinically Significant>Abnormal, 
Not Clinically Significant>Normal order during the on-treatment period. 
4.2. Primary Endpoints 
The primary endpoints are safety endpoints. Details can be found in Safety Endpoints, Section 
4.5.  
4.3. Secondary Endpoints 
4.3.1. 
Pharmacokinetic Evaluations 
PK evaluations details can be found in Secondary Endpoints, Section 4.6.1.  
4.3.2. 
Efficacy Endpoints 
Efficacy analysis will be assessed in the All Treated Population.  
 
Best Overall Response (BOR) 
BOR will be determined using time point responses (TPRs) up until the last evaluable TPR prior 
to or on the date of (i) disease progression as defined by RECIST Version 1.1 or death; or (ii) 
withdrawal of consent. 
The timing of an overall TPR will always be derived based on scan dates not response 
assessment dates. If there is more than one date per visit due to scans on different dates, take the 
earliest date if timepoint response is PD, otherwise take the latest date. 
For a scheduled tumor scan assessment, it is expected that there may be a variation for the actual 
timing of scans among target, non-target, and new lesions. In assigning a date for the overall 
response assessment at a visit, the earliest date collected at that visit will be used. Within a 
grouped timepoint, if there are multiple assessments on different dates for the same target 
lesions, the last assessment will be used.  
The best overall response is defined as the best response (in the order of CR, PR, SD, PD and 
NE) among all responses recorded during the on-treatment period. SD must meet 49-day rule as 
follow:  
Best overall response of SD can only be made after the subject is on study for a minimum of 
49 days (counted from Cycle 1 Day 1).  If the subject is on study for less than 49 days, any 
tumor assessment indicating stable disease before this time period will have a best response 
of NE unless PD is identified. 


 
 
 
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Objective Response Rate 
 ORR is defined as the proportion of subjects with a BOR of CR or PR as determined by the 
Investigator using RECIST version 1.1.  BOR is defined as the best response recorded from the 
start of study drug (s) until documented RECIST version 1.1 progression. 
Disease Control Rate 
DCR is defined as the proportion of subjects with a BOR of CR, PR, or SD as determined by the 
Investigator using RECIST version 1.1. As previously stated, SD must meet 49-day rule as 
defined in section “Best Overall Response”. 
Time to Response 
TTR is defined as the time (months) from start of study drug until the date of first occurrence of 
PR or CR for responders only.  
TTR (months) = (<date of first occurrence of PR or CR > - <date of first dose of study drug> + 
1)/30.4375. 
Duration of Response 
Duration of response is defined as the time (months) from the first occurrence of PR or CR 
whichever comes first, until disease progression or death. Duration of response will be 
summarized for responders only. 
DoR (months) = (<date of first documentation of definitive PD or last tumor assessment (PFS 
endpoint date)> - <date of first occurrence of response> + 1)/30.4375. 
Subjects will be censored using the censoring algorithm of the PFS (see Table 2). 
 
Progression-Free Survival 
Progression-free survival is defined as the time (months) from the start of subject drug (s) until 
the first radiographic documentation of objective progression as assessed by the investigator 
using RECIST Version 1.1 or death from any cause. PFS will be determined using all the 
assessment data up until the last evaluable visit prior to or on the date of (i) disease progression 
as defined by RECIST Version 1.1 or death; or (ii) withdrawal of consent, whichever is earlier. 
Subjects without report of PD or death from any cause at the time of analysis are censored as 
described in Table 2. 


 
 
 
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Table 2 Censoring Rules for PFS 
No Situation 
Date of 
Progression or 
Censoring 
Outcome 
Censor reason 
1 
No baseline tumor assessment and 
alive 
Date of first dose Censored 
No baseline assessment 
2 
No post-baseline tumor assessment 
and alive 
Date of first dose Censored 
No post-baseline assessment 
3 
No baseline and/or post-baseline 
tumor assessment and death prior to 
the planned time of the second 
scheduled post-baseline assessment 
(i.e., Study Day 98 + a 3-day 
window) 
Date of death 
Event 
 
4 
Progression, without missing two 
consecutive radiological assessment 
visits prior to progression 
Date of 
progression 
Event 
 
5 
Death due to any cause, without 
missing two consecutive radiological 
assessment visits prior to death 
Date of death 
Event 
 
6 
No disease progression or death 
Date of last 
adequate tumor 
assessment 
Censored 
Progression free at time of analysis: 
the subject is known to be alive 
without any progression happened at 
the data cut-off date 
7 
Death or PD occurred after two or 
more consecutive missed 
radiological assessment visits 
Date of last 
adequate 
radiological 
assessment prior 
to missed visits 
Censored 
 
 
4.3.3. 
Taste and Palpability 
Taste and palpability details can be found in Other Endpoints, Section 4.6.2. 
4.4. Exposure Endpoints 
No exposure endpoints are defined for this study in the protocol; however, the following 
exposure parameters will be derived for surufatinib and gemcitabine separately: 
Total Duration of Exposure 
Duration of exposure will be calculated in weeks for each treatment separately, as follows:   
Total duration of exposure (weeks) = [date of last dose – date of first dose + days to the next 
planned dose after discontinuation (or death date if death date is earlier than the next planned 
dose)] / 7 
If death occur within the last cycle, then death date can be used as the last dose date. 
Specifically, surufatinib is dosed daily, therefore. 


 
 
 
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Duration of Exposure (weeks) = (date of last dose – date of first dose + 1) / 7 
Gemcitabine is dosed on days 15 and 22 during Cycle 1 and days 1 and 8 during subsequent 
cycles, therefore. 
Duration of Exposure (weeks) = [date of last dose – date of first dose + days to the next planned 
dose after Gemcitabine discontinuation (or death date if death date is earlier than the next 
planned dose)]/ 7 
Days until the next dose will need to be computed depending on the day and cycle of 
administration. For example, for cycle 1 "days until the next dose” after dose administration on 
day 15 will be 7. Additionally, interruptions, compliance, and dose changes are not taken into 
account for duration of exposure. 
Number of Cycles Received 
Subjects are considered to have started a cycle if, for that cycle, they have received at least one 
dose of any study drug. 
Number of cycles is the number of cycles in which the subject took any dose of study drug. 
Dose Intensity and Cumulative Dose Received 
Dose intensity(mg/day) = cumulative dose (mg) / total duration of exposure (days) 
Cumulative dose (mg) is defined as the sum of the total dosage that the subject actually received 
during an exposure period. 
Relative Dose Intensity 
Relative dose intensity (%) = (dose intensity (mg/day) / planned dose intensity (mg/day)) * 100 
Planned dose intensity = planned total dose (mg) / total duration of exposure (days) 
Planned total dose (mg) = total duration of exposure * daily dose. 
Number of days with recorded dose 
Number of days in which the subject took any dose of study drug. 
4.5. Safety Endpoints 
Safety endpoints are the primary endpoints. The Safety Analysis Set will be used to evaluate the 
safety variables including AEs, clinical laboratory data, vital signs, single 12-lead ECG 
parameters, ECHO/MUGA parameters, physical examinations, performance status (PS), and 
death. One of three possible scales of PE are collected per individual: Lansky, Karnofsky, or 
Eastern Cooperative Oncology Group (ECOG). The safety data during the treatment period will 
be evaluated, with treatment period as defined in section 4.1.3. 


 
 
 
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4.5.1. 
Dose Limiting Toxicities 
DLTs are AEs where the question “Was the event due to a Dose Limiting Toxicity (DLT)?” in 
the CRF is selected as “yes”. Determination of a DLT will be made by the Investigator and the 
HMPL monitor as per definition given in section 4.2 of the protocol. 
4.5.2. 
Adverse Events (AEs) 
The severity of all AEs will be graded by investigator according to National Cancer Institute 
(NCI) CTCAE version 5.0, and the AE, from verbatim text to Preferred Term (PT) and System 
Organ Class (SOC), will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
AEs will be collected throughout the study, from informed consent until 30+7 days after the last 
dose of study drug. 
Treatment-emergent AEs (TEAEs) are defined as AEs that started or worsened in severity on or 
after the first dose of study drug and no later than 30 + 7 days after the date of last study drug 
administration. After this period, treatment-related serious AEs (SAEs) will also be considered as 
TEAEs. AEs with an unknown/not reported onset date will also be considered as TEAEs. 
Other AE variables from CRF include, but are not limited to, drug-related AEs, action taken, 
outcome, seriousness, AE leading to study withdrawal.  
Dose Delays, Dose Interruptions, Dose Reductions, and Treatment Discontinuation Due to 
AE 
For surufatinib, dose interruptions, dose reductions and treatment discontinuation (due to AE) 
information will be taken from the “Adverse Events” Case Report Form (CRF) page, question 
“Action Taken with Surufatinib”. 
For gemcitabine, dose delays, dose interruptions, dose reductions and treatment discontinuation 
(due to AE) will also be taken from the “Adverse Events” CRF page, question “Action Taken 
with Gemcitabine”. 
AEs of Special Interest (AESI)   
AEs of special interest (AESI), serious or non-serious, will be identified based on the PT list 
outlined in Appendix 1. The AESIs include 4 categories:  
x Hepatic disorders 
x Hypertension 
x Hemorrhage 
x Acute renal failure 
4.5.3. 
Laboratory 
Blood and urine samples for the determination of clinical chemistry, hematology, and urinalysis 
laboratory variables described in Table 3 will be measured. 




 
 
 
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parameter for which CTCAE toxicity grades are not defined, will not be included in any analyses 
for which toxicity grades are required. 
Analysis of Abnormal Hepatic Laboratory Values 
The following categories of abnormal hepatic laboratory values will be evaluated for any 
occurrence among all post baseline assessments.  
x AST or ALT ≥ 3x Upper Limit of Normal (ULN) and ≤ 5x ULN 
x AST or ALT ≥ 5x ULN 
x Total bilirubin elevations ≥ 2x ULN 
x Potential drug-induced liver injury (DILI): (AST or ALT ≥ 3x ULN) and (total bilirubin 
≥ 2x ULN) 
x Hy's Law criteria: (AST or ALT ≥ 3x ULN) and (total bilirubin ≥ 2x ULN) and (ALP < 
2x ULN) 
4.5.4. 
Electrocardiogram (ECG) 
ECG parameters include heart rate (bpm), PR interval (msec), RR interval (msec), QT interval 
(msec), Corrected QT interval by Fridericia (QTcF) (msec) and QRS interval (msec) from the 
“Triplicate 12-lead ECG” CRF page.  
ECGs will be performed in triplicate at screening or if a single read has a QTcF ≥ 480 msec, and 
whenever feasible. If more than one ECG is performed at a visit, the triplicate ECGs will be 
taken approximately 2 minutes apart.  The combined values for the quantitative parameters from 
the ECGs will be averaged to provide a single value for each time point. The average will be 
used for statistical summaries, but each individual result will be presented separately in listings.  
Clinically significant ECG findings will be identified from the CRF, page “Triplicate 12-lead 
ECG” using the “Clinical Significant” question.  
 
 


 
 
 
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4.5.5. 
Vital Signs 
Vital signs include systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) 
(mmHg), heart rate (bpm), height (cm), weight (kg), respiratory rate (breaths/min) and body 
temperature (°C).   
Blood pressure (BP) assessments will be performed in triplicate at screening and in triplicate at 
later timepoints if BP was abnormal at screening. The combined systolic/diastolic blood pressure 
values from the available measurements will be averaged to provide a single value for each time 
point. The average will be used for statistical summaries but each of the individual results will be 
presented separately in listings. 
For vital signs, change from baseline to each post-baseline visit and timepoint will be calculated.  
Additionally, the minimum and maximum values for each subject over the entire treatment 
period for each vital sign parameter will also be derived. For these minimum and maximum 
values, change from baseline will be derived. The potentially clinically significant findings of 
vital signs, based on individual readings rather than average values, will also be defined based on 
criteria defined in Table 4.  
Table 4 Potentially Clinically Significant Criteria for Vital Signs 
Vital Sign Parameter 
Criterion value   
SBP (mmHg), DBP (mmHg), 
Heart rate (bpm) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40 
 
4.5.6. 
Performance Status  
PS will be collected for each subject at screening and during the treatment period (i.e., typically 
Day 1 of a Cycle). In addition to the collected PS score during a Cycle, the maximum post-
baseline value for a subject will be derived; both scheduled and unscheduled assessments will be 
used to identify the maximum post-baseline values. 
4.5.7. 
Echocardiogram 
Echocardiograms are to be performed at Screening, and at the 30-day safety follow-up visit. 
Assessment parameters include left ventricular ejection fraction and overall interpretation of 
cardiac function. MUGAs are permitted if echocardiograms cannot be performed. 
4.5.8. 
Physical Examination 
The results on physical examination (PE) will not be tabulated but abnormal findings in PE will 
be reported as AEs. PE abnormalities will be presented in a listing. 


 
 
 
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4.5.9. 
Knee X-Ray/MRI 
A by-subjects listing of knee X-Ray/MRIs data will be provided. 
4.6. Other Endpoints  
4.6.1. 
PK Endpoints 
Evaluation on PK will be performed on the PK analysis set. Detailed analyses will be described 
in a separate analysis plan.  
4.6.2. 
Taste and Palatability 
Data for the evaluation of taste of surufatinib oral suspension will be summarized by Day 1 and 
Day 8 visit, on a scale of 1 (very bad) through 5 (very nice). 




 
 
 
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5.1.2. 
Handling Missing Data 
In general, the observed case (OC) data for a visit will consist of the actual observations recorded 
for the visit. If missing, the OC data will remain missing - no missing imputation will be 
performed. Safety analyses will be conducted on the OC data only. Partial dates will not be 
possible for death or tumor assessments. 
Imputation of missing AE and concomitant medication onset and stop dates will be used to 
determine the prior/concomitant status of each AE and each medication. The specific imputation 
rules are provided below, refer to Section 5.1.2.1 for the method of imputation of missing AE 
onset and stop dates, Section 5.1.2.2. for the method of imputation of missing concomitant onset 
and stop dates. However, the listings will show the dates as reported. 
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. Unless otherwise specified, subjects with missing data will be excluded 
only from analyses for which data are not available. 
5.1.2.1. 
Adverse Events Start/End Date 
AEs with onset/end dates that are partially/completely missing will be imputed as follows.  
(i) AE start date: 
 If the AE onset date is completely missing, the AE start date will be imputed as the 
reference start date; 
 If the AE onset date is partial missing, then  
 If both the year and the month are available and the year and the month are the 
corresponding year and month of the reference start date, then the AE start date will 
be imputed as the reference start date;  
 If both the year and the month are available and the year and the month are not equal 
to the corresponding year and month of the reference start date, then the AE start date 
will be imputed as the 1st day of the month; 
 If only the year is available and the available year is the corresponding year of the 
reference start date, then the AE start date will be imputed as the reference start date; 
 If only the year is available, and the available year is not equal to the corresponding 
year of the reference start date, then the AE start date will be imputed as the January 
1st of the year 
(ii) AE end date will be imputed as below for the partial date only, the imputation rules only 
apply when the AE is not ongoing: 
 If both the year and the month are available, AE end date will be imputed as the last day 
of the month; 
 If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date for subjects  who are known to be dead at end 
of study or cut off date, then the date of the death will be used for AE end date. If the imputed 


 
 
 
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AE end date is after the last known alive date for subjects alive at the end of study or cut off date, 
the date of last known alive date will be use for AE end date.  
For AE continuing at the cut-off date, the end date will not be imputed and instead will be 
reported as “ongoing”. 
5.1.2.2. 
Concomitant Medication/Procedure/Surgery Start/End Date 
Concomitant Medication/Procedure/Surgery with onset/end dates that are partially/completely 
missing will be imputed as follows. 
(i) start date: 
 1st day of the month will be used to impute the start date if only the day is missing 
 January 1st will be used to impute the start date if both the day and month are missing 
 If the date is completely missing, then the day before the reference start date will be 
imputed as the start date. 
(ii) end date: 
 Last day of the month will be used to impute the end date if only the day is missing 
 December 31st of the year will be used to impute the end date if both the day and month 
are missing 
 If the date is completely missing, assign ‘continuing’ status to the end date 
If the imputed end date is after the death date or last known alive date, the date of the death or 
last known alive date will be imputed as the Concomitant medication/procedure/surgery end 
date. 
5.1.3. 
Visit Windowing 
No analysis visit windowing will be performed for this study. Any visit-based summaries, or 
listings where visit is provided will use the visit directly from the CRF assigned visit 
information. 
5.1.4. 
Adjustment of Covariates 
No adjustments for covariates will be made in this study. 
5.2. Analysis Methods  
5.2.1. 
Subject Disposition 
Number of participants screened for the study will be provided for the following: 
 Number of subjects who signed the informed consent  
 Number of screen failures 
 Primary reason for screen failure 
 Number of subjects who do not receive study drug 
 Number and percentage of subjects who received study drug 
 Number and percentage of subjects who discontinued study drug(s) 


 
 
 
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 Subjects still on treatment  
 Primary reason for study drug discontinuation 
 Number of subjects going into Survival follow-up  
 Number and percentage of subjects who discontinue the study 
 Primary reason for study discontinuation 
For enrolled subjects (non-screen failures), the number of subjects included in and excluded from 
each of the analysis sets will be summarized, along with reasons for exclusion from the analysis 
sets. A listing will also be presented.  
5.2.2. 
Protocol Deviation 
A listing of all protocol deviations will be provided. 
5.2.3. 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be presented for the Safety Analysis Set. 
Continuous demographic variables: age, height, weight, body surface area and body mass index 
will be summarized using descriptive statistics (mean, standard deviation, median, minimum, 
and maximum). For all the other categorical variables, results will be presented as number and 
percentage of subjects. A listing will also be provided. 
The following demographic and baseline characteristics will be reported for this study: 
x Age (years) = (date of informed consent-date of birth+1)/365.25 
x Gender 
x Race  
x Ethnicity  
x Weight at Baseline (kg) 
x Height at Baseline (cm) 
x Body Surface Area (BSA) at Baseline (m2) 
x Body Mass Index (BMI) at Baseline (kg/m2) = weight(kg)/(height(m))2 
x PS at Baseline 
5.2.4. 
Disease History 
Prior cancer diagnoses are defined as those received prior to the administration of study drug and 
are recorded in CRF page “Oncology History”. Safety Analysis Set will be used and results will 
be presented in a listing. 
5.2.5. 
Medical History  
The conditions, diseases, and therapies from the “Medical History” CRF page are those non-
cancer related conditions, diseases and therapies that stopped prior to the study entry. Medical 


 
 
 
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history will be coded to SOC and PT using MedDRA central coding dictionary. The version of 
MedDRA to be used is 25.1. 
A listing containing medical history by participants will be provided. 
5.2.6. 
Prior Anti-cancer Medication/Radiotherapy/Procedure or Surgery 
(including subsequent) 
Prior anti-cancer medication, radiotherapy, and procedure or surgery, as well as subsequent 
procedure or surgery will be summarized and listed.  
5.2.6.1. 
Prior Anti-cancer Medication 
Prior anti-cancer medications are defined as those taken by the subject prior to the administration 
of study drug and are recorded in CRF page “Previous cancer therapy”.  
Prior anti-cancer medications will be coded to Anatomical Therapeutic Classification (ATC) 
therapeutic group (i.e., ATC Level 2) and PT using the World Health Organization Drug 
Dictionary (WHO-DD) available at the time of analysis. 
The prior anti-cancer medications will be summarized by presenting the number and percentage 
of subjects by PT and ATC. Subjects taking the same medication multiple times will only be 
counted once for that PT or ATC. Each summary will be ordered by descending order of 
incidence of ATC and PT within each ATC. If the frequencies tie, an alphabetic order will be 
applied.  
In addition, the Best Overall Response (BOR) and reason for treatment discontinuation will be 
presented descriptively for prior anti-cancer medications. 
All prior anti-cancer medications will also be presented in a subject listing. 
5.2.6.2. 
Prior Anti-cancer Radiotherapy 
Prior anti-cancer radiotherapy is defined as those taken by the subject prior to the administration 
of study drug and are recorded in CRF page “Radiotherapy History”.  
All prior anti-cancer radiotherapy, including BOR will be presented in subject listing.  
5.2.6.3. 
Prior and Subsequent Procedure or Surgery 
Prior procedures or surgeries are defined as those taken by the subject prior to the administration 
of study drug and are recorded in CRF page “Procedure/Surgical History”. Subsequent procedure 
or surgery are defined as those taken by the subject after the discontinuation of the study drug 
and are recorded in CRF page “Related Procedures/Surgeries”.  
Prior and subsequent procedures and surgeries will be coded using MedDRA 25.1. 
The prior procedures or surgeries will be summarized by presenting the number and percentage 
of subjects by SOC and PT. Subjects taking the same medication multiple times will only be 
counted once for that SOC and PT. Each summary will be ordered by descending order of 
incidence of SOC and PT within each SOC. If the frequencies tie, an alphabetic order will be 
applied. Similarly, the subsequent anti-cancer procedure or surgery will be summarized.  


 
 
 
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In addition, the purpose of procedure will be presented descriptively for prior procedure or 
surgery. 
All prior and subsequent procedure or surgery will be presented in a subject listing. 
5.2.7. 
Prior and Concomitant Medications 
Prior medications will be defined as medications that stopped before the day of first dose of 
subject drug(s) and are recorded in CRF page “Prior and Concomitant Medications”. 
Concomitant medications will be defined as medications that 
1) started before the first dose of subject drug(s) and were continuing at the time of the 
first dose of subject drug(s), or 
2) started on or after the date of the first dose of subject drug(s) up to 30 days + 7 days 
after the last treatment. 
Concomitant medications will be coded to ATC therapeutic group and PT using the WHO-DD 
drug codes from the version of WHO-DD Version available at the time of analysis. 
Prior and concomitant medications will be summarized and listed by drug and drug class. 
5.2.8. 
Efficacy Analyses 
All efficacy analyses will be performed on the All Treated Population. 
5.2.8.1. 
Primary Efficacy Analyses 
No primary efficacy endpoints are defined for this study. 
5.2.8.2. 
Sensitivity Analysis for Primary Efficacy Endpoint 
No sensitivity analysis for the primary efficacy endpoints is defined for this study. 
5.2.8.3. 
Multiplicity Control  
 There will be no adjustments made for multiplicity. 
5.2.8.4. 
Secondary Efficacy Analyses 
Findings corresponding to efficacy analysis will be provided in listings. Tumor assessment will 
be presented for target lesions, non-target lesions, and new lesions. Additionally, sum of tumor 
diameter, and disease response will be listed as well.  
5.2.9. 
Exposure of Study Drug 
Drug exposure will be summarized and presented. Exposure of both surufatinib and gemcitabine 
will be summarized as follows: 
x Number of cycles started as a continuous variable 
i.e., the number of cycles in which the subject took/received any dose of the study 
medication. 


 
 
 
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x Number of cycles started categorized as 1, 2, 3, 4, 5, and ≥ 6 
x Total duration of exposure as a continuous variable 
x Number of days with recorded dose 
x Cumulative dose received (mg) as a continuous variable 
x Dose intensity as a continuous variable 
x Relative dose intensity as a continuous variable 
x Relative dose intensity categorized as <50%; ı50 to <70%; ı70 to <90%; ı90 to 
<110%; ı 110% 
x Number and percent of subjects exposed for specific periods of time as İ 1 day, 2 days 
to 1 week, >1 week and İ 1 months, and >1 month and İ 6 months 
The number and percentage of subjects with any dose modification will be presented. Dose 
modifications will be further characterized by presenting the numbers and percentages of 
subjects with any dose interruption, dose delay, dose reduction, and treatment discontinuation 
because of AEs. Reasons for dose modifications (adverse event or ‘other’) for each drug will be 
presented in a listing.  
Details of study drug administration will be included in subject listings. 
5.2.10. 
Safety Analyses 
Safety data will be summarized for the Safety Analysis Set.  
5.2.10.1. 
Dose Limiting Toxicity (DLT) 
The primary safety endpoint is the occurrence of DLTs in the DLT Evaluation Period (the first 
35-day cycle). Data is recorded as in CRF page “Adverse Events”. 
The number and percentage of subjects with DLTs will be summarized based on the number of 
subjects in the DEAS by SOC and PT.  
By-subject listing of DLTs will also be presented. 
5.2.10.2. 
Adverse Events 
Only those AEs that are treatment emergent will be included in summary tables as recorded in 
CRF page “Adverse Events”. 
All AEs, treatment-emergent or otherwise, will be presented in subject data listings.  The number 
and frequency of subjects experiencing AEs will be summarized according to SOC and PT.  If a 
subject reports a TEAE more than once within that SOC/PT, the AE with the highest severity will 
be used in the corresponding severity summaries. 
The following safety summaries will be produced: 


 
 
 
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x Overview of TEAEs (summary of the following categories, but only at the subject level, 
not by SOC and PT) 
x Summary of DLTs by SOC and PT 
x Summary of TEAEs, including highest severity and relationship to each study drug 
(surufatinib and gemcitabine), by SOC and PT 
x Summary of serious TEAEs, by SOC and PT 
x Summary of TEAEs leading to dose interruption, dose reduction, or termination of study 
drug, by SOC and PT 
The above summaries (excluding summaries by relationship to study drug) will be repeated for 
TEAEs related to study drug. 
Toxicities for clinical labs will be characterized according to CTCAE, Version 5.0 where 
possible. Any occurrence of grade 3 or grade 4 during the overall treatment period will be 
summarized by SOC and PT. 
5.2.10.3. 
Death 
Number of deaths and primary cause of death will be summarized, and details of deaths will be 
presented in a data listing and are recorded in CRF page “Death Details”. 
5.2.10.4. 
Laboratory Evaluations 
For hematology, clinical chemistry and coagulation laboratory data, the observed values and 
change from baseline will be summarized by visit and for minimum and maximum post-baseline 
values using descriptive statistics. Data is recorded as in CRF Laboratory pages. 
Listings of all laboratory data including urinalysis, and pregnancy will be provided. Potentially 
clinically significant Liver Enzyme (ALT, AST, Bilirubin) will also be summarized. 
5.2.10.5. 
Electrocardiogram 
Descriptive statistics will be presented for each ECG parameter for the observed values and 
change from baseline to post baseline. A listing of all ECG data will be provided. Data is 
recorded as in CRF page “Triplicate 12-lead ECG”. 
The criteria for potentially clinically significant findings are defined in Table 5. The frequency 
and percentage of subjects with any potentially clinically significant findings during the 
induction treatment period will be presented. The supportive data will be provided in subject data 
listings.  
Moreover, the minimum, and maximum, and their corresponding change from baseline ECG 
parameter values will be summarized descriptively overall treatment period. 
5.2.10.6. 
Vital Signs 
For vital sign parameters (SBP, DBP, Heart Rate (and Pulse), Respiratory Rate and Temperature) 
the observed values and change from baseline will be summarized using descriptive statistics at 
each visit during the treatment period. Data is recorded as in CRF page “Vital Signs”. 


 
 
 
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Additionally, the frequency and percentage of subjects with any potentially clinically significant 
findings (defined in Table 4) during the overall treatment period will be presented for SBP, DBP, 
and Heart Rate. A listing of all vital signs data will be provided.  
Moreover, the minimum, and maximum, and their corresponding change from baseline vital sign 
values will be summarized descriptively for the overall treatment period. 
5.2.10.7. 
Performance Status 
Descriptive statistics will be presented for PS score for the observed values and change from 
baseline. Negative change scores indicate an improvement, and positive scores indicate a decline 
in performance. Data is recorded as in CRF page “Karnofsky / Lansky / ECOG Performance 
Status”. 
A listing of PS score for all subjects will be provided. 
5.2.10.8. 
Echocardiogram 
Descriptive statistics for Echocardiogram/MUGA parameters will be summarized by visit. A by-
subjects listing of Echocardiogram/MUGA values at each time point will be listed. Data is 
recorded as in CRF page “ECHO or MUGA Scan”. 
5.2.10.9. 
Physical Examination 
A listing of PE data for all subjects will be provided (where available). Data is recorded as in 
CRF page “Physical Examination”. 
5.3. Subgroup Analyses 
No subgroup analyses will be performed for this study. 
5.4. Other Analyses 
5.4.1. 
Taste and Palatability 
Data for the evaluation of taste of surufatinib oral suspension on a scale of 1 (very bad) through 5 
(very nice) will be summarized by visit using frequencies and percentages. See Appendix 9 of 
the Protocol for details. A listing of the evaluation of taste data for all subjects will also be 
provided. 
 


 
 
 
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6. PLANNED ANALYSIS  
6.1. Safety Review Committee 
The Safety Review Committee (SRC) will be established under a charter to conduct safety data 
reviews.  The SRC will be comprised of sponsor and Contract Research Organization (CRO) 
medical team members and the site investigators.  The SRC will determine whether it is safe to 
continue to the next predefined dose level, stay at the currently assigned dose level, or whether 
the dose should be de-escalated to a lower dose level and finally to determine the MTD/RP2D. 
6.2. Final Analysis 
The timing of analysis for each cohort may be different depending on completion of each cohort, 
and the final analysis of the study will be conducted at the time of the analysis of the last cohort. 


 
 
 
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7. CHANGE FROM THE PROTOCOL 
Proteinuria and Thyroid dysfunction are mentioned in Section 8.5 AESI of protocol, but they 
were removed as AESI in this SAP, since they are already considered fully characterized, and 
there are no new or additional mitigation activities. Some summaries will be dropped if there is 
not a sufficient amount of data to present, but rather present the data in listings. Additionally, 
some efficacy may not be possible to derive depending on the data available at the time of 
Database Lock. 


 
 
 
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REFERENCE 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 1982; 
38:29-41. 
Clopper, C.J. and Pearson, E.S. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika, 1934;26:404-413. 




 
 
 
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