Clinical trial NCT03251378
Conditions: Advanced Solid Tumors Metastatic Colon Cancer Metastatic Breast Cancer Triple Negative Breast Cancer HER2-negative Breast Cancer Hormone Receptor Positive Breast Carcinoma Rectal Cancer
Keywords: VEGF colorectal breast
Sponsor: Hutchison Medipharma Limited
Start date: 2017-12-11; Completion date: 2023-03-30
Enrollment: 129 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors, metastatic colorectal cancer and metastatic breast cancer.

Detailed description:
The study was an open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The study consisted of two phases:

* A dose escalation phase - Two dose cohorts were evaluated including 3 mg orally QD 3 weeks on/1 week off and 5 mg orally QD 3 weeks on/1 week off. A 3+3 design was used for this portion of the study.
* A dose expansion phase - Five cohorts were evaluated in Dose Expansion phase. Cohort A evaluated the MTD/RP2D in patients with advanced solid tumors of any type. Cohort B and Cohort C evaluated the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E evaluated the MTD/RP2D in metastatic breast cancer patients.

Study was conducted at 9 sites in the United States.

Arms: arm 1: 3 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off arm 2: 5 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off arm 3: 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with advanced solid tumors of any type. arm 4: 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have progressed on or had intolerable toxicity to TAS-102, regoragenib, or both. arm 5: 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have not been treated with TAS-102 or regorafenib. arm 6: 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic Her2-negative, hormone receptor positive breast cancer. arm 7: 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic triple negative (Her2-negative, ER-negative, PR-negative) breast cancer.
Interventions: intervention 1: Fruquintinib (HMPL-013)
Intervention descriptions: intervention 1: Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3, with a novel chemical structure which belongs to the quinazoline class.

Protocol documents:
Prot_000.pdf: 
Date:  09 Jan 2020                                 Confidential                            1/144 
Protocol Number: 2015-013-00US1                                                        Version 4.0  
TITLE PAGE 
 
Clinical Study Protocol  
A Multi-Center, Open-Label, Phase 1/1b Clinical Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Anticancer Activity of Fruquintinib in Patients 
with Advanced Solid Tumors 
 
Protocol Number： 
2015-013-00US1 
Investigational Product： 
Fruquintinib (HMPL-013) 
IND: 
131038 
Sponsor： 
Hutchison MediPharma Limited 
NO. 4, Lane 898, Cailun Road, Zhangjiang 
Hi-Tech Park, Shanghai, China 
Post Code: 201203   
Protocol Version： 
Version 4.0 (Amendment 4) 
Protocol Date: 
09 Jan 2020 
Previous Version: 
Version 3.0 
Previous Protocol Date: 
09 December 2018  
Phase: 
1 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
INTRODUCTORY AND CONFIDENTIALITY STATEMENT 
This protocol has been prepared according to the International Conference for 
Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice (issued 
in June 1996, with an implementation date of January 17, 1997), Food and Drug 
Administration (FDA) Good Clinical Practice (GCP) guidelines, and Code of Federal 
Regulations (CFR): 21 CFR 312, 21 CFR 50, 21 CFR 56.  
The submission/document contains trade secrets and confidential commercial information, 
disclosure of which is prohibited without providing notice to Hutchison MediPharma 
Limited and opportunity to object. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
EDITION HISTORY 
Version 1.0 
31 December 2015 
Version 1.1 (Amendment 1) 
31 July 2017 
Version 2 (Amendment 2) 
2 July 2018 
Version 3 (Amendment 3) 
9 December 2018 
Version 4 (Amendment 4) 
09 January 2020 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
AMENDMENT SUMMARY 
This Protocol 2015-013-00US1 Version 4 (Amendment 4), replaces Protocol 2015-013-
2015 Version 3 (Amendment 3; 9 December 2018).  A complete amendment history is 
available in Appendix K. 
The primary purpose of Amendment 4 is to add an additional 10 patients to cohort B and to 
add 3 additional cohorts to the expansion phase of the study.  The changes made in this 
amendment are described in the table below. 
Description and Rationale for Change 
Sections 
Removed references to tumor types in the study title 
and in the objectives and endpoints of the dose 
expansion stage to reflect enrollment of patients of 
different tumor types 
Title page 
Signature Page 
Synopsis 
Section 2.2  Dose Expansion Phase (dose 
expansion) 
Added 10 patients to the planned 30 patients with 
refractory mCRC in Cohort B.  This patient 
population with mCRC reflects the current 
treatment practice in the US, in which TAS-102 and 
regorafenib are approved and used in the 3L+ 
setting.  Removed references to assessment times 
planned for Cohort B to reflect addition of other 
expansion cohorts that have different assessment 
times 
Section 1.4  Study Rationale 
Section 2.2.1  Primary Objective 
Section 2.2.2  Primary Endpoint 
Section 3.1  Description of the Study 
Section 3.1.2  Dose Expansion Phase 
Added Expansion Cohort C, which consists of 
approximately 40 patients with mCRC who have 
progressed on all standard therapies but who have 
not received prior TAS-102 and/or regorafenib 
(Cohort C). 
Enrollment of this cohort is based on the positive 
results of the phase 3 FRESCO trial conducted in 
China that led to approval of fruquintinib in that 
indication by the CFDA.  Cohort C represents a 
patient population in the US that is similar to that of 
the phase 3 FRESCO study. 
Section 1.4  Study Rationale 
Section 2.2.1  Primary Objective 
Section 3.1  Description of the Study 
Section 3.1.2  Dose Expansion Phase 
Added expansion Cohort D, which consists of 
approximately 
15 patients 
with 
advanced, 
refractory HR+/Her2- metastatic breast cancer 
(mBC), and expansion Cohort E, which consists of 
approximately 15 patients with triple-negative 
breast cancer (TNBC). 
Cohorts D and E were added based on data from 
phase 1 studies of fruquintinib conducted in China 
(2009-013-00CH1) and in the US (Protocol 2015-
013-00US1) 
suggesting 
clinical 
activity 
in 
populations with mBC. 
Section 1.4  Study Rationale 
Section 2.2.1  Primary Objective 
Section 3.1  Description of the Study 
Section 3.1.2  Dose Expansion Phase 
Revised total sample size of planned enrollment 
from approximately 50 patients to 128 patients and 
total sample size of enrollment in the expansion 
cohorts from approximately 36 to 116 patients. 
Section 3.2  Sample Size 
Section 8.6  Determination of Sample 
Size 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Description and Rationale for Change 
Sections 
Added justification of sample sizes for Expansion 
Cohorts B, C, D, and E. 
Changed the primary endpoint for the dose 
expansion phase to add progression-free survival 
(PFS) rate at week 12 for Cohorts B and C, PFS rate 
at week 16 for Cohort D, and PFS rate at week 24 
for Cohort E.  Added clarification of definition of 
PFS rate. 
Section 2.2.2  Primary Endpoint (dose 
expansion stage) 
Section 8.5  Efficacy Analysis 
Revised inclusion criterion 4 to have separate 
inclusion criteria for dose escalation and for 
expansion cohorts.  Added inclusion criteria for 
Cohorts C, D, and E.  
Section 4.1  Inclusion Criteria 
Added Inclusion Criterion 5 to specify that hormone 
receptor positive mBC patients must have 
progressed on at least two lines of prior systemic 
therapy, 
including 
hormonal 
therapy 
or 
chemotherapy. 
Section 4.1  Inclusion Criteria 
Added Inclusion Criterion 6 specify that triple-
negative 
breast 
cancer 
patients 
must 
have 
progressed on at least one cytotoxic therapy in the 
metastatic setting, with exception of subjects who 
progressed within 12 months of adjuvant therapy. 
Section 4.1  Inclusion Criteria 
Revised Inclusion Criterion 7 (formerly Inclusion 
Criterion 5) to add that patients may qualify for 
enrollment in this study if they have bone lesions in 
the absence of measurable disease 
Section 4.1  Inclusion Criteria 
Revised Exclusion Criterion 11 to exclude patients 
with history of a thromboembolic event within 6 
months, rather than 12 months, prior to screening. 
Section 4.2  Exclusion Criteria 
Added an end-of-study definition per regulatory 
requirements 
Section 3.7  End of Study (new section) 
Added survival follow-up of patients 
Section 3.1.1  Dose Escalation Phase 
Section 3.1.2  Dose Expansion Phase 
Appendix A  Schedule of Events 
Revised tumor assessment schedule and analysis 
plan to reflect addition of Cohorts C, D, and E 
Section 6.4  Efficacy Assessments 
Section 8.5  Efficacy Analysis 
Appendix A  Schedule of Events 
Added that, for cardiac monitoring, MUGAs are 
permitted if echocardiograms cannot be performed. 
Section 6.3.4  Cardiac Monitoring 
Appendix A  Study Schedule of Events 
Revised specifications for recording of deaths 
Section 7.1.8.5  Death 
Revised sections related to pharmacokinetics to be 
consistent with the most current version of the 
Investigator’s Brochure (version 11.0). 
Section 1.2.2  Nonclinical 
Pharmacokinetics 
Section 5.3.3  Drug-Drug Interactions 
Appendix F  Fruquintinib and 
Concomitant Medication 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Description and Rationale for Change 
Sections 
Revised conditions for termination of the study by 
the sponsor.  Removed provision that the study is 
considered completed when all patients have 
continued study drug or the last patient has 
completed 1 year of treatment. 
Section 3.5  Study Early Termination 
(formerly named Study Completion or 
Early Discontinuation) 
Increased the estimated number of enrollment sites 
from up to 10 sites to approximately 12 sites. 
Section 3.3  Investigational Site 
Clarified that dose-limiting toxicity assessment 
does not apply to the expansion cohorts. 
Section 3.1.1a  Dose-Limiting Assessment 
Window 
Section 6.5.2  Assessments during 
Treatment Phase 
Section 7.1.2  Reporting of Dose Limiting 
Toxicity 
Clarified definition of DLT evaluable patients as 
those who have not received any prior anti-cancer 
therapy 
Section 3.1.1b  Definition of DLT 
Evaluable Patients  
Corrected list of laboratory tests.  Removed fecal 
occult blood testing from laboratory tests and added 
reticulocyte count and cholesterol tests. 
Section 6.1.3  Laboratory Tests 
Appendix A  Study Schedule of Events 
Appendix J  Clinical Management of 
Severe or Serious Hemorrhagic Events 
Removed provision that any data analysis carried 
out independently by the investigator should be 
submitted to Hutchison MediPharma prior to 
publication or presentation. 
Section 8  Statistical Analysis 
Reorganized the Study Assessments and Methods 
section for improved clarity and flow 
Section 6  Study Assessments and 
Methods 
Added study schema for improved clarity 
Figure 5  Study Schema 
Moved summaries of prior protocol amendments to 
a new appendix 
Appendix K  Protocol Amendment History 
(new appendix) 
Non-substantive editorial and formatting changes 
were made for administrative purposes or 
improvement in clarity. 
Throughout entire document 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
SIGNATURE PAGE 
Declaration of Investigator 
Protocol Title：A Multi-Center, Open-Label, Phase 1/1b Clinical Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Anticancer Activity of Fruquintinib in 
Advanced Solid Tumors 
I agree to the terms of this CSP.  I will conduct the study according to the procedures 
specified herein and according to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
Investigator (name and institutional affiliation)： 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 


SIGNATURE PAGE 
Declaration of Sponsor 
This clinical study protocol and/or its amendment(s) have been subject to critical review 
and have been approved by the sponsor. 
 
 
Clinical Development and Regulatory Affairs Department 
Hutchison M d · Pharma (US) Inc. 
 
 
, Hutchison MediPharma Limited 
Date: See Signature Page 
Protocol Number: 20I5-013-00US 1 
Confidential 
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Version 4.0 


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Protocol Number: 2015-013-00US1
    Version 4.0 
SYNOPSIS 
Protocol Number 
2015-013-00US1 
Study Title 
A Multi-Center, Open-Label, Phase 1/1b Clinical Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Anticancer Activity of 
Fruquintinib in Patients with Advanced Solid Tumors 
Sponsor 
Hutchison MediPharma Limited 
Investigational 
Product 
Fruquintinib (HMPL-013) 
Investigational 
Centers 
Approximately 12 sites in the United States of America 
Planned Enrollment 
Total of approximately 128 patients.  
•
Approximately 12 patients will be enrolled in the dose escalation
phase.
•
Approximately 116 patients will be enrolled in the dose
expansion phase in the following cohorts:
o
6 patients in cohort A (solid tumors)
o
40 patients in cohort B (mCRC, prior treatment with
TAS-102 or regorafenib required)
o
40 patients in cohort C (mCRC, no prior treatment with
TAS-102 or regorafenib)
o
15 patients in cohort D (HR+/Her2- breast cancer)
o
15 patients in cohort E (triple negative breast cancer)
Study Duration 
Estimated 36 months, including the dose escalation phase and dose 
expansion phase.   
Study Objectives 
and Endpoints: 
Dose Escalation 
Phase 
The primary objective of the dose escalation phase is to evaluate the 
safety and tolerability of fruquintinib in patients with advanced solid 
tumors and to determine the recommended Phase 2 dose (RP2D). 
The primary endpoint of the dose escalation phase is the incidence of 
DLT in each cohort.  DLT is defined as: 

Any Grade 4 non-hematologic toxicity;

Any Grade 3 non-hematologic toxicity related to study drug
except for nausea/vomiting, diarrhea, constipation, hypertension
and electrolyte imbalances downgraded within 3 days with
appropriate supportive treatment;

Grade 4 neutropenia lasting >3 days;

Grade 3 febrile neutropenia (absolute neutrophil count [ANC])
<1.0 × 109/L with a single temperature of >38.3°C or a sustained
temperature of ≥38°C for more than one hour;

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia
associated with bleeding;


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
 Dose interruption for >14 days due to toxicity. 
The MTD is the highest dose at which no more than 1 of 6 patients 
developed a DLT.  If 2 or more patients developed DLT at a 
particular dose level, then that dose has exceeded the MTD. 
The safety and tolerability of fruquintinib will primarily be evaluated 
by the frequency and severity of AEs.  Other safety parameters 
include physical examination, vital signs, laboratory test results (ie, 
hematology, chemistry panel, thyroid function, and urinalysis), 12-
lead electrocardiogram, and echocardiogram. 
The secondary objectives of the dose escalation phase are: 
• 
To evaluate the PK characteristics of multiple-dose fruquintinib 
and to investigate the metabolite profile of fruquintinib in the 
plasma of patients with solid tumors.  
• 
To evaluate the anticancer activity of fruquintinib in patients with 
solid tumors according to RECIST Version 1.1.  
The secondary endpoints of the dose escalation phase are: 
• 
The primary PK parameters include: maximum plasma 
concentration (Cmax), time to reach maximum concentration 
(Tmax), terminal half-life (t1/2), area under the concentration-time 
curve in a selected time interval (AUC0-t), area under the 
concentration-time curve in the time interval from 0 to infinity 
(AUC0∞∞-∞), apparent clearance (CL/F), apparent volume of 
distribution (Vz/F) during the terminal phase according to 
CL/F/Ke, and the accumulation index based on AUC. 
• 
The objective response rate (ORR), disease control rate (DCR), 
duration of response (DoR), progression-free survival (PFS), 
overall survival (OS) and percentage change in tumor size from 
baseline according to RECIST v. 1.1. 
Study Objectives 
and Endpoints: 
Dose Expansion 
Phase 
The primary objective of the dose expansion phase is: 
To evaluate the anticancer activity of fruquintinib at the recommended 
Phase 2 dose (RP2D) from the dose escalation phase, in patients with 
advanced solid tumors. 
The primary endpoint of the dose expansion phase is: PFS rate. 
The secondary objectives of the dose expansion phase are: 
• 
To evaluate anticancer efficacy of fruquintinib, as assessed by 
ORR, DCR, DoR, PFS, and OS 
• 
To evaluate the pharmacokinetic (PK) characteristics of multiple 
dose fruquintinib and investigate the metabolite profile of 
fruquintinib in plasma.  
• 
To evaluate the safety of fruquintinib. 
The secondary endpoints of the dose expansion phase are: 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
• 
The objective response rate (ORR), disease control rate (DCR), 
duration of response (DoR), PFS, overall survival (OS), and 
percentage change in tumor size from baseline according to 
RECIST V. 1.1 
• 
The primary PK parameters include: maximum plasma 
concentration (Cmax), time to reach maximum concentration 
(Tmax), terminal half-life (t1/2), area under the concentration-
time curve in a selected time interval (AUC0-t), area under the 
concentration-time curve in the time interval from 0 to infinity 
(AUC0-∞), apparent clearance (CL/F), apparent volume of 
distribution (Vz/F) during the terminal phase according to 
CL/F/Ke, and the accumulation index based on AUC. 
• 
Safety, as assessed by the incidence and severity of AEs, physical 
examinations, vital signs, laboratory test results, 12-lead 
electrocardiogram, and echocardiogram. 
Study Design 
This is an open-label study of fruquintinib comprised of a dose 
escalation phase in patients with advanced solid tumors of any type, and 
a dose expansion phase in patients with advanced solid tumors of any 
type (Cohort A), in patients with refractory mCRC (Cohorts B and C), or 
in patients with mBC (Cohorts D and E). 
Dose Escalation/ Phase： 
• 
Approximately 12 evaluable patients will be enrolled.  The 
actual number of patients enrolled will depend on the dose-
limiting toxicity (DLT) profile as well as maximum tolerated 
dose (MTD) level reached in this trial. 
• 
The dose levels to be investigated are 3 mg and 5 mg QD, 
3 weeks on/1week off. 
• 
Six DLT-evaluable patients will be enrolled in the dose 
escalation phase and will be treated with fruquintinib 3 mg QD 
(3 weeks on/1week off) orally.  If no more than 1 DLT occurs 
during the DLT observational window (ie, from Days 1-28 in 
Cycle 1) among the 6 patients, the trial will continue to enroll 
another 6 patients in the next dose cohort in which fruquintinib 5 
mg QD (3 weeks on/1week off) will be tested.  
• 
Safety monitoring and evaluation for the dose escalation phase 
will be carried out by the Safety Review Committee (SRC).   
• 
If no more than 1 patient at the dose level of 5 mg QD 
experiences a DLT, the dose escalation phase is completed and 
the expansion phase of the study will be conducted. 
• 
Upon completion of the dose escalation phase, the SRC will 
review aggregated safety and PK data and then select a 
fruquintinib dose as the recommended Phase 2 dose (RP2D) for 
the expansion phase of the trial. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
• 
Blood samples for PK assay will be collected in Cycle 1 at the 
following time points: pre-dose (within 10 minutes), 1, 2, 4, 8, 
and 24 hours post dose on Days 1, 14 and 21. 
• 
Prior to confirmation of a DLT, if a patient received medical 
intervention or missed 4 or more fruquintinib doses during the 
DLT observational window, the patient will not be qualified as 
DLT-evaluable and will therefore be replaced. 
• 
If a patient does not meet the definition of DLT-evaluable 
patient during the DLT observation period, the patient will be 
replaced. 
• 
Patients who have completed the DLT observation period (Days 
1-28, Cycle 1) and are deemed to be benefiting from the 
fruquintinib treatment at the investigator’s discretion may 
continue the fruquintinib treatment until disease progression, 
death, intolerable toxicity, or at investigator’s discretion that the 
patient can no longer benefit from the study drug. 
• 
Tumor evaluations during the dose escalation phase are 
scheduled at screening and every 8 weeks (± 1 week) thereafter, 
ie, C3D1, C5D1, C7D1, etc (odd-numbered cycles).  Response 
assessments will be performed by the investigator using 
according to RECIST Version 1.1.  
• 
Patients will be followed until death or study completion. 
Dose Expansion Phase: 
Once the RP2D is determined, patients may enroll into one of the 
following cohorts and will receive fruquintinib at the RP2D: 
• 
Cohort A: Patients with advanced, refractory solid tumors of any 
type.  
• 
Cohort B: Patients with refractory mCRC who have progressed 
on all standard chemotherapies and relevant biologics and have 
also progressed on, or had intolerable toxicity with, at least 
1 FDA-approved third-line therapy (TAS-102 or regorafenib). 
• 
Cohort C:  Patients with refractory mCRC who have progressed 
on all standard chemotherapies and relevant biologics and have 
not received prior TAS-102 or regorafenib. 
• 
Cohort D:  Patients with hormone-receptor positive (ER+ 
and/or PR+)/Her2- metastatic breast cancer who have progressed 
on at least two line of prior systemic therapy. 
• 
Cohort E:  Patients with advanced triple negative breast cancer 
(TNBC) who have progressed on at least one cytotoxic therapy 
in the metastatic setting. 
The safety of all enrolled patients in the expansion cohorts will be closely 
monitored from the first day of fruquintinib dosing until 30 days after the 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
last dose.  All serious adverse events (SAEs) should be reported from the 
day the ICF is signed until 30 days after the last dose, regardless of 
relationship to study drug.  All adverse events (AEs) will be graded in 
accordance with the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Tumor response will be assessed according to RECIST Version 1.1 at 
screening and at study visits as defined in the Schedule of Events in 
Appendix A.  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. 
Patients will be followed until death or study completion 
Study Treatment 
Dose Escalation Phase: 
Fruquintinib will be administered orally once daily (QD) 3 weeks 
on/1 week off for every 28-day treatment cycle until disease progression, 
death, intolerable toxicities, or at investigator’s discretion that the patient 
can no longer benefit from the study drug.  
Dose Expansion Phase: 
Fruquintinib will be administered orally QD 3 weeks on/1 week off for 
every 28-day treatment cycle until disease progression, death, intolerable 
toxicities, or at investigator’s discretion that the patient can no longer 
benefit from the study drug. 
End of Treatment 
(EOT) 
The criteria for the end of study treatment are as follows (if any of the 
following criteria is met): 
1. 
Disease progression (according to RECIST Version 1.1) unless 
there is reasonable evidence of clinical benefit to justify 
continuation on the study treatment.  The decision to continue 
treatment should be made by the investigator in consultation with 
the sponsor.  The disease progression date is the date when the 
radiological disease progression is first reported according to 
RECIST Version 1.1 criteria; 
2. 
Death; 
3. 
End of this study. 
Early discontinuation of study treatment will occur if any of the following 
criteria is met: 
1. 
Patient’s withdrawal of consent; 
2. 
Intolerable toxicity; 
3. 
Poor patient compliance; 
4. 
Use of other antitumor treatment during the study; 
5. 
Pregnancy occurred during the study treatment period; 
6. 
Patient is lost to follow-up; 
7. 
Treatment discontinuation is in the best interest of the patient 
based on the assessment of the investigator and the sponsor. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
End of Study 
The end of study is defined as the last visit of the last patient. 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet all of the 
following Inclusion Criteria: 
1. 
Fully understand the study and voluntarily sign the informed 
consent form; 
2. 
≥18 years of age;  
3. 
Body weight ≥40 kg;  
4. 
Dose Escalation Phase: 
 
Histologically or cytologically documented, locally advanced or 
metastatic solid malignancy of any type (except squamous NSCLC) 
that has progressed on approved systemic therapy, and for whom no 
effective therapy or standard of care exists.  
Dose Expansion Phase:  
Cohort A:  Histologically or cytologically documented, locally 
advanced or metastatic solid malignancy of any type (except 
squamous NSCLC), that has progressed on approved systemic 
therapy, and for whom no effective therapy or standard of care exists. 
Cohort 
B: 
Histologically 
or 
cytologically 
documented 
adenocarcinoma of the colon or rectum that has progressed on, or had 
intolerable toxicity to, at least 1 FDA-approved third-line systemic 
therapy (TAS-102 or regorafenib).  Treatment failure is defined as: 
disease progression during or within 3 months after the last dose of 
standard therapy, or discontinuation of standard therapy because of 
unacceptable toxicity.  Patients must also have been previously 
treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, an anti-VEGF biological therapy, and, if RAS wild 
type, an anti-EGFR therapy.  
Eligibility also requires knowledge of tumor RAS status (wild-type 
or mutant) as reported by investigators. 
Cohort 
C: 
Histologically 
or 
cytologically 
documented 
adenocarcinoma of the colon or rectum.  Patients must have 
progressed on, or had intolerable toxicity to, at least two prior 
regimens of standard chemotherapy, but must not have received prior 
TAS-102 or regorafenib.  Treatment failure is defined as: disease 
progression during or within 3 months after the last dose of standard 
therapy, or discontinuation of standard therapy because of 
unacceptable toxicity.  Prior therapy could have included adjuvant 
chemotherapy if a tumor had recurred within 6 months after the last 
administration of treatment.  Patients must have been previously 
treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, an anti-VEGF biological therapy and, if RAS wild-
type, an anti-EGFR therapy. 
Eligibility also requires knowledge of tumor RAS status (wild-type 
or mutant) as reported by investigators. 
Cohorts D and E: 
Her2-negative metastatic breast cancer, with Her2-negative defined 
as immunohistochemistry (IHC) 0, 1+, or 2+.  If IHC 2+, a negative 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
in situ hybridization (FISH, CISH, or SISH) test is required by local 
laboratory testing 
a. 
Cohort D only: Histologically- or cytologically-confirmed 
hormone-receptor positive (ER+ and/or PR+) breast cancer, by 
local assessment,  
OR 
b. 
Cohort E only: Histologically- or cytologically- confirmed 
triple negative breast cancer with ER-negative, PR-negative 
tumors as defined by local criteria.  
5. 
Hormone receptor positive mBC patients must have progressed on at 
least 2 lines of prior systemic therapy, including hormonal therapy or 
chemotherapy.  However, patients may not have received more than 
3 prior lines of cytotoxic chemotherapy in the metastatic setting. 
There is no limit to number of prior lines of hormonal therapy. 
6. 
Triple negative breast cancer patients must have progressed on at 
least 1 cytotoxic therapy in the metastatic setting, with the exception 
of subjects who progressed within 12 months of adjuvant therapy. 
However, patients may not have received more than 5 prior lines of 
cytotoxic chemotherapy in the metastatic setting. 
7. 
Have measurable disease per RECIST Version 1.1 or bone lesions in 
the absence of measurable disease (expansion phase only).  
Lesions that received radiotherapy are not measurable per RECIST 
Version 1.1.  
8. 
Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1;  
9. 
Expected survival of more than 12 weeks;  
10. For female patients of childbearing potential and male patients with 
partners of childbearing potential, agreement to use a highly effective 
form(s) of contraception, that results in a low failure rate (<1% per 
year) when used consistently and correctly, starting during the 
screening period, continuing throughout the entire study period, and 
for 90 days after taking the last dose of study drug.  Such methods 
include: 
oral 
hormonal 
contraception 
(combined 
estrogen/ 
progestogen, or progestogen-only), associated with inhibition of 
ovulation together with a barrier method (eg, diaphragm, always 
containing a spermicide), intrauterine device (IUD), intrauterine 
hormone-releasing 
system 
(IUS), 
bilateral 
tubal 
ligation, 
vasectomized partner (on the understanding that this is the only one 
partner during the whole study duration), or sexual abstinence.  Oral 
contraception should always be combined with an additional 
contraceptive method (ie, barrier method) because of a potential 
interaction with the study drug.  The same rules are valid for male 
patients involved in this clinical trial if they have a partner of 
childbirth potential.  Male patients must always use a condom. 
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (ie, ≥12 
continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of 


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the ovaries and/or uterus). 
Exclusion Criteria 
Patients will be excluded from the study, if any of the following criteria 
is met: 
1. 
Cohort C only:  patients who have been previously been treated 
with TAS-102 or regorafenib  
2. 
Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100 × 
109/L, or hemoglobin <9.0 g/dL.  Blood transfusion within 1 week 
prior to enrollment for the purpose of increasing the likelihood of 
eligibility is not allowed; 
3. 
Serum total bilirubin >1.5 × the upper limit of normal (ULN); 
4. 
Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 1.5 × ULN in patients without hepatic metastases; ALT or 
AST > 3 × ULN in patients with hepatic metastases;  
5. 
Serum potassium, calcium, or magnesium levels out of the normal 
laboratory reference range, and clinically significant in the 
investigator’s judgment;  
6. 
Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. 
Creatinine clearance can either be measured in a 24-hour urine 
collection or estimated by the Cockcroft-Gault equation as follows: 
CrCl (mL/min) = [(140 - age) × (weight in kg) ÷ [72 × (serum 
creatinine in mg/dL)] (0.85 if female).  
7. 
Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. 
Patients with greater than 1+ proteinuria on urinalysis must undergo 
a 24-hour urine collection;  
8. 
Uncontrolled hypertension, defined as: systolic blood pressure 
≥140 mmHg and/or diastolic blood pressure ≥90 mm Hg;  
9. 
International Normalized Ratio (INR) >1.5 or activated partial 
thromboplastin time (aPTT) > 1.5 × ULN, unless the patient is 
currently receiving or intending to receive anticoagulants for 
prophylactic purposes.  
10. Risk of, or active hemorrhage: history or presence of active 
gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an 
unresected gastrointestinal tumor, history of perforation or fistulas; 
or any other condition that could possibly result in gastrointestinal 
tract hemorrhage or perforation; within the 6 months prior to 
screening; 
11. History or presence of hemorrhage from any other site (eg, 
hemoptysis or hematemesis) within 2 months prior to screening;  
12. History of a thromboembolic event (including deep vein thrombosis 
[DVT], pulmonary embolism [PE], stroke and/or transient ischemic 
attack) within 6 months prior to screening;  
13. Patients with squamous NSCLC;  
14. Clinically significant cardiovascular disease, including but not 
limited to acute myocardial infarction or coronary artery bypass 
surgery within 6 months prior to enrollment, severe or unstable 


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angina pectoris, New York Heart Association Class III/IV congestive 
heart failure, ventricular arrhythmias requiring treatment, or left 
ventricular ejection fraction (LVEF) < 50%;  
15. Mean corrected QT interval using the Fridericia method 
(QTcF) > 480 msec or any factors that increase the risk of QTc 
prolongation or risk of arrhythmic events such as hypokalemia, 
congenital long QT syndrome, family history of long QT syndrome, 
or unexplained sudden death under 40 years of age in a first-degree 
relative.  
16. Concomitant medications with a known risk of causing QT 
prolongation and/or torsade de pointes (See list in Appendix E; 
source list is continuously updated online at www.qtdrugs.org ). 
17. Patients who have ever received a VEGFR inhibitor except for 
patients with refractory mCRC enrolled in the dose expansion phase. 
18. Systemic anti-neoplastic therapies (except for those described in 
Exclusion 18) or any investigational therapy within 4 weeks prior to 
the first dose of study drug, including chemotherapy, radical 
radiotherapy, hormonotherapy, biotherapy and immunotherapy;  
19. Systemic small molecule targeted therapies (eg, tyrosine kinase 
inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior 
to the first dose of study drug;  
20. Palliative radiotherapy for bone metastasis/lesion within 2 weeks 
prior to the initiation of study drug;  
21. Brachytherapy (ie, implantation of radioactive seeds) within 60 days 
prior to the first dose of study drug. 
22. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks 
before the first dose of study drug (3 weeks for St John’s Wort); P-
glycoprotein (P-gp) or breast cancer resistance protein (BCRP) 
substrate within 2 weeks before the first dose of study drug.  
23. Surgery or invasive procedure (ie, a procedure that includes a biopsy) 
within 60 days prior to the first dose of study drug or unhealed 
surgical incision; 
24. Any unresolved toxicities from a previous antitumor treatment 
greater than CTEAE v. 4.03 Grade 1 (except for alopecia). 
25. Known human immunodeficiency virus (HIV) infection;  
26. Known clinically significant history of liver disease, including 
cirrhosis, current alcohol abuse, or active viral hepatitis.  For 
patients with evidence of chronic hepatitis B virus (HBV) infection, 
the HBV viral load must be undetectable on suppressive therapy, if 
indicated.  Patients with HCV infection who are currently on 
treatment are eligible if they have an undetectable ICV viral load. 
27. Evidence of ongoing or active infection requiring intravenous 
antibiotics;  
28. Tumor invasion of a large vascular structure (eg, pulmonary artery, 
superior or inferior vena cava).  
29. Women who are pregnant or lactating;  


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30. Brain metastases and/or spinal cord compression untreated with 
surgery and/or radiotherapy, and without clinical imaging evidence 
of stable disease for 14 days or longer; patients requiring steroids 
within 4 weeks prior to start of study treatment will be excluded; 
31. No other malignancy, except for non-melanoma skin cancer, during 
the 5 years prior to screening;  
32. Inability to take medication orally, dysphagia or an active gastric 
ulcer resulting from previous surgery (eg, gastric bypass) or a severe 
gastrointestinal disease, or any other condition that investigators 
believe may affect absorption of the investigational product;  
33. Other disease, metabolic disorder, physical examination anomaly, 
abnormal laboratory result, or any other condition that investigators 
suspect may prohibit use of the investigational product, affect 
interpretation of study results, or put the patient at undue risk of harm 
based on the investigator’s assessment.  
34. Known hypersensitivity to fruquintinib or any of its excipients. 
Statistical Analysis: 
By-subject listings will be created for variables from each CRF module, as applicable. 
Summary tables for continuous variables will contain at least the following statistics: number of 
patients (n), mean, standard deviation (SD), median, minimum, and maximum.  Summary 
tables for categorical variables will include n, and percentage. 
Safety Assessment 
All patients who have received at least one dose of fruquintinib will be 
included in the safety analysis set (SAS).  
All DLTs will be listed by dose cohort in DLT-evaluable patients for the 
dose escalation phase only. 
Safety will be evaluated based on the frequency and severity of AEs, 
change of laboratory test results, changes in vital signs, change in ECG, 
and change in echocardiogram.  Safety data will be listed and 
summarized by dose cohort, for patients overall, and for patients with 
mCRC (cohorts’ B and C) and mBC (cohorts’ D and E) who received 
fruquintinib at the RP2D. 
The severity of all AEs will be graded by the investigator according to the 
NCI CTCAE v4.03.  All AEs will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA).  Treatment-emergent AEs 
(TEAEs) will be classified by MedDRA System Organ Class (SOC) and 
specified by Preferred Term (PT).  The incidence of TEAEs, SAEs, 
adverse events of special interest (AESIs), TEAEs leading to dose 
interruption, dose reduction, or study drug discontinuation will be 
summarized.   
For the laboratory assessments, such as hematology, serum biochemistry, 
urinalysis, and other urine parameters will be programmatically graded 
according to CTCAE severity grade.  Summary tables will be presented 
to show the number of patients by CTCAE severity grade with 


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corresponding percentages.  For parameters for which a CTCAE scale 
does not exist, the frequency of patients with values below, within, and 
above the normal ranges will be summarized.  Shift tables for selected 
hematology and serum biochemistry will also be presented showing 
change in CTCAE severity grade from baseline to worst grade post-
baseline. 
Pharmacokinetics 
All patients who received at least one dose of fruquintinib and have at 
least one plasma sample obtained and analyzed will be included in the 
Pharmacokinetic Analysis Set (PKAS).  
A non-compartmental model analysis will be performed for plasma 
concentration data by the central laboratory using WinNonlin (enterprise 
version).  The following summary statistics will be presented for 
concentration data and PK parameters, where appropriate: mean, standard 
deviation, coefficient of variation (CV%), median, minimum, maximum, 
geometric mean, and geometric mean CV%. 
Efficacy 
All patients from the safety analysis set who have at least one post-
baseline tumor assessment will be included in the efficacy analysis set 
(EAS).  
The ORR and DCR will be summarized by dose cohort with percentages 
and 95% exact confidence intervals for the EAS.  The PFS rate at 
specific time points (eg, PFS rate at 12 weeks for Cohort C) and its 95% 
confidence interval will be estimated using the Kaplan-Meier method. 
PFS, DoR, and OS will be summarized descriptively using Kaplan-Meier 
medians and quartiles for patients in the SAS.  Percentage change in 
tumor size will be determined for patients with measurable disease at 
baseline and will be derived at each visit by the percentage change in the 
sum of the diameters of target lesions (TLs) compared to baseline.  The 
best percentage change in tumor size will be summarized using descriptive 
statistics and presented using a waterfall plot. 


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TABLE OF CONTENTS 
TITLE PAGE...................................................................................................................... 1 
EDITION HISTORY ......................................................................................................... 3 
AMENDMENT SUMMARY ............................................................................................ 4 
SIGNATURE PAGE .......................................................................................................... 7 
SYNOPSIS .......................................................................................................................... 9 
TABLE OF CONTENTS ................................................................................................. 20 
ABBREVIATIONS AND DEFINITIONS ..................................................................... 25 
1 
BACKGROUND ....................................................................................................... 28 
1.1 
Physical, Chemical and Pharmaceutical Properties of Fruquintinib ............... 28 
1.1.1 
Nomenclature ............................................................................................... 28 
1.1.2 
Structure ....................................................................................................... 29 
1.1.3 
General Properties ........................................................................................ 29 
1.1.4 
Presentation .................................................................................................. 29 
1.1.5 
Composition ................................................................................................. 29 
1.1.6 
Storage Conditions ....................................................................................... 29 
1.2 
Summary of Nonclinical Studies ..................................................................... 30 
1.3 
Clinical Experience .......................................................................................... 33 
1.3.1 
Clinical Pharmacokinetics ........................................................................... 33 
1.3.2 
Clinical Safety .............................................................................................. 34 
1.3.3 
Clinical Efficacy .......................................................................................... 37 
1.4 
Study Rationale ................................................................................................ 40 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 41 
2.1 
Dose Escalation Phase ..................................................................................... 41 
2.1.1 
Primary Objective ........................................................................................ 41 
2.1.2 
Primary Endpoint ......................................................................................... 42 
2.1.3 
Secondary Objectives ................................................................................... 42 
2.1.4 
Secondary Endpoints ................................................................................... 42 


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2.2 
Dose Expansion Phase ..................................................................................... 43 
2.2.1 
Primary Objective ........................................................................................ 43 
2.2.2 
Primary Endpoint ......................................................................................... 43 
2.2.3 
Secondary Objectives ................................................................................... 43 
2.2.4 
Secondary Endpoints ................................................................................... 43 
3 
INVESTIGATIONAL PLAN ................................................................................... 44 
3.1 
Description of the Study .................................................................................. 44 
3.1.1 
Dose Escalation Phase ................................................................................. 44 
3.1.2 
Dose Expansion Phase ................................................................................. 46 
3.2 
Sample Size ..................................................................................................... 47 
3.3 
Investigational Site .......................................................................................... 47 
3.4 
Safety Review Committee ............................................................................... 47 
3.5 
Study Early Termination .................................................................................. 48 
3.6 
Patient Discontinuation .................................................................................... 48 
3.7 
End of Study .................................................................................................... 49 
4 
PATIENT SELECTION ........................................................................................... 50 
4.1 
Inclusion Criteria ............................................................................................. 50 
1.1 
Exclusion Criteria ............................................................................................ 52 
5 
STUDY TREATMENT ............................................................................................. 55 
5.1 
Investigational Product .................................................................................... 55 
5.1.1 
Investigational Product Supply .................................................................... 55 
5.1.2 
Drug Formulation and Specification ............................................................ 55 
5.1.3 
Packaging and Drug Labeling ...................................................................... 55 
5.1.4 
Drug Storage ................................................................................................ 55 
5.1.5 
Drug Accountability ..................................................................................... 56 
5.1.6 
Dose and Administration .............................................................................. 56 
5.2 
Dose Modification ........................................................................................... 56 
5.2.1 
General Dose Adjustment Note ................................................................... 56 
5.2.2 
Dose Modification Guidance ....................................................................... 57 
5.3 
Concomitant and Excluded Therapies ............................................................. 62 
5.3.1 
Concomitant Therapies ................................................................................ 62 
5.3.2 
Excluded Therapies ...................................................................................... 63 


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5.3.3 
Drug-Drug Interactions ................................................................................ 64 
6 
STUDY VISITS, ASSESSMENTS, AND METHODS ........................................... 65 
6.1 
Screening and Pre-treatment Assessments ...................................................... 65 
6.2 
Assessments During Treatment Phase ............................................................. 65 
6.3 
Safety Assessments .......................................................................................... 65 
6.3.1 
Vital Signs Assessment ................................................................................ 65 
6.3.2 
Physical Examination ................................................................................... 66 
6.3.3 
Laboratory Tests ........................................................................................... 66 
6.3.4 
Cardiac Monitoring ...................................................................................... 66 
6.4 
Efficacy Assessments....................................................................................... 67 
6.5 
Study Completion/Early Termination Visit ..................................................... 67 
7 
SAFETY PLAN ......................................................................................................... 69 
7.1 
Adverse Events ................................................................................................ 69 
7.1.1 
Adverse Events ............................................................................................ 69 
7.1.2 
Reporting of Dose Limiting Toxicity ........................................................... 69 
7.1.3 
Serious Adverse Events and other AEs that require Expedited Reporting .. 69 
7.1.4 
Adverse Events Reporting Period ................................................................ 70 
7.1.5 
Eliciting Adverse Events .............................................................................. 71 
7.1.6 
Assessment of Severity ................................................................................ 71 
7.1.7 
Causality of Adverse Events ........................................................................ 72 
7.1.8 
Recording Adverse Events ........................................................................... 72 
7.2 
Expedited Reporting Requirements ................................................................. 75 
7.3 
Duration of Follow-Up for Adverse Events .................................................... 75 
8 
STATISTICAL ANALYSIS ...................................................................................... 76 
8.1 
Analysis Populations ....................................................................................... 76 
8.2 
Analysis of the Conduct of the Study .............................................................. 76 
8.3 
Safety Analysis ................................................................................................ 77 
8.4 
Pharmacokinetic Analysis ................................................................................ 77 
8.5 
Efficacy Analysis ............................................................................................. 78 
8.6 
Determination of Sample Size ......................................................................... 80 
9 
ETHICS ..................................................................................................................... 82 
9.1 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) ......... 82 


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9.2 
Ethical Conduct of the Study ........................................................................... 82 
9.3 
Patient Informed Consent ................................................................................ 82 
10 
STUDY DOCUMENTATION, CASE REPORT FORM AND RECORDS ... 83 
10.1 
Source Data Verification .................................................................................. 83 
10.2 
Use of Computerized System .......................................................................... 83 
10.3 
Retention of Records ....................................................................................... 83 
11 
MONITORING .................................................................................................... 84 
12 
DATA QUALITY ................................................................................................. 84 
12.1 
Assignment of Preferred Terms and Original Terminology ............................ 84 
13 
USE OF INFORMATION AND PUBLICATION............................................. 85 
13.1 
Use of Information ........................................................................................... 85 
13.2 
Publication ....................................................................................................... 85 
14 
REFERENCES ..................................................................................................... 87 
Appendix A 
 Study Schedule of Events ................................................................... 89 
Appendix B 
 ECOG Performance Status.................................................................. 94 
Appendix C 
 Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST Version 1.1) ..................................................................................................... 95 
Appendix D 
 Handling and Shipment of Pharmacokinetic Samples ...................... 101 
Appendix E 
 Prohibited Concomitant Medications that Have a Known Risk of QT 
prolongation and/or Torsades des Pointes (TdP)........................................................... 103 
Appendix F  Fruquinitinib and Concomitant Medication .......................................... 105 
Appendix G 
 Guideline to Interpreting the Causality Question ............................. 108 
Appendix H 
 Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) . 109 
Appendix I 
Management of Hypertension in Patients Receiving Fruquintinib ........ 111 
Appendix J 
Clinical Management of Severe or Serious Hemorrhagic Events .......... 114 
Appendix K 
 Protocol Amendment History............................................................ 117 
 
List of Tables 
Table 1 
Fruquintinib VEGFR Kinase Activity: Selectivity Profile and Bioactivities .. 31 
Table 2 
Pharmacokinetic Parameters of Fruquintinib at Steady State in Patients 
(Study 2009-013-00CH1) ........................................................................................... 34 
Table 3 
Identified Risks in Patients Treated with Fruquintinib .................................... 35 


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Table 4 
Potential Risks in Patients Treated with Fruquintinib ..................................... 37 
Table 5 
Overall Best Response by Dose Cohort (Study 2009-013-00CH1) ................ 37 
Table 6 
Drug Formulation and Strength ....................................................................... 55 
Table 7 
Dose Modification Sequence by Starting Dose ............................................... 58 
Table 8 
Dose Modification for Hematologic and Non-Hematologic Toxicity ............. 58 
Table 9 
Dose Modification for PPE .............................................................................. 59 
Table 10 
Dose Modification for Proteinuriaa ................................................................. 59 
Table 11 
Dose Modification for Hypertension ............................................................... 60 
Table 12 
Dose Adjustment for Decreased Platelet Count .............................................. 61 
Table 13 
Dose Adjustment for Hemorrhage at any Site ................................................. 61 
Table 14 
Dose Adjustment for Abnormal Liver Function .............................................. 62 
Table 15 
 Estimated Incidence Rates and 2-Sided 95% Confidence Intervals for N=15 
Patients ........................................................................................................................ 81 
Table 16 
Estimated Incidence Rates and 2-Sided 95% Confidence Intervals for N=40 
Patients ........................................................................................................................ 81 
 
List of Figures 
Figure 1 
Kaplan-Meier Curve of PFS, by Treatment (Study 2012-013-00CH1) ........... 38 
Figure 2 
Kaplan-Meier Curve of PFS, by Trial Treatment (Study 2014-013-00CH1) .. 38 
Figure 3 
Kaplan-Meier Graph of OS by Trial Treatment (Study 2013-013-00CH1 
[FRESCO]) ................................................................................................................. 39 
Figure 4 
Kaplan-Meier Graph of PFS by treatment arm (Study 2013-013-00CH1) ..... 40 
Figure 5 
 Study Schema ................................................................................................ 44 
 
 


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ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
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 
BCRP 
Breast cancer resistance protein 
BP 
Blood pressure 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence intervals 
CL/F 
Apparent clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRO 
Contract Research Organization 
Css_av 
Mean concentration at steady state 
Css_max 
Maximum concentration at steady state 
CT 
Computed tomography 
CV (%) 
Coefficient of variation (percent) 
DCR 
Disease control rate 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EAS 
Efficacy Analysis Set 
EGFR 
Epidermal growth factor receptor 
FDG-PET 
18F-fluorodeoxyglucose positron emission tomography 
FRESCO 
Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer 
Patients 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation 


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Abbreviation 
Definition 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
INR 
International normalized ratio 
Ke 
Elimination rate constant 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (version [v] 4.03) 
NOAEL 
No observed adverse effect level 
NSCLC 
Non−−−small cell lung cancer 
ORR 
Objective response rate 
PD 
Progressive disease 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PKAS 
Pharmacokinetic Analysis Set 
POC 
proof-of-concept 
PPE 
Palmar-plantar erythrodysesthesia 
PR 
Partial response 
PSA 
Prostate-specific antigen 
PT 
Preferred Term MedDRA) 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using the Fridericia method 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors (Version [V] 1.1) 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Stable disease 
SDV 
Source data verification 
SOC 
System Organ Class (MedDRA) 
SRC 
Safety Review Committee 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TL 
Target lesion 
Tmax 
Time to reach maximum plasma concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 


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Abbreviation 
Definition 
VEGFR 
Vascular endothelial growth factor receptor 
Vz/F 
Apparent volume of distribution (determined according to 
CL/F/Ke) 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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1 
BACKGROUND 
Angiogenesis is a prominent feature of many physiological and pathological processes, 
including wound healing, luteinization, and tumor growth [1,2].  It is regulated by a balance 
between local pro-angiogenic and anti-angiogenic factors.  Vascular endothelial growth 
factor (VEGF) is an important pro-angiogenic factor.  It is a key regulator of physiological 
angiogenesis during embryogenesis, skeletal growth, and reproductive functions.  It is 
also implicated in pathological angiogenesis such as that associated with tumor growth.  
In the normal state, endothelial cells divide approximately every 7 years, but in the 
malignant state, this growth rate is accelerated, and endothelial cells can divide as rapidly 
as every 7 to 10 days.  An “angiogenic switch” is necessary for tumors to obtain the 
necessary nutrients and oxygen to grow larger than a diameter of 1 mm. 
The biologic effects of VEGF are mediated through binding to 3 VEGF receptors, VEGFR-
1 (Flt-1), VEGFR-2 (KDR or Flk-1), and VEGFR-3.  Binding of VEGF to its receptors 
begins the signaling cascade that regulates cellular events involved in new blood vessel 
formation that produces a number of biologic effects including endothelial cell mitogenesis 
and migration, increased vascular permeability, and inhibition of endothelial cell apoptosis.  
Newly formed tumor vessels are markedly dependent on VEGF, and VEGF mRNA is 
upregulated in many tumors.  Tumor cells represent the major source of VEGF, but tumor-
associated stroma is also an important site of VEGF production[2,3]. 
Overexpression of VEGF has been associated with the promotion of tumor growth, 
elevation of the vascular permeability of tumor vessels, and poor prognosis in solid tumors, 
including colorectal carcinoma[4,5], gastric carcinoma[6,7], breast cancer[8,9] and lung 
cancer[10]. 
Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) with a novel chemical 
structure, which belongs to the quinazoline class.  It is a potent and highly selective 
VEGFR inhibitor discovered by Hutchison MediPharma Limited using rational drug 
design and high-throughput in vitro and in vivo biological screening of a large number of 
compounds  
1.1 Physical, Chemical and Pharmaceutical Properties of Fruquintinib 
1.1.1 
Nomenclature 
Chinese generic name: 呋喹替尼 
English generic name: Fruquintinib 
Investigational product ID: HM5006462, HMPL-013 (or 013 as abbreviation) 
Chinese chemical name:  
6-(6,7-二甲氧基喹唑啉-4-氧)-N,2-二甲基-苯并呋喃-3-甲酰胺 
English chemical name:  


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6-(6, 7-dimethoxyquinazolin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide 
1.1.2 
Structure 
 
Molecular formula: C21H19N3O5 
Molecular weight: 393.39 
1.1.3 
General Properties 
White to off-white crystalline powder soluble in glacial acetic acid; very slightly soluble 
in methanol, acetonitrile, tetrahydrofuran, acetone, 0.1 mol/L hydrochloric acid solution; 
almost insoluble in water and 0.1 mol/L sodium hydroxide solution. 
1.1.4 
Presentation 
Fruquintinib drug product is presented as 2 capsule strengths with 1 mg and 5 mg drug 
substance per capsule, respectively, for oral administration. 
1.1.5 
Composition 
The 1 mg capsule is presented as a size 3 hard gelatin capsule containing 52 mg of white 
to off-white blend powder that is composed of fruquintinib drug substance, 
microcrystalline cellulose, starch, and talc.  The 5 mg capsule is presented as a size 1 hard 
gelatin capsule containing 260 mg of same blend powder as the 1 mg capsules. 
1.1.6 
Storage Conditions 
Fruquintinib capsules are stored at controlled room temperature with excursions allowed 
to 30°C and protected from moisture. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
1.2 Summary of Nonclinical Studies 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  


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Protocol Number: 2015-013-00US1                                                        Version 4.0  


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
1.3 Clinical Experience 
The safety and efficacy of fruquintinib (HMPL-013) has been studied in a number of 
Phase 1, 2, and 3 studies in patients with a variety of solid tumors, including metastatic 
colorectal cancer (mCRC), and locally advanced, metastatic, or recurrent non˗small cell 
lung cancer (NSCLC) as a single agent or in combination with other anti-cancer therapies.  
Summary details can be found in the IB (Section 1.2)[11]. 
1.3.1 
Clinical Pharmacokinetics 
The PK of fruquintinib was evaluated in patients with advanced malignant solid tumors 
treated with a single-dose or multiple-dose regimen (Study 2009-013-00CH1).  
Following administration, a single oral dose of 1, 2, 4, 5 and 6 mg, fruquintinib showed a 
very low clearance.  The selection of the once daily (QD) dose regimen was justified by 
the terminal elimination t1/2 of >35 hours.  The AUC and Cmax generally increased dose-
proportionally at the dose levels from 1 mg to 6 mg.  Following multiple dosing, 
fruquintinib exposure reached steady state after QD administration for 14 days.  Based on 
the AUC for the QD dosing interval (24 hours), accumulation of fruquintinib exposure 
from the first dose to steady state was approximately 3-fold. 
The PK of a 4-week continuous dosing regimen of 5 mg QD was compared to a 3-week 
continuous dosing regimen of 6 mg QD followed by a 1-week break in fruquintinib therapy 
in patients with solid cancers (Study 2009-013-00CH1).  The PK results showed that 
fruquintinib PK profiles were similar for the 2 dosing regimens on the same dosing days 
(see Table 2).  


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Table 2 Pharmacokinetic Parameters of Fruquintinib at Steady State in Patients 
(Study 2009-013-00CH1) 
Steady 
State 
1 mga 
2 mga 
4 mga 
5 mga 
6 mga 
5 mg 3/1b 
6 mg 3/1 b 
Tmax (h) 
1 
3.0 ± 1.7 
5.1 ± 7.9 
1.0 ± 0.0 
4.0 ± 0.0 
3.6 ± 3.8 
2.0 ± 1.0 
Css_max 
(ng/mL) 
82.1 
109 ± 14.9 
290 ± 61.1 
398 ± 43.7 
508 ± 63.6 
383 ± 51.5 
457 ± 103 
Css_av 
(ng/mL) 
55.3 
-- 
217 ± 51.1 
324 ± 64.1 
385 ± 50.6 
295 ± 26.7 
354 ± 89.2 
AUC0-12h 
(ng•h/mL) 
718 
1130 ± 
92.9 
2741 ± 643 
4080 ± 678 
5135 ± 600 
-- 
-- 
AUC0-24h 
(ng•h/mL) 
-- 
-- 
5212 ± 
1227 
7784 ± 
1539 
9230 ± 1215 
7070 ± 642 
8500 ± 2142 
DF (%) 
53.0 
-- 
56.3 ± 22.3 
33.9 ± 18.1 
52.8 ± 10.8 
43.8 ± 12.3 
42.0 ± 7.0 
R-AUCc 
4.0 
3.1 ± 0.7 
3.0 ± 0.6 
-- 
2.5 ± 0.7 
3.0 ± 0.6 
3.2 ± 0.5 
a 
Steady state of Day 14 at once daily continuous regimen. 
b 
Steady state of Day 21 at once daily 3 weeks on/1 week off regimen. 
c 
Accumulation index R-AUC represented the ratio of AUC0-24h at the steady state/AUC0-24h on Day 1. If AUC0-
24h unavailable, AUC0-12h was used. 
 
Two additional dosing regimens were compared: a 4-week continuous dosing regimen of 
4 mg QD, and a 3-week continuous dosing regimen of 5 mg QD followed by a 1-week 
break in fruquintinib therapy, were also evaluated in patients with advanced colorectal 
cancer (Study 2012-013-00CH3).  Overall, the PK profiles of fruquintinib obtained in this 
study were similar to those in the prior trial (Study 2009-013-00CH1). 
The effect of food intake on fruquintinib PK was investigated in healthy male adult 
volunteers at a single oral dose of 4 mg (Study 2012-013-00CH2).  The food effect was 
evaluated by assessment of the bioequivalence between the fasting condition (fasted) and 
the fed condition (food intake).  Fruquintinib exposure was represented by AUC0-∞ and 
Cmax.  The geometric mean ratios (90% confidence interval [CI]) of fasted/food intake 
met the bioequivalence criteria of 80%-125% for AUC and 70%-143% for Cmax.  
Absorption appeared to occur more slowly in the fed condition than in the fasting condition.  
1.3.2 
Clinical Safety  
Fruquintinib has not been approved in the United States, and clinical development is 
ongoing.  The expected events (identified risks) seen with fruquintinib treatment based 
on preclinical and clinical data and/or published data on compounds with similar 
mechanisms of action are summarized in Table 3.  The potential risks of fruquintinib are 
presented in Section 6.5.2 of the IB[11]. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Table 3 Identified Risks in Patients Treated with Fruquintinib 
System Organ Class 
Identified Risks 
Frequencya 
Percentage 
Endocrine Disorders 
Hypothyroidism 
Very common 
(14.2%) 
Gastrointestinal 
Disorders 
Abdominal pain/abdominal discomfort 
Very common 
(26.7%) 
Anal pain 
Common 
(3.1%) 
Diarrhea 
Very common 
(25.6%) 
Oral pain  
Very common 
(11.1%) 
Stomatitis  
Very common 
(26.7%) 
General Disorders 
and Administration 
Site Conditions 
Asthenia 
Very common 
(10.4%) 
Hepatobiliary 
Disorders 
Hepatic function abnormal  (most frequently reported 
as ALT/AST increased and blood bilirubin 
increased) ) 
Very common 
(47.9%) 
Infections and 
Infestations 
Infection (most frequently reported as respiratory tract 
infection and urinary tract infection) 
Very common 
(25.1%) 
Investigations 
Amylase increased 
Common 
(3.6%) 
Thyroid function test abnormal 
Very common 
(27.7%) 
Platelet decreased  
Very common 
(19.4%) 
Weight decreased 
Very common 
(19.2%) 
WBC decreased  
Very common 
(14.0%) 
Neutrophil decreased 
Very common 
(10.4%) 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
System Organ Class 
Identified Risks 
Frequencya 
Percentage 
Metabolism and 
Nutrition Disorder 
Decreased appetite 
Very common 
(23.3%) 
Musculoskeletal and 
Connective Tissue 
Disorders 
Arthralgia 
Very common 
(10.1%) 
Back pain 
Very common 
(15.0%) 
Musculoskeletal pain 
Very common 
(11.9%) 
Renal and Urinary 
Disorders 
Proteinuria 
Very common 
(52.1%) 
Respiratory, 
Thoracic and 
Mediastinal 
Disorders 
Dysphonia 
Very common 
(37.6%) 
Pharyngolaryngeal pain/discomfort 
Common 
(8.8%) 
Skin and 
Subcutaneous Tissue 
Palmar-plantar erythrodysaesthesia (PPE) syndrome 
Very common 
Rash 
Very common 
Dermatitis 
Common 
Vascular Disorders 
Hemorrhages (most frequently reported as occult 
blood positive, haematuria or blood urine present, and 
epistaxis)  
Very common 
(40.7%) 
Hypertension  
Very common 
(55.4%) 
a 
Frequency ≥1/10: very common; frequency ≥1/100 to <1/10: common. See fruquintinib IB edition 
10, Tables 47 and 48. 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
 
Table 4 Potential Risks in Patients Treated with Fruquintinib 
Preferred Term 
n/N 
% 
Gastrointestinal 
perforation/fistula 
3/386 
0.8% 
Wound healing delayed 
1 (PI assessment: not related) 
0.5% 
Reversible posterior 
leukoencephalopathy (RPLS) 
0 
0 
 
Please refer to the fruquintinib IB[11] for a complete summary of safety information.  
Mitigation and management of the identified and potential risks for fruquintinib are 
presented in Section 5.2 of the IB[11]. 
1.3.3 
Clinical Efficacy 
The efficacy data in the Phase 1 study conducted in China (Study 2009-013-00CH1) 
showed encouraging clinical activity for fruquintinib.  A response was observed in the 
majority of heavily pre-treated patients with advanced cancers (see Table 5).  The results 
of two Phase 2 proof-of-concept (POC) studies provided evidence of clinical efficacy in 
patients with metastatic CRC (Study 2012-013-00CH1, third- or later lines therapy) and 
NSCLC (Study 2014-013-00CH1, third-line therapy) as compared with placebo.  The 
progression free survival (PFS) results established POC in both studies by meeting their 
respective primary efficacy endpoints. 
Table 5 Overall Best Response by Dose Cohort (Study 2009-013-00CH1) 
Dose 
Cohort 
Response in Evaluable Patients (N = 34) 
Disease Control (%) 
Objective Response (%) 
CR 
PR 
SD 
PD 
CR+PR+SD 
CR+PR 
1 mga 
0 
0 
1 
0 
1 (100) 
0 
2 mga 
0 
0 
2 
0 
2 (100) 
0 
4 mga 
0 
7 
6 
2 
13 (86.7) 
7 (46.7) 
5 mga 
0 
1 
2 
0 
3 (100) 
1 (33.3) 
6 mga 
0 
0 
0 
1 
0 
0 
5 mgb 
0 
5 
1 
1 
6 (85.7) 
5 (71.4) 
6 mgb 
0 
1 
2 
2 
3 (60.0) 
1 (20.0) 
Total 
0 
14 
14 
6 
28 (82.3) 
14 (41.1) 
a 
Continuous regimen. 
b 
3 weeks on/1 week off regimen. 
 
Study 2012-013-00CH1 was a Phase 2 study investigating the efficacy of fruquintinib in 
the third-line and later setting in patients with mCRC[12].  A total of 71 patients were 
included in this study.  Compared to the placebo group, the fruquintinib group had a 


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significantly longer PFS: The median (95% CI) PFS of the fruquintinib group was 
4.731 (2.858, 5.585) months, while the median (95% CI) PFS of placebo group was 
0.986 (0.953, 1.577) months (see Figure 1).  The p-value of the stratified log-rank test 
was <0.001.  Stratified HR (95% CI) was 0.302 (0.154, 0.589). 
Figure 1 Kaplan-Meier Curve of PFS, by Treatment (Study 2012-013-00CH1) 
 
 
2014-013-00CH1 study was a Phase 2 study investigating the efficacy of fruquintinib in 
the third-line setting in advanced NSCLC[13].  A total of 91 patients were included in this 
study.  As shown in Figure 2, fruquintinib significantly improved PFS when patients were 
treated with fruquintinib monotherapy compared with placebo.  
Figure 2 Kaplan-Meier Curve of PFS, by Trial Treatment (Study 2014-013-00CH1) 
  
 
Study 2013-013-00CH1 (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer 
patients [FRESCO]) was a Phase 3 study that investigated the efficacy and safety of 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
fruquintinib in the third-line or later setting in patients with mCRC[14].  A total of 
416 patients were included in this study.  The primary endpoint was overall survival (OS).  
Key secondary endpoints were PFS (time from randomization to disease progression of 
death), ORR (confirmed CR or PR), and disease control rate (CR or PR, or stable disease 
[SD] recorded ≥ 8 weeks post randomization.  Duration of response was also assessed.  
Safety outcomes included TEAEs. 
The fruquintinib group had a significantly longer OS and PFS compared to the placebo 
group.  The median (95% CI) OS of the fruquintinib group was 9.30 (8.18, 1.45) months, 
while the median (95% CI) OS of the placebo group was 6.57 (5.88, 8.11) months 
(Figure 3).  The p-value of the stratified log-rank test was <0.001.  The stratified hazard 
ratio (HR [95% CI]) was 0.65 (0.51, 0.83).  The median PFS (95% CI) of the fruquintinib 
group was 3.71 (3.65, 4.63) months, while the median (95% CI) PFS of the placebo group 
was 1.84 (1.81. 1.84) months (Figure 4). 
Figure 3 Kaplan-Meier Graph of OS by Trial Treatment (Study 2013-013-00CH1 [FRESCO]) 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Figure 4 Kaplan-Meier Graph of PFS by treatment arm (Study 2013-013-00CH1) 
 
1.4 Study Rationale 
During the pathogenesis of cancer, tumors can secrete a variety of factors to stimulate the 
formation of tumor vasculature to increase their supply of nutrients and oxygen.  Such 
tumor vasculature is often formed by rapid endothelial cell proliferation and packed 
coarsely, leading to increased permeability and tumor cell leakage into the circulation.[1] 
Vascular endothelial cell growth factor (VEGF) and fibroblast cell growth factor (FGF) 
play key roles in tumor angiogenesis and have become two molecular targets of intense 
research for anti-angiogenesis therapies[2-3].  Highly selective antibodies against VEGF or 
its receptor VEGFR have demonstrated significant clinical benefit and have been widely 
used for the treatment of certain cancers[4].  Small molecule drugs, including sunitinib and 
sorafenib, targeting the VEGF receptor (VEGFR) tyrosine kinase signaling pathway have 
also contributed significantly in treating cancer[5,6].  However, most of the early 
generation small molecule VEGFR tyrosine kinase inhibitors (TKIs) inhibit many kinases 
other than VEGFR, resulting in “off-target” toxicities[7].  Therefore, improving kinase 
selectivity has become a key focus for newer generation TKIs.  
Fruquintinib, discovered by Hutchison MediPharma, demonstrated much improved kinase 
selectivity compared to sunitinib and sorafenib in the preclinical setting.  Fruquintinib 
selectively inhibits VEGFR, sparing many other kinases.  Preclinical safety evaluation 
results supported an acceptable safety profile for fruquintinib. 
The safety, tolerability, and pharmacokinetic properties of fruquintinib were assessed in a 
Phase 1 dose escalation study (Study 2009-013-00CH1) that was carried out in patients 
with advanced solid tumors in China.  Results indicated that fruquintinib was well 
tolerated up to 4 mg QD continuous therapy and 6 mg QD 3 weeks on/1 week off.  The 
maximum tolerated dose (MTD) has been reached in patients treated with the continuous 
regimen, but not in patients treated with the 3 weeks on/1 week off regimen.  The most 
frequently reported adverse events, including palmar-plantar erythrodysaesthesia (PPE), 


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proteinuria, and hypertension.  The occurrence of aforementioned AEs and laboratory 
abnormalities are commonly reported in drugs of this class and can be managed effectively.  
Preliminary clinical efficacy was seen in patients with partial response (PR) and durable 
stable disease (SD).   
Although the MTD was not reached, the experience in China demonstrated that 
fruquintinib 5 mg (3 weeks on/1 week off) treatment had improved PFS in Chinese patients 
with metastatic CRC and NSCLC as compared with placebo and was well tolerated.  The 
extensive clinical trial experience in China is the rationale for investigating the 3 mg and 
5 mg regimens in the present Phase 1 study.  If there are clinically significant differences 
in the PK of fruquintinib in patients in the United States (US) compared to those of patients 
in China, the dose escalation sequence may need to be revisited. 
The rationale for adding approximately 40 patients with refractory mCRC in dose 
expansion Cohort B is provided by the results of the phase 3 FRESCO study completed in 
China (study 2013-013-00CH1 [FRESCO]).  FRESCO[14] was a randomized, placebo-
controlled, Phase 3 study of fruquintinib that demonstrated a significantly longer OS and 
PFS for fruquintinib compared to placebo in patients who had progressed on at least 2 lines 
of chemotherapy and relevant biologics and supported its approval by the CFDA.  
FRESCO showed an acceptable safety profile for fruquintinib that was consistent with 
other clinical trials.  For additional information about this trial, see Section 1.3.3 above, 
including Figure 3 and Figure 4.  This cohort will evaluate the safety and efficacy of 
fruquintinib in a patient population of mCRC that is reflective of treatment practice in the 
US where TAS-102 and regorafenib are approved and used in the third-line or greater 
setting. 
The rationale for adding expansion Cohort C of approximately 40 patients with mCRC who 
have progressed on all standard chemotherapy and relevant biologics but who have not 
received TAS-102 or regorafenib is also based on the positive results of the Phase 3 
FRESCO study completed in China (study 2013-013-00CH1 [FRESCO]).  This cohort 
will evaluate the safety and efficacy of fruquintinib in a patient population in the US that 
is similar to that of FRESCO. 
The rationale for adding Cohorts D (HR+/Her2-) and E (TNBC) of patients each with mBC 
is to evaluate the safety and efficacy of fruquintinib in patients with mBC based on data 
from Phase 1 studies of fruquintinib conducted in China (Protocol 2009-013-00CH1) and 
in the US (Protocol 2015-013-00US1), suggesting clinical activity in the proposed 
populations of mBC and based on data showing the clinical efficacy of anti-angiogenics in 
mBC. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 Dose Escalation Phase 
2.1.1 
Primary Objective  
The primary objective of the dose escalation phase is to evaluate the safety and 
tolerability of fruquintinib in patients with advanced solid tumors and to determine the 
recommended Phase 2 dose (RP2D). 


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2.1.2 
Primary Endpoint 
The primary endpoint of the dose escalation phase is the incidence of DLT in each cohort. 
 
DLT is defined as: 
 Any Grade 4 non-hematologic toxicity; 
 Any Grade 3 non-hematologic toxicity related to study drug except for 
nausea/vomiting, diarrhea, constipation, hypertension and electrolyte imbalances 
downgraded within 3 days with appropriate supportive treatment; 
 Grade 4 neutropenia lasting >3 days; 
 Grade 3 febrile neutropenia (absolute neutrophil count [ANC] <1.0 × 109/L with a 
single temperature of >38.3°C or a sustained temperature of ≥38°C for more than 
one hour);  
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; 
 Dose interruption for >14 days due to toxicity. 
The MTD is the highest dose at which no more than 1 of 6 patients developed DLT.  If 
2 or more of 6 patients developed DLT at a particular dose level, then that dose has 
exceeded the MTD. 
In general, the safety and tolerability of fruquintinib will be evaluated based on the AE 
data.  Other safety parameters include physical examination, vital signs, laboratory test 
results (ie, hematology, chemistry panel, thyroid function, and urinalysis), 12-lead 
electrocardiogram, and echocardiogram.  
2.1.3 
Secondary Objectives 
The secondary objectives of the dose escalation phase include the following: 
• To evaluate the PK characteristics of multiple-dose fruquintinib and investigate the 
metabolite profile of fruquintinib in the plasma of patients with solid tumors. 
• To evaluate the anticancer activity of fruquintinib in patients with solid tumors 
according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 
2.1.4 
Secondary Endpoints 
• The primary PK parameters include: maximum plasma concentration (Cmax), time 
to reach maximum concentration (Tmax), terminal half-life (t1/2), area under the 
concentration-time curve in a selected time interval (AUC0-t), area under the 
concentration-time curve in the time interval from 0 to infinity (AUC0∞-∞), apparent 
clearance (CL/F), apparent volume of distribution (Vz/F) during the terminal phase 
according to CL/F/Ke, and the accumulation index based on AUC. 


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• The objective response rate (ORR), disease control rate (DCR), duration of 
response (DoR), PFS, overall survival (OS) and percentage change in tumor size 
from baseline according to RECIST Version 1.1. 
2.2 Dose Expansion Phase 
2.2.1 
Primary Objective 
The primary objective in the dose expansion phase is to evaluate the anticancer activity of 
fruquintinib at the recommended Phase 2 dose (RP2D) from the dose escalation phase, in 
patients with advanced solid tumors. 
2.2.2 
Primary Endpoint 
The primary endpoint is PFS rate. 
2.2.3 
Secondary Objectives 
• To evaluate anticancer activity of fruquintinib, as assessed by ORR, DCR, DoR, 
PFS, and OS.  
• To evaluate the pharmacokinetic (PK) characteristics of multiple-dose fruquintinib 
and investigate the metabolite profile of fruquintinib in plasma. 
• To evaluate the safety of fruquintinib 
2.2.4 
Secondary Endpoints 
• The objective response rate (ORR), disease control rate (DCR), duration of 
response (DoR), PFS, overall survival (OS) and percentage change in tumor size 
from baseline according to RECIST Version 1.1. 
• The primary PK parameters include maximum plasma concentration (Cmax), time 
to reach maximum concentration (Tmax), terminal half-life (t1/2), area under the 
concentration-time curve in a selected time interval (AUC0-t), area under the 
concentration-time curve in the time interval from 0 to infinity (AUC0∞-∞), 
apparent clearance (CL/F), apparent volume of distribution (Vz/F) during the 
terminal phase according to CL/F/Ke, and the accumulation index based on AUC. 
• 
Safety, as assessed by the incidence and severity of AEs, physical examinations, vital 
signs, laboratory test results, 12-lead electrocardiogram, and echocardiogram. 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Description of the Study 
This is an open-label phase 1/1b study of fruquintinib comprised of a dose escalation phase that will 
enroll patients with advanced solid tumors of any type, and a dose expansion phase that will enroll 
patients with advanced solid tumors of any type (Cohort A), refractory mCRC (Cohorts B and C), or 
mBC (Cohorts D and E) (see study schema in Figure 5.) 
Figure 5 
 
Study Schema 
 
3.1.1 
Dose Escalation Phase   
• Approximately 12 evaluable patients will be enrolled.  The actual number of 
patients will depend on the occurrence of dose-limiting toxicities (DLTs) as well as 
the MTD level reached in this trial. 
• The dose levels to be investigated are 3 mg and 5 mg QD, 3 weeks on/1 week off. 
• Six DLT-evaluable patients will be enrolled in the phase and will be treated with 
fruquintinib 3 mg QD (3 weeks on/1 week off) orally.  If no more than 1 DLT 
occurs during the DLT observational window (ie, from Days 1-28 in Cycle 1) 
among the 6 patients, the trial will continue to enroll another 6 patients in the next 
dose cohort in which fruquintinib 5 mg QD (3 weeks on/1 week off) will be tested. 
• Safety monitoring and evaluation for the Dose Escalation phase will be carried out 
by the Safety Review Committee (SRC).  Additional information about the SRC 
is provided in Section 3.4. 


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• If no more than 1 patient at the dose level of 5 mg QD experiences a DLT, the dose 
escalation phase is completed and the expansion phase of the study will be 
conducted. 
• Upon completion of the dose escalation/ phase, the SRC will review the aggregated 
safety and PK data and then select a fruquintinib dose as the RP2D for the 
expansion phase of the trial. 
• Blood samples for PK assay will be collected in Cycle 1 at the following time points: 
pre-dose (within 10 minutes), 1, 2, 4, 8, and 24 hours post dose on Days 1, 14 and 
21. 
• Prior to confirmation of a DLT, if a patient has received any prophylactic medical 
intervention or missed 4 or more fruquintinib doses during the DLT observational 
window, the patient is not DLT evaluable and will be replaced. 
• If a patient does not meet the definition of DLT evaluable patient criterion during 
the DLT observation period, the patient will be replaced. 
• Patients who have completed the DLT observation period (Days 1-28, Cycle 1) and 
are deemed to be benefiting from the fruquintinib treatment at the investigator’s 
discretion may continue the fruquintinib treatment until disease progression, death, 
intolerable toxicity, or at investigator’s discretion that the patient can no longer 
benefit from the study drug. 
• Please see Appendix A for the Schedule of Events and Section 5.2 for the dose 
modification instructions. 
• Patients will be followed until death or study completion. 
a. Dose-Limiting Toxicity Assessment Window 
The DLT assessment window will be 28 days in the first cycle (Days 1-28).  Any patient 
who is not considered evaluable for DLT as defined below will be replaced by an additional 
patient at that same dose level.  
NOTE:  Dose-limiting toxicity assessment does not apply to the expansion cohorts. 
b. Definition of DLT Evaluable Patients: 
A DLT evaluable patient has to meet the following criteria: 
• Has not received any prior anti-cancer therapy prior to DLT; AND 
• Has completed the first 28-day treatment cycle with complete safety evaluations 
and has received at least 85% of the assigned fruquintinib dose;  
OR 


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• Has a confirmed DLT during the first 28-day treatment cycle. 
c. Definition of a Dose-Limiting Toxicity 
 A DLT is defined as one of the toxicities defined for the primary endpoint of the 
dose escalation phase in Section 2.1.2.  These AEs occur during the DLT 
assessment window (Days 1-28, Cycle 1) and are determined by the investigator to 
have a reasonable possibility of being related to fruquintinib.   
 Any Grade 4 non-hematologic toxicity; 
 Any Grade 3 non-hematologic toxicity related to study drug except for 
nausea/vomiting, diarrhea, constipation, hypertension and electrolyte imbalances 
downgraded within 3 days with appropriate supportive treatment; 
 Grade 4 neutropenia lasting >3 days; 
 Grade 3 febrile neutropenia (absolute neutrophil count [ANC] <1.0 × 109/L with a 
single temperature of >38.3°C or a sustained temperature of ≥38°C for more than 
1 hour;  
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; 
 Dose interruption for >14 days due to toxicity; 
In the absence of clinical abnormality, repeat laboratory testing will be conducted to 
confirm significant laboratory findings prior to designation as a DLT. 
d. Definition of MTD 
The MTD is the highest dose at which no more than 1 of the 6 patients in each cohort of 
the dose escalation phase develops a DLT.  If 2 or more of 6 patients in each cohort of the 
dose escalation phase develop DLT at a particular dose level, that dose has exceeded the 
MTD.  
3.1.2 
Dose Expansion Phase 
The objectives of the dose expansion phase are to evaluate the anticancer activity and safety 
of fruquintinib at the RP2D determined at the end of the dose escalation phase, as described 
in Section 2.2. 
Once the RP2D is determined, patients may enroll into one of the following cohorts and 
will receive fruquintinib at the RP2D.   
• Cohort A: Patients with advanced, refractory solid tumors of any type 
• Cohort B: Patients with refractory mCRC who have progressed on all standard 
chemotherapies and relevant biologics and have also progressed on, or had 
intolerable toxicity with, at least 1 FDA-approved third-line therapy (TAS-102 or 
regorafenib).  


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• Cohort C: Patients with refractory mCRC who have progressed on all standard 
chemotherapies and relevant biologics and have not received prior TAS-102 or 
regorafenib. 
• Cohort D: Patients with hormone-receptor positive (ER+ and/or PR+)/Her2- 
metastatic breast cancer who have progressed on at least two line of prior systemic 
therapy. 
• Cohort E: Patients with advanced triple negative breast cancer (TNBC) who have 
progressed on at least one cytotoxic therapy in the metastatic setting. 
Detailed patient inclusion and exclusion criteria for each expansion cohort is described in 
Sections 4.1 and 4.2.  
The safety of all enrolled patients will be closely monitored from the first day of 
fruquintinib dosing until 30 days after the last dose.  All SAEs should be reported from 
the day the informed consent form (ICF) is signed through 30 days after last dose regardless 
of relationship to study drug.  All AEs will be graded in accordance with the NCI CTCAE 
v4.03.   
Tumor response will be assessed according to RECIST Version 1.1 at screening and at 
study visits according the Schedule of Events (Appendix A).  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. 
Patients will be followed until death or study completion (Appendix A). 
3.2 Sample Size 
Approximately 128 patients will be enrolled in this dose escalation/dose expansion study.  
Approximately 12 patients will be enrolled in the dose escalation phase, and approximately 
116 additional patients (6 with advanced solid tumors of any type, 40 with refractory 
mCRC who progressed on TAS-102 and/or regorafenib, 40 with mCRC who had not 
received TAS-102 or regorafenib, 15 with refractory HR+/HER2- mBC, and 15 with 
advanced, refractory TNBC) will be enrolled in the dose expansion phase. 
3.3 Investigational Site 
Approximately 12 sites will participate in the study. 
3.4 Safety Review Committee 
A Safety Review Committee (SRC) will be established under a charter to conduct safety 
data review and to determine the next step for dose escalation.  Safety monitoring and 
evaluation for dose escalation decisions will be carried out by the SRC upon completion 
of the of the DLT observation period of the last patient in each cohort.  The SRC is chaired 
by the Sponsor’s fruquintinib Clinical Program Leader; members will include the principal 
investigators (PIs), the Sponsor’s PK scientist, medical monitor, and the CRO’s medical 
monitor.  
Dose escalation decisions are based on AE and PK data from this ongoing trial, as well as 
consideration of safety and PK data at comparable drug exposure from patients in 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
previously conducted clinical trials in China. 
Regular safety data review will be conducted at pre-defined intervals and at the end of the 
DLT observation period (ie, first treatment cycle) of each dose cohort.  Safety and PK 
data from all enrolled patients will include laboratory test results, AEs, electrocardiogram 
(ECG) results, and PK data. 
3.5 Study Early Termination  
Hutchison MediPharma has the right to stop the study at any time.  The reasons for 
stopping the study may include, but are not limited to: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
3.6 Patient Discontinuation 
All study participants have the right to withdraw from the study at any time.  The 
investigator has the right to discontinue a patient from the study for any medical condition 
that the investigator determines may jeopardize the patient’s safety if he or she continues 
in the study and for reasons of non-compliance (eg, missed doses, visits) or pregnancy or 
if the investigator determines it is in the best interest of the patient.  Any patient who 
discontinues treatment should be encouraged to return to the study site for a treatment 
completion visit.  See Appendix A for the assessments that are to be performed for 
patients who prematurely withdraw from the study during the treatment period.  The 
primary reason for discontinuation must be recorded on the appropriate Case report form 
(CRF). 
Study drug treatment will end if a patient meets any of the following 3 criteria:  
1. 
Disease progression (according to RECIST Version 1.1) unless there is reasonable 
evidence of clinical benefit to justify continuation on the study treatment.  The 
decision that the patient should continue treatment should be made by the 
investigator in consultation with the Sponsor.  The disease progression date is the 
date when radiological disease progression is first reported according to 
RECIST Version 1.1 criteria; 
2. 
Death; 
3. 
End of this study. 
Early discontinuation of study treatment will occur if any of the following criteria is 
met: 
1. 
Patient withdrawal of consent; 
2. 
Intolerable toxicity; 
3. 
Poor patient compliance; 
4. 
Use of other antitumor treatment during the study; 
5. 
Pregnancy occurred during the study treatment period; 
6. 
Patient is lost to follow-up; 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
7. 
Treatment discontinuation is in the best interest of the patient based on the 
assessment of the investigator and the Sponsor. 
3.7 End of Study  
End of the study is defined as the last visit of the last patient. 


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4 
PATIENT SELECTION 
Patients with locally advanced or metastatic solid tumors of any type, and patients with 
refractory mCRC for whom approved therapy either does not exist or has proven to be 
ineffective or intolerable are eligible to participate in this study.  Patients will undergo a 
screening period of up to 4 weeks, during which they will be assessed for compliance with 
the inclusion and exclusion criteria as outlined below. 
4.1 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet all of the following Inclusion 
Criteria:  
1. Fully understand the study and voluntarily sign the ICF;  
2. ≥18 years of age;  
3. Body weight ≥40 kg;  
4. Dose Escalation Phase: 
Histologically or cytologically documented, locally advanced or metastatic solid 
malignancy of any type (except squamous NSCLC) that has progressed on approved 
systemic therapy, and for whom no effective therapy or standard of care exists. 
Dose Expansion Phase:  
Cohort A: Histologically or cytologically documented, locally advanced or 
metastatic solid malignancy of any type (except squamous NSCLC), that has 
progressed on approved systemic therapy, and for whom no effective therapy or 
standard of care exists. 
Cohort B: Histologically or cytologically documented adenocarcinoma of the colon 
or rectum that has progressed on, or had intolerable toxicity to, at least 1 FDA-
approved third-line systemic therapy (TAS-102 or regorafenib).  Treatment failure is 
defined as disease progression during or within 3 months after the last dose of standard 
therapy, or discontinuation of standard therapy because of unacceptable toxicity.  
Patients must also have been previously treated with fluoropyrimidine-, oxaliplatin-, 
and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS 
wild type, an anti-EGFR therapy. 
Eligibility also requires knowledge of tumor RAS status (wild-type or mutant) as 
reported by investigators. 
Cohort C: Histologically or cytologically documented adenocarcinoma of the colon 
or rectum.  Patients must have progressed on, or had intolerable toxicity to, at least 2 
prior regimens of standard chemotherapy, but must not have received prior TAS-102 
or regorafenib.  Treatment failure is defined as disease progression during or within 
3 months after the last dose of standard therapy, or discontinuation of standard therapy 
because of unacceptable toxicity.  Prior therapy could have included adjuvant 
chemotherapy if a tumor had recurred within 6 months after the last administration of 


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treatment.  Patients must have been previously treated with fluoropyrimidine-, 
oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, 
if RAS wild-type, an anti-EGFR therapy 
Eligibility also requires knowledge of tumor RAS status (wild-type or mutant) as 
reported by investigators. 
Cohorts D and E:  
Her2-negative 
metastatic 
breast 
cancer, 
with 
Her2-negative 
defined 
as 
immunohistochemistry (IHC) 0, 1+, or 2+.  If IHC 2+, a negative in situ 
hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. 
a. Cohort D only:  Histologically- or cytologically-confirmed hormone-
receptor positive (ER+ and/or PR+) breast cancer, by local assessment. 
OR 
b. Cohort E only:  Histologically- or cytologically- confirmed triple 
negative breast cancer with ER-negative, PR-negative tumors as defined 
by local criteria. 
5. Hormone receptor positive mBC patients must have progressed on at least 2 lines of 
prior systemic therapy, including hormonal therapy or chemotherapy.  However, 
patients may not have received more than 3 prior lines of cytotoxic chemotherapy in 
the metastatic setting.  There is no limit to number of prior lines of hormonal therapy. 
6. Triple negative breast cancer patients must have progressed on at least 1 cytotoxic 
therapy in the metastatic setting, with the exception of subjects who progressed within 
12 months of adjuvant therapy.  However, patients may not have received more than 
5 prior lines of cytotoxic chemotherapy in the metastatic setting. 
7. Have measurable disease per RECIST Version 1.1, or bone lesions in the absence of 
measurable disease (Dose Expansion phase only).  Lesions that received radiotherapy 
are not measurable per RECIST Version 1.1.  
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;  
9. Expected survival of more than 12 weeks;  
10. For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement to use a highly effective form(s) of contraception, 
that results in a low failure rate (<1% per year) when used consistently and correctly, 
starting during the screening period, continuing throughout the entire study period, and 
for 90 days after taking the last dose of study drug.  Such methods include: oral 
hormonal contraception (combined estrogen/ progestogen, or progestogen-only), 
associated with inhibition of ovulation together with a barrier method (eg, diaphragm, 
always containing a spermicide); intrauterine device (IUD), intrauterine hormone-
releasing system (IUS), bilateral tubal ligation, vasectomized partner (on the 
understanding that this is the only one partner during the whole study duration), or 
sexual abstinence.  Oral contraception should always be combined with an additional 
contraceptive method (ie, barrier method) because of a potential interaction with the 
study drug.  The same rules are valid for male patients involved in this clinical trial 


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if they have a partner of childbirth potential.  Male patients must always use a 
condom. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (ie, ≥12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of the ovaries and/or uterus). 
1.1 
Exclusion Criteria 
Patients will be excluded from the study if any of the following criteria is met: 
1. Cohort C only: patients who have been previously been treated with TAS-102 or 
regorafenib 
2. Absolute neutrophil count (ANC) <1.5 × 109/L, platelet count <100 × 109/L, or 
hemoglobin <9.0 g/dL.  Blood transfusion within 1 week prior to enrollment for the 
purpose of increasing the likelihood of eligibility is not allowed; 
3. Serum total bilirubin >1.5 × upper limit of normal (ULN); 
4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 × ULN in 
patients without hepatic metastases; ALT or AST > 3 × ULN in patients with hepatic 
metastases;  
5. Serum potassium, calcium, or magnesium levels out of the normal laboratory reference 
range, and clinically significant in the investigator’s judgment;  
6. Creatinine >1.5 × ULN or creatinine clearance <60 mL/min.  Creatinine clearance 
can either be measured in a 24-hour urine collection or estimated by the Cockcroft-
Gault equation as follows: CrCl (mL/min) = [(140 - age) × (weight in kg) ÷ [72 × 
(serum creatinine in mg/dL)] (0.85 if female).  
7. Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h.  Patients with greater 
than 1+ proteinuria on urinalysis must undergo a 24-hour urine collection;  
8. Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or 
diastolic blood pressure ≥90 mmHg;  
9. International Normalized Ratio (INR) >1.5 or activated partial thromboplastin time 
(aPTT) > 1.5 × ULN, unless the patient is currently receiving or intending to receive 
anticoagulants for prophylactic purposes.  
10. Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or 
ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history 
of perforation of fistulas; or any other condition that could possibly result in 
gastrointestinal tract hemorrhage or perforation within 6 months prior to screening  
11. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) 


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within 2 months prior to screening;  
12. History of a thromboembolic event (including deep vein thrombosis [DVT], 
pulmonary embolism, stroke and/or transient ischemic attack) within 6 months prior 
to screening;  
13. Patients with squamous NSCLC;  
14. Clinically significant cardiovascular disease, including but not limited to acute 
myocardial infarction or coronary artery bypass surgery within 6 months prior to 
enrollment, severe or unstable angina pectoris, New York Heart Association 
Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or 
left ventricular ejection fraction (LVEF) <50%;  
15. Mean corrected QT interval (QTc) using the Fridericia method (QTcF) >480 msec or 
any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, 
or unexplained sudden death under 40 years of age in a first-degree relative.  
16. Concomitant medications with a known risk of causing QT prolongation and/or 
torsade de pointes (see list in Appendix E; source list is continuously updated online 
at www.qtdrugs.org); 
17. Patients who have ever received a VEGFR inhibitor, except for patients with mCRC 
enrolled in the dose expansion phase; 
18. Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any 
investigational therapy within 4 weeks prior to the first dose of study drug, including 
chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy; 
19. Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 
5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;  
20. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation 
of study drug;  
21. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first 
dose of study drug; 
22. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose 
of study drug (3 weeks for St John’s Wort); P-glycoprotein (P-gp) or breast cancer 
resistance protein (BCRP) substrate within 2 weeks before the first dose of study drug 
(see Appendix F for a list of such medications);  
23. Surgery or invasive procedure (ie, procedure that includes a biopsy) within 60 days 
prior to the first dose of study drug or unhealed surgical incision;  
24. Any unresolved toxicities from a previous antitumor treatment greater than 


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CTCAE v 4.03 Grade 1 (except for alopecia);  
25. Known human immunodeficiency virus (HIV) infection; 
26. Known clinically significant history of liver disease, including cirrhosis, current 
alcohol abuse, or active viral hepatitis.  For patients with evidence of chronic 
hepatitis B (HBV), the HBV viral load must be undetectable on suppressive therapy, 
if indicated.  Patients with a history of hepatitis C virus (HCV) infection must have 
been treated and cured.  For patients with HCV who are currently on treatment, they 
are eligible if they have an undetectable HCV viral load. 
27. Evidence of ongoing or active infection requiring intravenous antibiotics;  
28. Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior 
vena cava).  
29. Women who are pregnant or lactating;  
30. Brain metastases and/or spinal cord compression untreated with surgery and/or 
radiotherapy, and without clinical imaging evidence of stable disease for 14 days or 
longer; patients requiring steroids within 4 weeks prior to start of study treatment will 
be excluded; 
31. No other malignancy, except for non-melanoma skin cancer, during the 5 years prior 
to screening;  
32. Inability to take medication orally, dysphagia or an active gastric ulcer resulting from 
previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other 
condition that investigators believe may affect absorption of the investigational 
product;  
33. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory 
result, or any other condition that investigators suspect may prohibit use of the 
investigational product, affect interpretation of study results, or put the patient at undue 
risk of harm based on the investigator’s assessment;  
34. Known hypersensitivity to fruquintinib or any of its excipients. 
 
 


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5 
STUDY TREATMENT 
5.1 Investigational Product 
5.1.1 
Investigational Product Supply 
Fruquintinib will be supplied by Hutchison MediPharma Limited. 
5.1.2 
Drug Formulation and Specification 
Hutchison MediPharma Limited authorizes WuXi AppTec (Shanghai) Co. Ltd to 
manufacture and package fruquintinib capsules.  The technical guidance and quality 
assurance will be conducted by Hutchison MediPharma Limited. 
Table 6 Drug Formulation and Strength 
Formulation 
Strength 
Route of Administration 
Capsule 
1 mg 
Oral 
Capsule 
5 mg 
Oral 
 
5.1.3 
Packaging and Drug Labeling 
The investigational drug is packaged in white high-density polyethylene bottle with 
30 capsules of 1 mg per bottle and 25 capsules of 5 mg per bottle. 
The following information will appear on the label affixed to either the bottle or carton; 
additional information will be added as required: 
• Sponsor identification 
• Protocol number 
• Drug identification 
• Quantity of contents 
• Storage conditions 
• Dosing instructions 
• Route of administration 
• Blank spaces to write the patient's identification number  
• Lot number 
 
5.1.4 
Drug Storage 
All study drugs should be kept in a secure place under appropriate storage conditions (10ºC 
to 30ºC).  The investigational product label on the pack specifies the appropriate storage.  
Fruquintinib capsule should not be used beyond expiration date provided by the 
manufacturer.  The intended shelf life of fruquintinib capsules is 2 years. 


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The temperature log should be recorded and filed in the study binder. 
5.1.5 
Drug Accountability 
All study drug required for this study will be provided by Hutchison MediPharma.  The 
recipient will acknowledge receipt of the drug by returning the appropriate documentation 
form indicating shipment content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed of 
by the study site should be recorded by using the Drug Inventory Log. 
Study drug will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to Hutchison MediPharma or a Hutchison 
identified entity with appropriate documentation, as determined by the study site.  If the 
study site chooses to destroy study drug, the method of destruction must be documented. 
5.1.6 
Dose and Administration 
After the SRC review of Cohort 2, the RP2D was declared as 5 mg QD, 3 weeks on/1 
weeks off each 28-day cycle.  Patients from Cohort 1 who remain in the study may have 
their fruquintinib dose escalated to 5 mg QD at the discretion of the investigator and with 
the agreement of the Sponsor. 
If baseline (pre-dose) PK blood samples need to be collected on the days of PK sample 
collection, patients must take the investigational product after sampling at site.  
It is recommended that fruquintinib be taken with water (approximately 200 mL or 1 cup), 
1 hour before breakfast.  The administration time should be accurately recorded on the 
days of PK sampling. 
On the days of PK sampling, patients should avoid high-fat meals for the entire day and 
avoid consumption of any liquids other than water (up to 200 mL) within 1 hour before or 
after drug administration.  The patient is encouraged to avoid, or minimize the use of 
caffeine-containing foods or drinks, tobacco, tobacco products, and alcohol during the 
entire study.  If the patient cannot avoid taking any of the above listed substances during 
the study, it should be regarded as a habit and documented as demographic data. 
The following substances are prohibited during the study: grapefruit or grapefruit juice, 
illegal drug use, or excessive (> 1 drink/day) alcohol use. 
If patients miss a dose in the morning, a replacement dose can be taken before 6 pm on the 
same day.  Otherwise, the patient should not make up the missed dose, but should resume 
scheduled doses the next day per protocol.  The missed dose should be reported to the 
investigators and recorded in the CRF. 
5.2 Dose Modification 
5.2.1 
General Dose Adjustment Note 
The severity of AEs will be graded according to the NCI CTCAE v4.03.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome will be 
documented in the patient’s chart and recorded in the CRF. 


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● Any toxicity that meets the definition of DLT during the DLT observation period will 
be considered as DLT for purposes of dose escalation and MTD determination. 
● For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator feels 
it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline that 
increases to Grade 2 during treatment, this will be considered a shift of one grade and 
treated as Grade 1 toxicity for dose-modification purposes. 
● For toxicities that are considered by the investigator to be unlikely to develop into 
serious or life-threatening events, treatment will be continued at the same dose.  In 
addition, no dose reductions or interruptions will be required for anemia (non-
hemolytic) because it can be satisfactorily managed, unless serious (Grade ≥3) 
hemorrhage is present. 
● To recover from acute toxicity, unless otherwise indicated, the treatment can be 
interrupted for up to 14 days.  If a treatment delay longer than 14 days is required, the 
patient should be discontinued from the study drug.  Continuation/resumption of 
fruquintinib treatment after an interruption of more than 14 days must be discussed 
with the medical monitor or his or her designee. 
● Where several toxicities with different grades or severity occur at the same time, the 
dose modifications should be according to the highest grade observed. 
5.2.2 
Dose Modification Guidance 
5.2.2.1 Dose Modification Sequence by Starting Dose and for General Hematologic 
and Non-Hematologic Toxicity 
Dose reduction guidelines by starting dose and for haematologic and non-haematologic 
toxicities other than PPE, proteinuria, hypertension, decreased platelet count, hemorrhage, 
and liver function impairment are shown in Table 7 and Table 8.  In principle, treatment 
should be held until AE/toxicity resolves or improves to ≤Grade 1.  If a Grade 3 toxicity 
is expected to be manageable and reversible with a dose reduction, treatment should be 
held until toxicity resolves to ≤Grade 1.  Patients with Grade 3 non-haematologic toxicity 
that does not resolve to ≤Grade 1 within 2 weeks should permanently discontinue the study 
drug.  
Patients starting at 5 mg QD are allowed to have two dose reductions: one reduction from 
5 mg QD to 4 mg QD, and if not tolerated, then a second reduction from 4 mg QD to 3 mg 
QD.  Patients starting at 3 mg QD are allowed to have 1 dose reduction (ie, from 3 mg 
QD to 2 mg QD).  The lowest dose level permitted in the study is 2 mg (see Table 7). 
 
 


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Table 7 Dose Modification Sequence by Starting Dose  
Starting Dose* 
3 mg 
5 mg 
-1 Dose 
2 mg 
4 mg 
-2 Dose 
Off study drug 
3 mg 
 
Only 1 dose reduction is allowed 
for patients starting at 3 mg QD 
dose. 
A maximum of 2 dose reductions 
is allowed for patients starting at 
the 5 mg dose. 
* Doses are daily, on Days 1-21 each 28-day Cycle (3 weeks on, 1 week off) 
 
Table 8 Dose Modification for Hematologic and Non-Hematologic Toxicity 
NCI CTCAE v4.03 Toxicity Grading 
Action 
Grade 1 or 2a 
None 
Grade 3b 
Interrupt the dose until the toxicity resolved to ≤Grade 
1 or baseline level within 14 days, then reduce the dose 
to lower a dose level 
Grade 4 
Discontinue treatment permanently 
a Should any arterial thrombosis occur, the treatment should be terminated. 
b Including Grade 3 diarrhea and stomatitis, etc. that are ineffectively treated by drug therapies, but 
excluding Grade 3 menstrual cycle extension. 
5.2.2.2 Dose Modification and Treatment Suggestions for Selected Identified Risks 
The dose modification and treatment suggestions for specific identified risks are provided 
in Table 9 (PPE), Table 10 (proteinuria), Table 11 (hypertension), Table 12 (decreased 
platelet count), Table 13 (hemorrhage at any site), and Table 14 (abnormal liver function). 


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Table 9 Dose Modification for PPE 
AE Grading Standard 
Dose Adjustment 
Treatment Suggestions 
Grade 1: numb, paresthesia, 
dysesthesia, erythema, painless 
edema, desquamation, thicken 
skin and hand and foot discomfort 
which does not affect the normal 
activities; without any pain 
None. 
Active supportive treatment can be 
adopted to relieve the symptoms; for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment 
can be used. 
Grade 2: erythema with pain 
accompanied by hand and foot 
swelling and /or discomfort, 
which affects normal activities 
The drug could be 
interrupted; and no dose 
reduction if the AE recovers 
to Grade 1 or baseline level 
within 14 days. 
Active supportive treatment can be 
adopted to relieve the symptoms; for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment 
can be used. 
Grade 3: wet desquamation, 
ulcer, blister or severe hand and 
foot pain or severe discomfort, 
which affects work or normal 
activities. 
The drug can be 
interrupted; the drug should 
be reduced to a lower dose 
level if the AE recovers to 
Grade 1 or baseline level 
within 14 days. 
Active supportive treatment can be 
adopted to relieve the symptoms; 
Should the same AE occur for 3 
times or still occurs after 2 times of 
dose reduction, the drug should be 
terminated. 
 
Table 10 
Dose Modification for Proteinuriaa 
AE Grading Standard 
Dose Adjustment 
Treatment Suggestions 
Grade 1: Proteinuria 1+ by 
urinalysis;  
24-hour urine protein 
quantitation <1.0 g 
None 
Follow up at scheduled study visits.  
Grade 2: Proteinuria 2+ by 
the urinalysis; 
24-hour urine protein 
quantitation is between 1.0 
to <2.0 g  
None 
Provide supportive treatment and increase 
the frequency of urine monitor to once a 
week; consult nephrologist if necessary. 
Grade 2: Proteinuria 2+ or 
above by urinalysis;  
24-hour urine protein 
quantitation is between 2.0 
to <3.5 g (excluding 3.5 g) 
The drug can be interrupted 
and then reduced to lower if 
the AE recovers to Grade 1 or 
baseline level within 14 days. 
Provide supportive treatment and increase 
the frequency of urine monitor to once a 
week; consult nephrologist if necessary. 
Grade 3: 24-hour urine 
protein quantitation ≥3.5 g 
The drug can be interrupted 
and then reduced to lower 
dose level if AE recovers to 
Grade 1 or baseline level 
within 14 days. 
Provide supportive treatment and increase 
the frequency of urine monitor to once or 
twice a week; consult nephrologist if 
necessary.  Should the same AE occur for 
3 times or still occurs after 2 times of dose 
reduction, the drug should be terminated. 
a: If protein ≥ 2+ on urinalysis during the study, a 24-hour urine test should be conducted within 1 week, 
and dose modification will be done by the result of 24-hour urine protein quantitation. 
 


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Table 11 
Dose Modification for Hypertension 
AE Grading and 
Definitions 
Dose adjustment 
Treatment Suggestions 
Grade 1: 
prehypertension  
(systolic BP 120-139 
mmHg or diastolic 
BP 80-89 mmHg) 
None 
Follow up as planned schedule 
Grade 2: SBP 140-
159 mmHg or DBP 
of 90-99 mmHg; or 
DBP symptomatic 
increase >20 mmHg 
None 
Treatment objective: lower the blood 
pressure to <140/90 mmHg (or 
<130/80 mmHg in patients with 
chronic renal disease and/or diabetes).  
Refer to Appendix I.   
Grade 3: SBP ≥ 160 
mmHg or DBP 
≥100mmHg; or more 
than one drug or 
more intensive 
therapy are used 
Interrupted once Grade3 hypertension 
lasting more than 7 days after using 
or adjusting antihypertensive drug; 
Should the BP of the patient recover 
to Grade 1 or the baseline level, one 
time of dose reduction shall be made. 
Treatment objective: lower the blood 
pressure to <140/90 mmHg (or 
<130/80 mmHg in patients with 
chronic renal disease and/or diabetes).  
Refer to Appendix I. 
Grade 4: Life 
threatening (eg, 
malignant 
hypertension, 
temporary or 
permanent 
neurological deficits 
and hypertensive 
crisis) 
The drug should be terminated. 
Emergent medical treatment. 
 


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Table 12 Dose Adjustment for Decreased Platelet Count 
AE Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1:  
Platelet count <LLN - 
75,000/ mm3;  
<LLN - 75.0 ×109/L     
None 
Perform follow up visit as scheduled. 
Grade 2:  
Platelet count <75,000-
50,000/mm3;  
<75.0 - 50.0 ×109/L 
Be interrupted and continue the 
drug treatment with the same 
dose should the AE recovers to 
Grade 1 or baseline level within 
7 days. 
Hematology test should be monitored 
every 2-3 days; active treatment for 
platelet elevation is recommended. 
Be interrupted and then reduced 
to the lower dose level should 
the AE recovers to Grade 1 or 
baseline level within 7-14 days. 
Hematology test should be monitored 
every 2-3 days; active treatment for 
platelet elevation is recommended. 
Grade 3:  
Platelet count <50,000 - 
25,000/mm3;  
<50.0 - 25.0 × 109/L  
Be interrupted and reduced to 
the lower dose level should the 
AE recovered to Grade 1 or 
baseline level within 14 days. 
Hematology test should be monitored 
every 2-3 days; active treatment (platelet 
transfusion) to elevate the platelet count 
is recommended.  
Hematology examination should be 
performed once every week in the follow 
up visit. 
Grade 4:  
Platelet count 
<25,000/mm3;  
<25.0 × 109/L 
The study drug should be 
terminated permanently. 
Hematology test should be performed 
once daily until the AE recovers to Grade 
2 or a lower grade; platelet transfusion or 
other active treatment should be provided  
 
Table 13 Dose Adjustment for Hemorrhage at any Site 
AE Grading 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None 
Perform follow up visit as 
scheduled. 
Grade 2 
The drug can be interrupted and then reduced to the lower 
dose level should the AE recovered to Grade 1 or baseline 
level within 14 days. 
Provide Active treatmentb 
Grade 3 or 
abovea 
The study drug should be terminated permanently. 
Emergent medical 
interventionb 
a Refer to Appendix J for clinical management of severe or serious hemorrhage. 
b The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic drugs 
during study drug treatment and make a timely decision on whether to continue or stop such drugs in 
patients that report Grade ≥2 hemorrhagic events at any site, based on an individual assessment of the 
risk-benefit balance (See Section 5.3.1 Concomitant therapies). 
 


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Table 14 Dose Adjustment for Abnormal Liver Function 
AE Gradinga 
Dose Adjustment 
Treatment Suggestions 
Grade 1 
None. 
Perform follow-up visit as 
scheduled. 
Grade 2 or 3 (Liver 
function is abnormal but 
the biochemical criteria 
for Hy’s Lawb are not 
met) 
1. Drug interruption can be 
considered; 
2. The dose should be reduced to 
the lower dose level if the AE 
recovers to Grade 1 or baseline 
within 14 days. 
Provide supportive care and 
increase the frequency of liver 
function monitoring to 1-2 times a 
week. 
Grade 2 or 3 (Liver 
function is abnormal and 
the biochemical criteria 
for Hy’s Lawb are met) 
The study drug should be terminated 
immediately. 
Provide supportive care and 
increase the frequency of liver 
function monitoring to 2-3 times a 
week.  Urgent medical 
intervention indicated. 
Grade 4 
The study drug should be terminated. 
Urgent medical intervention 
indicated. 
a Including increasing of ALT, AST, and total bilirubin, whether or not the biochemical criteria for 
Hy’s Law have been met. 
b Hy’s Law is an increase in serum AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, and 
no other reason can be found to explain the biochemical changes, for example, new or worsening 
hepatobiliary metastases, elevated serum ALP indicating cholestasis, viral hepatitis, another suspect 
drug, or any other specific cause of severe hepatocellular injury.  The elevation in transaminases 
must precede or be coincident with (ie, on the same day as) the elevation in total bilirubin, but there 
is no specified timeframe within which the elevations in transaminases and total bilirubin must occur.  
See Section 7.1.2 for special reporting requirements and Appendix H for additional information 
regarding Hy’s Law. 
 
5.3 Concomitant and Excluded Therapies 
5.3.1 
Concomitant Therapies 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation and 
the termination visit.  All concomitant medications should be reported to the investigator 
and recorded on the appropriate CRF. 
Patients who use hormonal therapy with GnRH agonists for prostate cancer, oral 
contraceptives, hormone-replacement therapy, or other allowed maintenance therapy 
should continue their use.  
Prophylactic use of anticoagulation for the maintenance of patency of permanent 
indwelling central venous access devices or for patients at high risk of venous 
thromboembolism is permitted during study treatment.  If patients are receiving anti-
coagulation, they should be very closely monitored for potential haemorrhage, and: 


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• 
Patients who are receiving warfarin or Coumadin-like products should have their INR 
monitored and maintained at the lower third of the therapeutic range (ie, 2.0-2.3), 
unless a higher INR is required for anti-thrombotic efficacy.  
• 
Patients who require low-molecular-weight heparin should receive the prophylactic 
dose and monitoring as specified by the appropriate product information label. 
The investigator should closely monitor patients receiving anti-platelet and/or anti-
thrombotic drugs with INR, aPTT and platelet count during study drug treatment and make 
a timely decision on whether to continue or stop such drugs in patients that report Grade ≥2 
haemorrhagic events at any site, based on an individual assessment of the risk-benefit 
balance (See Appendix J for additional information on the clinical management of severe 
or serious haemorrhagic AEs). 
Patients that develop arterial thromboembolic events should discontinue the study drug.  
If a patient suffers a venous thromboembolic event while still receiving study drug, it may 
still be possible for him or her to remain on study treatment under close monitoring and 
dose modification of study drug.  
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
5.3.2 
Excluded Therapies 
Any therapy intended for the treatment of cancer (with the exceptions as noted above), 
whether currently marketed or experimental, is prohibited.  This includes, but is not 
limited to, the following: chemotherapy, hormonal therapy, biologic therapy, radiotherapy, 
or herbal therapy. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage 
colony-stimulating factors, platelet simulating factors or erythropoietin are not allowed 
during the DLT observation period in the dose escalation phase. 
Concomitant use of acid-reducing agents (eg, proton pump inhibitors, histamine receptor 
antagonists, antacids) during the dose escalation phase should be avoided as those agents 
may interfere with identifying reliable MTD and/or RP2D. 
Concomitant use of medications that have a known risk of causing QT prolongation and/or 
torsade de pointes (see “combined” list at http://www.qtdrugs.org, with attention to those 
drugs listed as KR (“known risk”).  
Palliative radiation for symptom control is allowed provided it does not compromise tumor 
assessments of target lesions.  However, fruquintinib treatment should be suspended 
during the radiation period and not resumed until at least 7 days after radiation only after 
meeting the following criteria: 
 
Radiation related toxicities resolves to ≤Grade 2; 
 
No disease progression observed. 


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5.3.3 
Drug-Drug Interactions 
The potential of pharmacokinetic drug-drug interaction was tested in vitro.  Fruquintinib 
was not a substrate of efflux transporters.  Fruquintinib showed dose-dependent inhibition 
on P-gp and BCRP.  Based on the data for digoxin transport (mediated by P-gp) and 
estrone-3-sulfate transport (mediated by BCRP), the IC50 on P-gp and BCRP was estimated 
to be 4.60 and 1.29 µM, respectively. 
According to the present metabolism data, enzymes CYP3A4/5 play an important role in 
the metabolism of fruquintinib.  Fruquintinib had no marked inhibitory effects on CYPs 
1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 (IC50 >10 µM) and no induction of CYP1A2, 
 and CYP3A4 at the tested concentration of 10 µM.  No marked time-dependent 
inhibition was observed for CYPS 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. 
Substrates of P-gp and BCRP, and inducers and inhibitors of CYP3A4/5 should not be 
administered concomitantly with fruquintinib, unless investigators consider it necessary.  
In this case, efficacy reduction and toxicity increases resulting from the interaction should 
be closely monitored.  Examples of the medicines to avoid are listed in Appendix F. 


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6 
STUDY VISITS, ASSESSMENTS, AND METHODS 
6.1 Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before performing 
any study-specific screening tests or procedures.  Medical history and demographic 
information, including clinically significant diseases within the previous 5 years, oncology 
history (including cancer name, primary diagnosis date, stage of diagnosis, prior anti-
cancer therapies, and procedures) should be recorded in CRF.  Informed consent forms 
for patients who are not subsequently enrolled will be maintained at the study site.  All 
screening evaluations must be completed and reviewed by the investigator and the clinical 
monitor to confirm that patients meet all eligibility criteria before the first administration 
of fruquintinib. 
Please see the Study Flowchart provided in Appendix A for the schedule of screening and 
pre-treatment assessments.  Screening and pre-treatment tests will be performed within 
28 days of the first dose of study drug, unless otherwise specified.  Results of standard of 
care tests performed prior to obtaining informed consent and within 28 days prior to study 
entry may be used (except hematology, coagulation tests, clinical chemistry, or urinalysis 
results). 
6.2 Assessments During Treatment Phase 
All visits must occur within ± 3 days (± 1 day during cycle 1) from the scheduled date, 
unless otherwise noted (see Appendix A).  All assessments will be performed on the day 
of the specified visit unless a time window is specified.  Please see the Study Flowchart 
provided in Appendix A for the schedule of treatment period assessments. 
If scheduled study assessments cannot be obtained because of a holiday, assessments 
during Cycle 1 should be done either prior to or immediately after the schedule interruption, 
regardless of the proximity to the next scheduled visits.  If assessments cannot be obtained 
due to a holiday for any other cycle, these assessments should be obtained at the soonest 
following date, unless the soonest following date is within 7 days of other, regularly 
scheduled study assessments. 
If during the DLT assessment window, 2 or more patients in a single cohort experience the 
same study drug-related Grade 3 toxicity that does not otherwise qualify as a DLT, the 
patients subsequently enrolled to this dose level and to the subsequent dose level will 
undergo increased monitoring during Cycle 1, as clinically indicated.  Note: DLTs will 
not be collected during the Dose Expansion Phase. 
6.3 Safety Assessments  
6.3.1 
Vital Signs Assessment 
Vital signs will include measurements of body temperature, heart rate, respiratory rate, and 
systolic and diastolic blood pressure while the patient is in a seated position.  The patient 
should be seated for approximately 5 minutes before the measurement of the blood pressure.  
For patients with a baseline history of hypertension, or those who develop hypertension 
during the study, blood pressure should be monitored daily by the patient at home, at 


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3 hours (±2 hours) after the daily doses of anti-hypertensive medication, and the results 
recorded in a blood pressure diary.  Patients monitoring their blood pressure should bring 
their diary to each study visit. 
6.3.2 
Physical Examination 
A complete physical examination at screening should include the evaluation of head, eye, 
ear, nose, and throat; and cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. 
At subsequent visits, a limited physical examination will be performed to assess changes 
from baseline abnormalities, any new abnormalities, and to evaluate patient-reported 
symptoms.  New or worsened abnormalities should be recorded as AEs if appropriate.  
In order to assess changes from baseline and screen for new abnormalities, the limited 
physical examination should assess for new or changed skin lesions, enlarged lymph nodes, 
and palpable masses.  Patient-reported symptoms should be directed to address the 
symptoms. 
Body height will be measured only at screening. 
6.3.3 
Laboratory Tests  
Samples for hematology, serum chemistry, urinalysis pregnancy, thyroid function, and 
specific tumor marker testing will be analyzed at the study site’s local laboratory.  
Laboratory assessments will include the following: 
Hematology (complete blood count [CBC], including red blood cell [RBC] count, 
hemoglobin, hematocrit, reticulocyte count, white blood cell [WBC] count with differential 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet 
count; INR and aPTT); 
Serum chemistry (blood urea nitrogen [BUN], creatinine and creatinine clearance, sodium, 
potassium, chloride, bicarbonate, calcium, magnesium, phosphorus, glucose, triglycerides, 
total bilirubin, total cholesterol, ALT, AST, alkaline phosphatase (ALP), lactate 
dehydrogenase [LDH], uric acid, total protein and albumin); 
Serum pregnancy test at screening and at the Treatment Completion Visit for all women of 
childbearing potential, including those who have had a tubal ligation; 
Urine pregnancy test at each day 1 visit, starting at Cycle 2 Day 1, for all women of 
childbearing potential, including those who have had tubal ligation; 
Urinalysis (pH, glucose, protein, and blood); 
Thyroid function (thyroid stimulating hormone [TSH], free T3, and free T4); and 
Specific tumor markers (tumor markers to be collected will be addressed in Section 6.4) 
The normal value range of laboratory examination indicators at the study site’s local 
laboratory will be collected prior to the study.  
6.3.4 
Cardiac Monitoring 
Left ventricular ejection fraction (LVEF) assessed via echocardiogram and 12-lead ECGs 


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are required to be performed as scheduled; ECG shall be performed pre-dose and at 3 hours 
(+ 15 minutes) post fruquintinib dose on Days 1 and 15 in Cycle 1.  ECG will be 
conducted on Day 1 of each cycle from Cycle 2 and onward.  QTcF interval should be 
calculated and be closely monitored.  See Appendix A.  MUGAs are permitted if 
echocardiograms cannot be performed. 
Test results will be reviewed by the investigator to determine patient eligibility at screening.  
Additional tests and other cardiac monitoring should be performed as clinically indicated 
during the study. 
6.4 Efficacy Assessments  
Tumor Assessment 
All measurable and evaluable lesions should be assessed and documented at screening and 
re-assessed at each subsequent tumor evaluation (see Appendix A).  Assessments should 
include computed tomography (CT) scans with oral or IV contrast (unless contraindicated) 
of the chest, abdomen, and pelvis.  MRI scans are allowed if CT contrast is 
contraindicated.  Other methods of assessment should be utilized as clinically indicated. 
Tumor assessments for dose escalation cohorts, Dose Expansion Cohort C, Dose 
Expansion Cohort D, and Dose Expansion Cohort E are scheduled at Screening and 
every 8 weeks (±1 week) thereafter, ie, C3D1, C5D1, C7D1, etc. (odd-numbered cycles).  
Tumor assessments for Dose Expansion Cohort A and Dose Expansion Cohort B are 
scheduled at Screening, C2D1, C3D1, C4D1, and every 8 weeks (±1 week) thereafter, ie, 
C6D1, C8D1, C10D1, etc. (even-numbered cycles). 
Subjects who permanently discontinue study drug for reasons other than progression of 
disease should continue to be followed for efficacy according to the schedule in 
Appendix A. 
All subjects are to have tumor assessments performed at the Treatment Completion visit, 
unless the subject was discontinued from treatment because of disease progression or the 
subject had tumor assessments performed within 14 days of the last dose of study drug. 
At the investigator’s discretion, CT scans may be repeated at any time if progressive 
disease is suspected. 
Disease status will be assessed using RECIST Version 1.1 (see Appendix C).  The same 
imaging procedure used to define measurable lesions at baseline must be used throughout 
the study for each patient. 
At the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST may be used.  Examples of other assessment methods include tumor markers, 
such as prostate-specific antigen (PSA) and cancer antigen 125 (CA-125) levels for patients 
with prostate and ovarian cancer, respectively.  However, tumor markers alone cannot be 
used to assess response.  If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete response. 
6.5 Study Completion/Early Termination Visit 
Patients who complete the study or discontinue study drug will be asked to return to the 


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clinic at 30 (± 7) days after the decision to permanently discontinue treatment with 
fruquintinib.  Ongoing AEs will be followed until the event has resolved to baseline grade, 
the event is assessed as stable by the investigator, new anti-tumor treatment is initiated, the 
patient is lost to follow-up, the patient withdraws consent, or when it has been determined 
that the study treatment or participation is not the cause of the AE. 
Please see the Study Flowchart provided in Appendix A for assessments to be performed 
at the study completion or early termination visit. 


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7 
SAFETY PLAN 
Patients will be evaluated clinically and with standard laboratory tests before and at regular 
intervals during their participation in this study.  Safety evaluations will consist of 
medical interviews, recording of AEs, physical examinations, and laboratory 
measurements. 
Except as noted in the current edition of the Investigator’s Brochure, no other special 
warnings or precautions are appropriate.  
7.1 Adverse Events  
7.1.1 
Adverse Events  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product or other protocol-imposed intervention, 
whether or not considered related to the medicinal product. 
Adverse events will be assessed according to the NCI CTCAE v4.03. 
7.1.2 
Reporting of Dose Limiting Toxicity 
Investigators are required to report DLT events to the Sponsor within 48 hours of first 
awareness, during the dose escalation stage.  The communication must include an email 
that describes the event and indicates which DLT criterion was met (see Section 3.1.1 c, 
Definition of a Dose-Limiting Toxicity).  The Sponsor’s medical monitor must confirm 
that the event meets the DLT definition and communicate this back to the investigator by 
email.  A notification of each DLT event will be distributed by email to all investigators 
shortly after confirmation.  DLT events are again reviewed together with other safety data 
and PK data, at the SRC meeting upon completion of the DLT window of each dose cohort. 
NOTE:  Reporting of DLTs is not required during the dose expansion phase. 
7.1.3 
Serious Adverse Events and other AEs that require Expedited Reporting 
7.1.3.1 Serious Adverse Event Definition 
A serious adverse event (SAE) is any AE that has any of the following characteristics: 
• Fatal (ie, the AE actually causes or leads to death, except for deaths caused by the 
progress of disease) 
• Life threatening (ie, the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
• Requires or prolongs inpatient hospitalization (excluding emergency or outpatient 
treatment) 
• Results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 


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• A congenital anomaly/birth defect in a neonate/infant born to a female patient or 
female partner of a male patient exposed to the investigational product(s) 
• Considered as a significant medical event by the investigator (eg, may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
• If an AE meets any of the above serious criteria, the AE should be reported to the 
sponsor as an SAE no more than 24 hours after awareness of the SAE. 
7.1.3.2 Potential Drug-Induced Liver Injury  
The investigator is required to discontinue study drug immediately and 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.  
• Serum AST or ALT ≥3 × ULN together with total bilirubin ≥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 Hy’s law is met, fruquintinib should be immediately discontinued, and patients 
need to be very closely monitored (bilirubin, ALP, AST, ALT measured 2-3 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.  
7.1.3.3 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. 
The management of severe or serious hemorrhagic events will be conducted according to 
Appendix J. 
7.1.4 
Adverse Events Reporting Period 
After informed consent, but prior to initiation of study drug, all SAEs regardless of 
attribution will be collected. 
After initiation of study drug, all AEs and SAEs, regardless of attribution will be collected 
until 30 days following the last dose of study drug or a new treatment of anti-tumor therapy, 
whichever is earlier.  After this period, investigators should report only SAEs that are 


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considered to be related to the study drug. 
7.1.5 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
7.1.6 
Assessment of Severity  
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs 
and SAEs, whether reported by the patient or noted by authorized study personnel, will be 
recorded in the patient’s medical record and on the appropriate AE/SAE form. 
For each AE and SAE recorded on the applicable CRF, the investigator will make an 
assessment of severity through clinical description by referring to the five-grade 
determination standard in the NCI CTCAE v4.03.  Please use the guideline below for the 
assessment of severity when the observed or reported AE is not listed in the NCI CTCAE 
v4.03: 
• Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)*. 
• Grade 3: severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**. 
• Grade 4: life-threatening consequences; urgent intervention indicated. 
• Grade 5: death related to AE. 
 
 


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Activities of Daily Living 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
7.1.7 
Causality of Adverse Events 
The investigator will assess causal relationship between study drug and each AE.  
For SAEs, a causal relationship will also be assessed for concomitant medications, study 
procedures and additional study drug, etc.  A guideline to the interpretation of causality is 
provided in Appendix G. 
7.1.8 
Recording Adverse Events 
When an AE or SAE is recorded, the preferred medical terminology or concept should be 
used.  Abbreviations and colloquialisms (eg, jargon or slang) should be avoided.  All 
AEs (including SAEs) should be recorded in the CRF on the AE page. 
All AEs (including SAEs) would be recorded on the AE CRF, and the check box for 
“Serious” would be ticked for entries that fit the criteria for SAEs.  The investigator would 
also complete an SAE report and submit this to the sponsor or its designee within 24 hours 
of knowledge of the event.  
Only one medical concept should be recorded in the event field on the CRF. 
7.1.8.1 Diagnosis vs Symptoms and Signs 
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (eg, record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE on the CRF.  If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
7.1.8.2 Adverse Event Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause with the exception of severe or serious 
secondary events.  For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF if the 
dehydration is mild.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF.  For example, if 
a severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately on the CRF. 


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7.1.8.3 Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the CRF.  The 
event’s initial severity should be recorded and updated when it increases so as to record to 
highest severity. 
A recurrent AE is one that occurs, resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on the CRF respectively. 
7.1.8.4 Abnormal Laboratory Values or Abnormal Vital Signs 
Not every laboratory abnormality/abnormal vital sign qualifies as an AE.  A laboratory 
test result/abnormal vital sign must be reported as an AE if it is a change from baseline and 
meets any of the following criteria:  
• Accompanied by clinical symptoms  
• Results in a change in study treatment (eg, dosage modification, treatment 
interruption, or treatment discontinuation)  
• Results in a medical intervention (eg, potassium supplementation for hypokalemia) 
or a change in concomitant therapy  
• Clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all laboratory findings and abnormal vital 
signs.  Medical and scientific judgment should be exercised in deciding if an isolated 
laboratory abnormality should be classified as an adverse event. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, 
ALP and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (eg, 
cholecystitis) needs to be recorded on the CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF.  If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE.  For example, an elevated serum potassium level of 
7.0 mmol/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, 
seriousness, or etiology changes.  
7.1.8.5 Death 
Deaths that occur during the protocol-specified AE reporting period that are attributed by 
the investigator solely to progression of disease should not be reported as AE/SAE.  All 
other on-study deaths, regardless of relationship to study drug, must be recorded on the AE 
CRF and immediately reported to the sponsor.  When a death is recorded, the underlying 
condition that caused or primarily contributed to the fatal outcome should be reported 
expeditiously as an SAE and death listed as the outcome of the event on the CRF.  If the 
primary cause of death is unknown and cannot be ascertained at the time of reporting, 


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please record “Unknown cause of death” on the AE CRF, and “unexplained/unknown death” 
should be expeditiously reported as a SAE before further investigations into the specific 
cause of death.  If the death is attributed to progression of disease, it should not be 
recorded or reported as an AE/SAE but the investigator will record the death on the End of 
Treatment and End of Study CRFs as appropriate.  
7.1.8.6 Preexisting Medical Condition 
A preexisting medical condition is one that is present at screening.  Such conditions 
should be recorded on the CRF as medical history.  A preexisting medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study (excluding deterioration of the study disease 
conditions).  When such events are recorded on the CRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors (eg, 
“more frequent headaches”). 
7.1.8.7 Hospitalization, Prolonged Hospitalization, or Surgery 
The investigator must document any AE that results in hospitalization or prolonged 
hospitalization unless the patient is hospitalized for 1 or more of the following reasons: 
• To undergo an efficacy measurement for the study 
• To undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
• To receive scheduled therapy for the target disease of the study 
In addition, hospitalization due solely to the progression of underlying advanced solid 
tumors should not be reported as a SAE. 
7.1.8.8 Pregnancy 
A female patient must be instructed to stop taking the study drug and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should report 
all pregnancies within 24 hours to the sponsor (the reporting period for pregnancy 
continues up to 30 days after completion of the study drug).  The investigator should 
counsel the patient and discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Pregnancies occurring up to 30 days after the completion of the study drug 
must also be reported to the investigator. 
Male patients must also be instructed to inform the investigator immediately if their partner 
becomes pregnant during the study or within 90 days after the last dose of study drug.  If 
such an event occurs, it should be reported as described above. 
Spontaneous abortion should always be classified as serious (as the sponsor considers these 
medically significant), recorded on the CRF, and expeditiously reported to sponsor. 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to the investigational product should be recorded and reported as 
an SAE. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
7.1.8.9 Worsening of Solid Tumor 
Worsening and/or progression of the patient’s solid tumor should not be recorded as an AE 
or SAE.  These data will be captured as efficacy assessment data only.  If there is any 
uncertainty about an AE being related only to the disease under study, it should be reported 
as an AE or SAE. 
7.2  Expedited Reporting Requirements 
Certain events require immediate reporting to allow the sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events (both initial and follow-up) to the sponsor immediately; under no 
circumstances should reporting take place more than 24 hours after the investigator learns 
of the event.  The following is a list of events that the investigator must report to the 
sponsor within 24 hours after first learning of the event, regardless of relationship to study 
drug: 
• Serious adverse events (from informed consent to 30 days following the last dose 
of study drug or a new treatment of anti-tumor therapy) 
• Potential DILI events, regardless of seriousness 
• Severe hemorrhagic events (NCI CTCAE Grade ≥3), regardless of seriousness 
• Pregnancies 
• SAEs occurring beyond the above-mentioned time limit (30 days after the 
discontinuation of the study drug), if considered related to the study investigational 
drug, should also be reported to the sponsor.  
7.3 Duration of Follow-Up for Adverse Events  
The investigator will follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the patient is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE.  Resolution of AEs and SAEs (with dates) 
should be documented on the appropriate CRF and in the patient’s medical record to 
facilitate source data verification (SDV).  For SAEs, if, after follow-up, return to baseline 
status or stabilization cannot be established, an explanation should be recorded in the 
additional case details section of the CRF. 
For some SAEs, additional case details deemed necessary to evaluate the SAE report (eg, 
hospital discharge summary, consultant report, or autopsy report) appropriately may be 
followed-up by telephone, fax, email, and/or a monitoring visit to obtain. 
All pregnancies that occur during the study should be followed until pregnancy outcome.  


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
8 
STATISTICAL ANALYSIS  
All statistical analysis will be performed under the direction of Hutchison MediPharma 
personnel. 
The final analysis of study data will be based on all patient data up to the time when either 
all patients have discontinued the study or the study has been terminated.  Details of the 
statistical analysis and data reporting will be provided in the Statistical Analysis Plan (SAP) 
document finalized prior to database lock. 
Data will be summarized using descriptive statistics (continuous data) and/or contingency 
tables (categorical data) for demographic and baseline characteristics, efficacy 
measurements, safety measurements, and PK measurements.  Information regarding 
compliance with disease assessments and availability of data will be documented.  
Graphical techniques (eg, waterfall plots, Kaplan-Meier curves) will be used when such 
methods are appropriate and informative.  The baseline value used in each analysis will 
be the last (most recent) pre-treatment value.  Analyses will be based upon the observed 
data unless methods for handling missing data are specified.  Analyses will be performed 
using SAS® (Version 9.1 or higher). 
8.1 Analysis Populations 
The following analysis populations are defined for the study: 
• Safety Analysis Set (SAS): This population includes all patients who have received 
at least one dose of fruquintinib.  Safety data will be evaluated based on this 
population’s outcome.  Patients in the SAS will be analyzed by their actual dose 
initially received.  If patients have dose reduction during the study, all data will be 
summarized/analyzed based on the initial dose of study drug received.   
• Pharmacokinetic Analysis Set (PKAS): This population will include all patients 
who received at least one dose of fruquintinib and have at least 1 PK sample 
obtained and analyzed. 
• Efficacy Analysis Set (EAS): This population includes all patients who have 
received at least 1 dose of fruquintinib and have at least 1 post-baseline tumor 
assessment.  All efficacy endpoints will be analyzed based on this analysis set. 
8.2 Analysis of the Conduct of the Study 
A patient listing of all treated patients will be generated to describe site, patient number, 
screening date, first dosing date, duration of study treatment, analysis set in which the 
patient is included and disposition.  In the patient disposition listing, reason for study drug 
discontinuation will be included.  A table will be created to summarize these categories 
in terms of number and percent for each of the analysis set defined above. 
Patient demographics and baseline characteristics, such as age, sex, race/ethnicity, weight, 
type of malignancy, duration of malignancy, site of metastatic disease, and baseline ECOG 
performance status, will be listed and summarized.  All summaries will be presented 
overall, by dose level, and by tumor specific cohorts. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Major protocol deviations related to study inclusion or exclusion criteria, conduct of the 
trial, patient management, or patient assessment will be listed. 
Study drug administration data will be listed by dose level, and any dose modifications will 
be flagged.  Descriptive information will be provided regarding number of cycles, total 
duration of study drug exposure, actual duration of study drug taken, cumulative dose of 
study drug, dose intensity and relative dose intensity and the number and timing of 
prescribed dose reductions and interruptions.  
8.3 Safety Analysis 
Safety will be assessed through AEs, laboratory assessments, vital signs, and ECG results.  
Safety data will be listed and summarized by dose cohort across the 2 phases.  All DLT 
events will be listed by dose cohort for the dose escalation phase only. 
Severity of AEs will be graded by the investigator according to NCI CTCAE v4.03.  If a 
CTCAE criterion does not exist, the grade corresponding to the appropriate adjective will 
be used by the investigator to describe the maximum intensity of the adverse event: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) 
(see Section 7.1.6).  All AEs will be coded with Medical Dictionary for Drug Regulatory 
Activities (MedDRA).  
All AEs will be listed.  The focus of safety data summarization will be on treatment-
emergent adverse events (TEAEs), which are defined as AEs that occur or worsen in the 
period extending from the first dose of study drug to 30 days after the last dose of study 
drug in this study. 
TEAEs will be summarized as the number of patients and corresponding percentage by 
MedDRA System Organ Class (SOC) as well as Preferred Term (PT).  The incidence of 
TEAEs, SAEs, adverse events of special interest (AESIs), AEs leading to dose interruption, 
reduction, or treatment discontinuation will be presented by SOC and PT; by relationship 
to the investigational product and by toxicity grade for each dose level.  Changes in 
laboratory data will be summarized by severity grade using the NCI CTCAE v4.03.  
When abnormal laboratory results at the patient level are counted, the worst value during 
study treatment will be chosen.  
8.4 Pharmacokinetic Analysis 
Data of plasma concentration versus time are analyzed for PK parameters using the non-
compartmental model by WinNonlin enterprise version software.  The mean value, 
standard deviation, coefficient of variation (CV%), median value, minimum value, 
maximum value, geometric mean value and geometric mean CV% will be reported. 
Individual and mean plasma fruquintinib concentration versus time data will be tabulated 
and presented.  The individual and mean PK parameters based on the fruquintinib 
concentration versus time data, will include, but not be limited to total plasma exposure 
(AUC0-t and AUC0∞∞-∞), maximum plasma concentration (Cmax), apparent clearance 
(CL/F), and apparent volume of distribution (Vz/F).  The terminal half-life (t1/2) will also 
be estimated.  The actual times of plasma sample collection will be used for the PK 
analysis. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
The methods for calculating pharmacokinetic parameters of fruquintinib: 
• Cmax: the maximum observed plasma concentration over the sampling period, taken 
directly from the data.  
• Tmax: time to reach Cmax, taken directly from the data.  
• The first-order rate constant associated with the negative slope of the terminal 
portion of the log-linear concentration-time curve.  A minimum of three points 
will be used. 
• Area under the plasma concentration versus time curve (AUC) to be determined by 
the trapezoidal rule (linear up/log down), where AUC0-t is the AUC from time zero 
until the last concentration point and AUC0∞∞-∞ is the AUC0-t + last concentration 
point divided by elimination rate constant (Ke). 
• Half-life (t1/2) to be determined according to t1/2 = 0.693/Ke where possible. 
• CL/F: apparent systemic clearance to be determined according to dose/AUC0∞∞-∞ 
• Vz/F: apparent volume of distribution, determined according to CL/F/Ke 
• Accumulation ratio: AUCDay14/AUCDay1 or AUCDay21/AUCDay1 
Where the concentration data are missing or listed as less than the lower limit of 
quantification, they will be regarded as zero (0) if occurring before Cmax.  After Cmax, zero 
points will not be included in calculations. 
Individual and mean fruquintinib concentrations will be plotted by dose level.  
Pharmacokinetic analysis of fruquintinib and its metabolites will be performed using the 
same technology. 
Venous blood samples for determination of concentrations of fruquintinib in plasma will 
be taken at the times presented in Appendix D.  If dose interruption occurs more than 
5 days (including 5 days) of PK sampling, the blood taking should be cancelled or at 
investigator’s discretion.  The date and time of collection of each sample and the date and 
time of dose will be recorded. 
8.5 Efficacy Analysis 
The efficacy endpoints include PFS, ORR, DCR, and OS.  Efficacy data will be listed and 
summarized by dose cohort and disease type. 
The ORR and DCR will be summarized with percentages and 95% exact confidence 
intervals.  The PFS rate at week 12 (Cohorts B and C) and week16 (Cohorts D and E) and 
its 95% confidence intervals will be estimated by the Kaplan-Meier method.  PFS, DoR, 
and OS will be summarized descriptively using Kaplan-Meier medians and quartiles.  
Percentage change in tumor size from baseline will be determined for patients with 
measurable disease at baseline and derived at each visit by the percentage change in the 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
sum of the diameters of target lesions (TLs) compared to baseline.  Best percentage 
change in tumor size will be summarized using descriptive statistics and presented using a 
waterfall plot. 
Objective Response Rate (ORR) 
The ORR is defined as the percentage of patients with at least one best overall response 
(BOR) of CR or PR according to RECIST Version 1.1.  To be assigned a status of PR or 
CR, changes in tumor measurements must be confirmed by repeat assessments performed 
no less than 4 weeks after the criteria for response are first met.  
The BOR in an individual patient according to the RECIST criteria is the best response 
recorded from the start of treatment until documented RECIST progression or the date of 
any further anticancer therapy, whichever comes first.  In the case of a patients without 
documented progression or additional anticancer therapy, BOR is determined using all 
available visit up until the last evaluable visit response. 
Disease Control Rate (DCR) 
Disease control rate is defined as the percentage of patients with a best overall response of 
CR, PR, or SD. 
Progression Free Survival (PFS) 
Progression free survival is defined as the time from date of first dose of study drug until 
the date of an objective disease progression as defined by RECIST v1.1 or death due to any 
cause. 
Patients who have not objectively progressed or died by the date of the analysis cut-off or 
received any further antitumor therapy will be censored at the time of the last evaluable 
objective tumor assessment before the cut-off date or the antitumor therapy start date. 
Progression-free survival rate is defined as the percentage of patients without evidence of 
progression or death at specific time points, such as week 12 (cohorts B and C), week 16 
(cohort D and E) on study. 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
Duration of Response (DoR) 
Duration of response is defined as the time from date of the first objective response, CR or 
PR, whichever comes first, until the occurrence of documented disease progression or 
death in the absence of disease progression.  If a patient does not progress following a 
response, then the DoR will be censored at the same time of PFS. 
Percentage Change in Tumor Size from Baseline 
Percentage change in tumor size will be determined for patients with measurable disease 
at baseline and is derived at each visit by the percentage change in the sum of the diameters 
of target lesions compared to baseline. 
Overall Survival (OS) 
Overall survival is defined as the time from the date of the first dose of study drug until the 
date of death (any cause).  Patients who did not die at the time of the statistical analysis 
will be censored at the time at which they were last known to be alive. 
8.6 Determination of Sample Size 
The total number of patients enrolled will depend on the number of dose escalations and 
the need to further characterize individual cohorts of single-agent fruquintinib administered 
at the RP2D. 
Dose Escalation Phase 
The sample size may vary depending on the number of dose levels evaluated and the 
number of DLTs observed in each cohort.  Patients who are considered not evaluable for 
DLT or PK will be replaced.  The sample size may increase when these patients are 
replaced. 
Dose Expansion Phase 
The primary objective of the dose expansion phase is to evaluate the anticancer activity of 
fruquintinib in patients with advanced solid tumors, treated at the RP2D from the dose 
escalation phase. 
Approximately 6 patients with advanced, refractory solid tumors of any type will be 
enrolled in Cohort A.  This sample size is not based on a formal statistical assumption. 
Additionally, enrollment in disease specific cohorts is planned as follows: 
• 40 patients in Cohort B (refractory mCRC with progression on TAS-102 and/or 
regorafenib)  
• 40 patients in Cohort C (refractory mCRC that has progressed on standard 
chemotherapies and relevant biologics but has NOT received TAS-102 or 
regorafenib)  
• 15 patients in Cohort D (HR+/Her2- mBC)  
• 15 patients in Cohort E [triple negative breast cancer (TNBC)]    
The number of patients in each cohort can provide adequate precision for the estimated 
incidence rates of patients having a specific AE, patients with CR/PR (ORR), patients with 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
CR/PR/SD (DCR), or PFS rate at a specific time point. 
Shown below in Table 15 and Table 16 are the range of incidence rates and the 
corresponding 95% Confidence Intervals (CI) for a sample size of 15 and 40 patients, 
respectively.  As shown in the table, the 95% CI is approximately equal to an estimated 
incidence rate of ±16% to 28% for a sample size of 15 patients and estimated incidence 
rate of ±7% to 16% for a sample size of 40 patients. 
Table 15 
 Estimated Incidence Rates and 2-Sided 95% Confidence Intervals for 
N=15 Patients 
Number of Cases 
Observed Incidence Rate 95% CI Lower Limit 95% CI Upper Limit 
0 
0 
0.00 
0.22 
3 
0.2 
0.04 
0.48 
6 
0.4 
0.16 
0.68 
9 
0.6 
0.32 
0.84 
12 
0.8 
0.52 
0.96 
15 
1 
0.78 
1.00 
95% Clopper-Pearson Interval for binomial distribution 
 
Table 16 
Estimated Incidence Rates and 2-Sided 95% Confidence Intervals for 
N=40 Patients 
Number of Cases 
Observed Incidence Rate 95% CI Lower Limit 95% CI Upper Limit 
0 
0 
0.00 
0.09 
4 
0.1 
0.03 
0.24 
10 
0.25 
0.13 
0.41 
20 
0.5 
0.34 
0.66 
30 
0.75 
0.59 
0.87 
40 
1 
0.91 
1.00 
95% Clopper-Pearson Interval for binomial distribution 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
9 
ETHICS 
9.1 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
This protocol, protocol amendment(s), the ICFs, any information to be given to the patient, 
and relevant supporting information must be submitted by the PI to the IEC/IRB for review 
and approval before the study is initiated.  In addition, any patient recruitment materials 
must be approved by the IEC/IRB. 
The PI is responsible for providing written summaries of the status of the study to the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) annually or more 
frequently in accordance with the regulatory requirements and policies and procedures 
established by the IEC/IRB.  Investigators are also responsible for promptly informing 
the IEC/IRB of any protocol changes or amendments and of any unanticipated problems 
involving risk to human patients or others. 
In addition to the requirements to report protocol-defined AEs to the sponsor or its designee, 
investigators are required to report promptly to their respective IEC/IRB all unanticipated 
problems involving risk to human patients.  Some IECs/IRBs may want prompt 
notification of all SAEs, whereas others require notification only about events that are 
serious, considered related to study drug, and unexpected. 
9.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of Helsinki. 
9.3 Patient Informed Consent 
The investigator or his/her representative will explain the nature of the study to the patient 
and answer all questions regarding this study.  Before any study-related screening 
procedures are performed on the patient, the ICF will be reviewed, signed, and dated by 
the patient and the person who administered the informed consent.  A copy of the signed 
informed consent document will be given to the patient and the original will be placed in 
the patient's medical record and must be available for verification by study monitors at any 
time.  If applicable, the ICF will be provided in a certified translation of the local language. 
The ICF should be revised whenever there are changes to procedures outlined in the 
document or when new information becomes available that may affect the willingness of 
the patient to participate. 
For any updated or revised ICFs, the case history for each patient shall document the 
informed consent process and that written informed consent was obtained from the patient 
for the updated/revised ICF for his/her continued participation in the study.  The final 
revised IEC/IRB-approved ICF must be provided to Hutchison MediPharma for regulatory 
purposes. 
Signed and dated ICFs must remain in each patient’s study file and must be available for 
verification by study monitors at any time. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
10 STUDY DOCUMENTATION, CASE REPORT FORM AND RECORDS 
10.1 
Source Data Verification 
Study monitors will perform ongoing source document verification to confirm that critical 
protocol data (ie, source data) entered into the CRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions that are 
certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of data entered 
into the CRFs must never be obliterated or destroyed. 
To facilitate source document verification, the investigator(s) and institution(s) must 
provide the sponsor direct access to applicable source documents and reports for trial-
related monitoring, sponsor audits, and IEC/IRB review.  The investigational site must 
also allow inspection by applicable regulatory authorities. 
10.2 
Use of Computerized System 
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record can 
serve as the source document if the system has been validated in accordance with FDA 
requirements pertaining to computerized systems used in clinical research.  An acceptable 
computerized data collection system (for clinical research purposes) would be one that (1) 
allows data entry only by authorized individuals; (2) prevents the deletion or alteration of 
previously entered data and provides an audit trail for such data changes (eg, modification 
of file); (3) protects the database from tampering; and (4) ensures data preservation. 
If a site’s computerized medical record system is not adequately validated for the purposes 
of clinical research (as opposed to general clinical practice), applicable hardcopy source 
documents must be maintained to ensure that critical protocol data entered into the CRFs 
can be verified. 
10.3 
Retention of Records 
US FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for Good Clinical 
Practice (GCP) require that records and documents pertaining to the conduct of this study 
and the distribution of investigational drug, including CRFs, consent forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 2 years after the last marketing application approval in an ICH region or after at least 2 
years have elapsed since formal discontinuation of clinical development of the 
investigational product.  All state and local laws for retention of records also apply.  No 
records should be disposed of without the written approval of Hutchison MediPharma.  
Written notification should be provided to Hutchison MediPharma for transfer of any 
records to another party or moving them to another location. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
11 MONITORING 
It is understood that the responsible Hutchison MediPharma monitor (or designee) will 
contact and visit the investigator regularly and will be allowed, on request, to inspect the 
various records of the trial (CRFs and other pertinent data) provided that patient 
confidentiality is maintained in accord with local requirements. 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout 
the study and to verify the adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF.  
The investigator (or deputy) agrees to cooperate with the monitor to ensure that any 
problems detected during these monitoring visits are resolved. 
12 DATA QUALITY 
The overall procedures for quality assurance of clinical study data are described in the 
sponsor or designee Standard Operational Procedures.  
Accurate and reliable data collection will be assured by verification and cross–check of the 
CRFs against the investigator’s records by the study monitor (source document 
verification], and the maintenance of a drug-dispensing log by the investigator.  
The sponsor or its agent will be responsible for data management of this study according 
to data management documents.  Any decision to use the CRF as a source document must 
be stated in the Data Validation Manual and the investigator must be advised of this 
decision.  A comprehensive validation check program will verify the data and discrepancy 
will be generated accordingly.  In the event of discrepant data, the sponsor or its agent 
will issue data queries to the site and request data clarification.  Site is required to respond 
to all queries and promptly enter date into the EDC system.  
The CRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the sponsor and records retention for the study data will 
be consistent with the sponsor’s standard procedures.  
In order to facilitate analysis of the biological samples collected in this study, the treatment 
code will be released to the responsible analytical person when the samples have been 
received at the analytical site and are ready for assay.  The result of the analysis must not 
be released with individual identification of the patient until the database is closed. 
12.1 
Assignment of Preferred Terms and Original Terminology  
For classification purposes, preferred terms will be assigned to the original terms entered 
in the CRF, using the most up to date version of MedDRA for AEs and diseases and World 
Health Organization (WHO) drug terms and procedures dictionary for treatments and 
surgical and medical procedures. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
13 USE OF INFORMATION AND PUBLICATION 
13.1 
Use of Information 
All information regarding fruquintinib and Hutchison MediPharma’s operations, such as 
Hutchison MediPharma’s patent applications, formulae, manufacturing processes, basic 
scientific data, or formulation information, supplied by Hutchison MediPharma and not 
previously published is considered confidential information. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by Hutchison MediPharma in connection with the 
development of fruquintinib.  This information may be disclosed as deemed necessary by 
Hutchison MediPharma or its designee to other clinical investigators, other pharmaceutical 
companies, and to the regulatory agencies.  To allow for the use of the information derived 
from this clinical study and to ensure complete and thorough analysis, the investigator is 
obligated to provide Hutchison MediPharma with complete test results and all data 
developed in this study and to provide direct access to source data/documents for trial-
related monitoring, audits, IEC/IRB review, and regulatory inspection. 
The investigator will maintain a confidential patient identification code list of all patients 
enrolled in the study (by name and patient number).  This list will be maintained at the 
site and will not be retrieved by Hutchison MediPharma or its designee. 
13.2 
Publication 
Core publication(s) will be authored by specified principal investigator(s) who contribute 
significantly to the implementation and conduct of the study and non-site personnel who 
contribute substantially to the design, interpretation, or analysis of the study (eg, Hutchison 
MediPharma or consultants).  Hutchison MediPharma scientists making significant 
contributions to the study will be included in the list of authors.  Hutchison MediPharma 
agrees that before it publishes any results of this study, it shall provide the investigator a 
pre-publication manuscript for review at least 30 days prior to the submission of the 
manuscript to the publisher. 
The investigators have the right to publish the results of the study, but with due regard to 
the protection of confidential information.  Accordingly, Hutchison MediPharma shall 
have the right to review and approve any paper for publication, including oral presentation 
and abstracts, which utilize data generated from this study.  At least 30 days before any 
such paper or abstract is presented or submitted for publication, a complete copy shall be 
given to Hutchison MediPharma for review.  Hutchison MediPharma shall review any 
such paper or abstract and give its comments to the author(s) promptly.  The investigator 
shall comply with Hutchison MediPharma’s confidential information in any such paper 
and agrees to withhold publication of the same for an additional 30 days in order to permit 
Hutchison MediPharma to obtain patent or other proprietary rights protection, if Hutchison 
MediPharma deems it necessary. 
This confidential information shall remain the sole property of Hutchison MediPharma, 
shall not be disclosed to others without the written consent of Hutchison MediPharma, and 
shall not be used except in the performance of this study. 
It is understood by the investigator that the information developed in the clinical study will 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
be used by Hutchison MediPharma in connection with the development of fruquintinib and, 
therefore, may be disclosed as required to other clinical investigators, other pharmaceutical 
companies, or to regulatory agencies.  It is understood that there is an obligation to 
provide Hutchison MediPharma with complete test results and all data resulting from this 
study and to provide direct access to source data/documents for study related monitoring, 
audits, IEC/IRB review, and regulatory inspection. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
14 REFERENCES 
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2. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr 
Rev 1997;18: 4−25. 
3. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 
2003; 9:669−76. 
4. Lee JC, Chow NH, Wang ST, et al. Prognostic value of vascular endothelial growth 
factor expression in colorectal cancer patients. Eur J Cancer 2000; 36:748−53. 
5. Takahashi Y, Kitadai Y, Bucana CD, et al. Expression of vascular endothelial growth 
factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation 
of human colon cancer. Cancer Res 1995;5 5:3964−8. 
6. Takahashi Y, Cleary KR, Mai M, et al. Significance of vessel count and vascular 
endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. 
Clin Cancer Res 1996; 2:1679−84. 
7. Maeda K, Chung YS, Ogawa Y, et al. Prognostic value of vascular endothelial 
growth factor expression in gastric carcinoma. Cancer 1996; 77:858−63. 
8. Berns EM, Klijn JG, Look MP, et al. Combined vascular endothelial growth factor 
and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-
positive advanced breast cancer. Clin Cancer Res 2003; 9:1253−8. 
9. Manders P, Beex LV, Tjan-Heijnen VC, et al. The prognostic value of vascular 
endothelial growth factor in 574 node-negative breast cancer patients who did not 
receive adjuvant systemic therapy. Br J Cancer 2002; 87:772−8. 
10. Fontanini G, Lucchi M, Vignati S, et al. Angiogenesis as a prognostic indicator of 
survival in non−small cell lung carcinoma: a prospective study. J Natl Cancer Inst 
1997; 89:881−6. 
11. Investigator’s Brochure for Fruquintinib  
12. Jin Li, Ruihua Xu, Y Bai et al. A randomized, double-blind, placebo-controlled, 
multicenter Phase 2 clinical trial of fruquintinib in patients with metastatic colorectal 
cancer (mCRC) ECCO abs # 2111 
13. Shun Lu, Jianhua Chang, Xiaoqing Liu et al. A Randomized, Multi-Center, Double-
Blind Phase II Study of Fruquintinib in Patients with Advanced Non-Small Cell 
Lung Cancer (NCT02590965). 17 World Conference on Lung Cancer #abs 4571 
14. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in 
patients with previously treated metastatic colorectal cancer: The FRESCO 
randomized clinical trial. JAMA 2018 Jun 26;319(24:2486-2496. 
15. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. 
Eribulin monotherapy versus treatment of physician's choice in patients with 
metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. 
Lancet 2011;377:914–23.  


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Protocol Number: 2015-013-00US1                                                        Version 4.0  
16. Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and 
safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced 
breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 
2007;25:3407–14.  
17. Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, et al. Phase III 
open-label randomized study of eribulin mesylate versus capecitabine in patients 
with locally advanced or metastatic breast cancer previously treated with an 
anthracycline and a taxane. J Clin Oncol 2015;33:594–601. 
 


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
Appendix A  
Study Schedule of Events 
          Date 
Procedure 
Screening 
Treatment2 
Treatment 
Completion3 
Follow-up 
Cycle 1 
Cycle 2-3 
Cycle 4 
and 
onwards 
 
Day -28 
to Day -
1 
Day -7 
to Day -
1 
Day 1 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 
22 
(±1d) 
Day 1 
(±3d) 
Day 
15 
(±3d) 
Day 1 of 
each 
subsequent 
cycle (±3d) 
 
30 (±7) days 
after permanent 
treatment 
discontinuation 
Every 12 (±2) weeks 
from Treatment 
Completion Visit 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
Tumor assessment 
(Dose Escalation, 
Expansion Cohorts 
C, D, E ) 
X 
 
Screening, then every 8 (±1) weeks thereafter ( eg C3D1, C5D1, 
C7D1, etc.)  
X4 
 
Tumor assessment 
(Dose Expansion 
Cohorts A and B 
only) 
X 
 
Screening, C2D1, C3D1 C4D1, and every 8 (±1) weeks thereafter 
(eg C6D1, C8D1, C10D1, etc.) 
X4 
 
Medical history, 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Vital signs6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete physical 
examination7 
 
X 
 
 
 
 
 
 
 
 
 
Limited physical 
examination7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Hematology8 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
          Date 
Procedure 
Screening 
Treatment2 
Treatment 
Completion3 
Follow-up 
Cycle 1 
Cycle 2-3 
Cycle 4 
and 
onwards 
 
Day -28 
to Day -
1 
Day -7 
to Day -
1 
Day 1 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 
22 
(±1d) 
Day 1 
(±3d) 
Day 
15 
(±3d) 
Day 1 of 
each 
subsequent 
cycle (±3d) 
 
30 (±7) days 
after permanent 
treatment 
discontinuation 
Every 12 (±2) weeks 
from Treatment 
Completion Visit 
Coagulation assay  
(aPTT, INR) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry panel9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis10 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Echocardiogram11 
X 
 
X (Every 12 weeks ± 1 week after the first dose) 
X 
 
Thyroid function 
test12 
X 
 
 
 
 
 
X 
 
X 
X 
 
Serum pregnancy 
tests 13 
 
X 
 
 
 
 
 
 
 
X 
 
Urine pregnancy 
tests13 
 
 
 
 
 
 
X 
 
X 
 
 
Specific tumor 
markers14 
Dose Escalation, 
Expansion Cohorts 
C, D, E) 
X 
 
Screening, then every 8 (±1) weeks thereafter: C3D1, C5D1, 
C7D1, etc  
 
 
Specific tumor 
markers14 
Dose Expansion 
Cohorts A and B 
only) 
 
 
Screening, C2D1, C3D1 C4D1, and every 8 (±1) weeks thereafter 
 
 
12-lead 
electrocardiogram15 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
PK plasma sampling 
 
 
PK samples are being collected on Days 1, 2, 14, and 15 of Cycle 
1 for Expansion Cohorts B, C, D, and E. Refer to Appendix D for 
 
 


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
          Date 
Procedure 
Screening 
Treatment2 
Treatment 
Completion3 
Follow-up 
Cycle 1 
Cycle 2-3 
Cycle 4 
and 
onwards 
 
Day -28 
to Day -
1 
Day -7 
to Day -
1 
Day 1 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 
22 
(±1d) 
Day 1 
(±3d) 
Day 
15 
(±3d) 
Day 1 of 
each 
subsequent 
cycle (±3d) 
 
30 (±7) days 
after permanent 
treatment 
discontinuation 
Every 12 (±2) weeks 
from Treatment 
Completion Visit 
specific timepoints 
Adverse event16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fruquintinib 
treatment 
 
 
Once daily, 3 weeks on/ 1 week off 
 
 
Survival follow up17 
 
 
 
 
X 
Note: 
1． A written informed consent form should be obtained prior to any protocol-specific procedure or test.  Tests completed within 28 
days prior to enrollment can be used for screening and do not need to be repeated (except hematology, coagulation test, clinical 
chemistry, or urinalysis results). 
2． Unless otherwise indicated, the visit window during the treatment period will be ± 3 days (± 1 day during cycle 1). 
3． Patients who complete or prematurely discontinue the study need to return to the study site for a follow-up at 30 (±7) days after 
the decision to discontinue treatment permanently.  Ongoing AEs will be followed until the event has resolved to baseline grade, 
the event is assessed as stable by the investigator, new anti-tumor treatment is initiated, the patient is lost to follow-up, the patient 
withdraws consent, or when it has been determined that the study treatment or participation is not the cause of the AE. 
4． The treatment completion visit tumor assessment can be omitted if treatment ended because of disease progression or the patient 
had a tumor assessment within 14 days prior to the last dose of study drug. 
5． Concomitant medication includes any prescribed or over-the-counter medicines.  All medication used by patients within 7 days 
before screening and 30 days after study treatment completion should be recorded.  At each visit, all medication used since the 
prior visit should be recorded. 


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
6． Vital signs include blood pressure, heart rate, respiratory rate, and temperature.  For patient with a baseline history of 
antihypertensive medications, blood pressure should be monitored at 3 hours (±2 hours) after the daily doses of anti-hypertensive 
medication. 
7． Please refer to Section 6.3.2 for the assessments that should be completed as part of the Complete and Limited Physical Exams. 
8． Hematology consists of complete blood count, including red blood cell count, hemoglobin, hematocrit, reticulocyte count, white 
blood cell count with differential (neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet 
count. 
9． The chemistry panel includes blood urea nitrogen, creatinine and creatinine clearance, sodium, potassium, chlorine, bicarbonate, 
calcium, magnesium, phosphorus, glucose, alanine aminotransferase, bilirubin (total), aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total cholesterol, triglycerides, uric acid, protein (total) and albumin. 
10． Urinalysis includes pH, glucose, protein, and blood.  A 24-hour urine should be collected from all patients with >1+ proteinuria 
for quantitative test of urine protein during the screening.  If protein ≥2+ during the period of study treatment, a 24-hour urine 
test should be conducted within 1 week. 
11． MUGAs are permitted if echocardiograms cannot be performed. 
12． Includes free T3, free T4, and thyroid-stimulating hormone (TSH). 
13． Women of childbearing potential will receive a serum pregnancy test during screening and within 30 days after treatment 
completion, and a urine pregnancy test on Day 1 of each 28-day cycle beginning at Cycle 2.  If pregnancy is suspected, additional 
tests should be completed.  In the case of menopausal women, the date of menopause onset should be recorded. 
14． CA125 level for patients with ovarian cancer, PSA for patients with prostate cancer, or other tumor markers (as appropriate) should 
be obtained as clinically indicated or with each tumor assessment. 
15． On Days 1 and 15 in Cycle 1, ECG should be performed at pre-dose and at 3 hours (± 15 minutes) post-dose (around Cmax after 
single dose and at steady state in order to evaluate concentration-QT relationship for fruquintinib).  Untimed ECG will be 
conducted on Day 1 of each cycle from Cycle 2 and onward. 
16． After informed consent, all SAEs and concomitant medications will be collected.  After initiation of study drug, all AEs and 
SAEs will be collected until 30 days following the last dose of study drug or a new treatment of anti-tumor therapy, whichever is 
earlier.  After this period, investigators should report only SAEs that are considered to be related to the study drug. 


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
17． For subjects in Expansion Cohorts B, C, D, and E - Survival follow-up (by telephone) should be performed every 12 (±2) weeks 
from the date of the Treatment Completion visit.  All subsequent anti-tumor therapy and information about ongoing or unresolved 
study drug-related SAEs will be collected.  For the patients that discontinue the study without PD, all available tumor assessment 
results during survival follow-up will be recorded in the CRF until confirmation of PD.  The date and cause of death should be 
recorded, if applicable.  Patients who withdraw consent are encouraged to be followed for survival.  If the patient has clearly 
expressed his/her refusal to be followed after withdrawal of consent, he/she will terminate the study and no survival follow-up will 
be performed. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix B  
ECOG Performance Status 
Grade 
Activity Level 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled cannot carry on any self-care, totally confined to bed or 
chair. 
5 
Death. 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix C  Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST Version 1.1) 
Quick Reference: 
http://ctep.cancer.gov/guidelines/recist.html 
 
Patient Eligibility  
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  Measurable disease is defined as the 
presence of at least one measurable lesion.  
In studies where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable 
disease only are also eligible.  
Methods 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 follow-up.  CT is the best 
currently available and reproducible method to measure lesions selected for response 
assessment.  MRI is also acceptable in certain situations (eg, for body scans but not 
for lung). 
• Lesions on a chest X-ray may be considered measurable lesions if they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
• Clinical lesions will only be considered measurable when they are superficial and 
≥10 mm in diameter, as assessed using calipers.  For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
• Ultrasound (US) should not be used to measure tumor lesions.  
• Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
response.  
• Cytology and histology can be used in rare cases (eg, for evaluation of residual masses 
to differentiate between Partial Response and Complete Response or evaluation of new 
or enlarging effusions to differentiate between Progressive Disease and 
Response/Stable Disease).  
• Use of endoscopy and laparoscopy is not advised.  However, they can be used to 
confirm complete pathological response.  
Baseline Disease Assessment  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Measurable lesions 
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have 
slice thickness >5 mm, the minimum size should be twice the slice thickness).  
• 10 mm caliper measurement by clinical exam (lesions that cannot be accurately 
measured with calipers should be recorded as non- measurable). 
• 20 mm by chest X-ray.  
Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  
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 can be 
considered measurable if the soft tissue component meets the definition of measurability 
described above.  
“Cystic lesions” thought to represent cystic metastases can be considered measurable 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.  
Non-measurable Lesions  
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with 10 to <15 mm short axis), 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, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.  Blastic bone 
lesions are non-measurable. 
Lesions with prior local treatment, such as those situated in a previously irradiated area or 
in an area treated with 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.  
Target Lesions  
• All measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements.  
• All measurements should be recorded in metric notation using calipers if clinically 
assessed.  


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
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 diameters, which will be 
used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  If lymph nodes are to be included in the sum, only the short 
axis will contribute.  
Non-target Lesions  
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be 
recorded at baseline.  Measurements of these lesions are not required and they should be 
followed as “present,” “absent,” or in rare cases, “unequivocal progression.” 
Evaluation of Target Lesions  
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.  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this may include the baseline sum).  The 
sum must also demonstrate an absolute increase of at least 5 mm.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD.  
Special Notes on the Assessment of Target Lesions  
Lymph nodes identified, as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  When lymph 
nodes are included as target lesions, the “sum” of lesions may not be zero even if complete 
response 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”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small.  However, sometimes lesions or lymph 
nodes become so faint on a CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being “too small to measure”, in which case a 
default value of 5 mm should be assigned. 
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 maximal longest diameter for the “coalesced lesion”. 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker levels.  All lymph nodes must be non-pathological in size (<10 mm short 
axis).  
Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker levels above normal limits.  
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  When 
patient has measurable disease, 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 such that, even in 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. 
When patient has only non-measurable disease:  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, a useful test that can 
be applied is to consider if the increase in overall disease burden based on change in non- 
measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease.  Examples include an increase in a pleural effusion 
from “trace” to “large” or an increase in lymphangitic disease from localized to widespread. 
New Lesions  
The appearance of new malignant lesions denotes disease progression:  
• The finding of a new lesion should be unequivocal (ie, not attributable to differences 
in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor, especially when the patient’s baseline lesions show 
partial or complete response).  
• 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.  
• A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and disease progression.  
It is sometimes reasonable to incorporate the use of 18F-fluorodeoxyglucose positron 
emission tomography (FDG-PET) scanning to complement CT 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:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is PD based on a 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD.  


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if 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).  
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.  
Time Point Response  
Below is a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline: Patients with target (+/– non-target) disease. 
 
Confirmation  
In non-randomized trials 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 trials.  However, in all other 
circumstances, (ie, in randomized phase 2 or 3 trials or studies where stable disease or 
progression are the primary endpoints), confirmation of response is not required since it 
will not add value to the interpretation of trial 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 6–8 weeks) that is defined in the study 
protocol.  
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (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 most likely happen in the case of 
PD.  
Reporting of Results  
• All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible.  Each patient 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
will be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
• All the patients who met the eligibility criteria should be included in the main analysis 
of the response rate. Patients in response categories 4-9 should be considered as failing 
to respond to treatment (disease progression).  Thus, an incorrect treatment schedule 
or drug administration does not result in exclusion from the analysis of the response 
rate. Precise definitions for categories 4-9 will be protocol specific. 
• All conclusions should be based on all eligible patients.  
• Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (eg, early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  
• The 95% confidence intervals should be provided.  
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix D  
Handling and Shipment of Pharmacokinetic Samples 
Blood samples will be taken for pharmacokinetic evaluation by cannula or direct 
venipuncture at the time points listed in Appendix D-1 (dose escalation phase) and 
Appendix D-2 (dose expansion phase).  The exact times and dates of blood sampling are 
to be recorded in the CRFs. 
Blood samples (2 mL) for fruquintinib pharmacokinetics will be collected into sodium 
heparinate vacutainers.  The tubes will be immediately inverted gently at least 5 times to 
mix the blood and then placed in ice bath prior to centrifugation.  The tubes will be 
centrifuged at approximately 1000 g and 4oC for 10 minutes, after which the plasma will 
be transferred immediately into 2 clean prelabeled tubes.  Approximately 0.5 mL plasma 
will be placed in each tube (Tube A and Tube B).  After the tubes are tightly capped, the 
samples should be stored immediately at -20°C or ˗80°C.  The whole process of plasma 
collection should be completed within 2 hours of the blood sampling.  According to the 
present results of plasma stability, fruquintinib can be stored at ˗20°C and at ˗80°C for 133 
days.  For long-term storage, it is recommended that the plasma samples be stored at 
˗80°C. 
Each sample will be identified by date of collection, study number, patient number and 
initials, and sample time point identifier (i.e. 30 minutes, 1 hour, 4 hours etc.).  Tube B 
samples must be labeled as “duplicate.” 
All plasma samples will be shipped on dry ice to the central laboratory within 30 days of 
sample collection.  The dry ice should be sufficient to keep the samples frozen during the 
whole shipment period.  The samples of Tube B are shipped out after the prior batch of 
Tube A has been received safely by the central laboratory.  Tube A samples will be used 
for bioanalysis.  Tube B samples will be stored in ˗80°C freezer for future use.  The 
laboratory should be notified at least 1 day prior to the arrival of the sample and be provided 
shipping details and tracking numbers for the shipment. 
Prior to shipment, a PK sample requisition form (containing the details of each 
sample/label identification included in the shipment) will be prepared.  All sample 
correspondence must contain the study number, study drug, and Site references (including 
emergency contact details and responsible shipment coordinator).  All of the sample 
details on this log must match the details included on the individual sample labels, as each 
sample label will be checked against the list by Centre Laboratories’ sample coordination 
personnel.  The log should be reviewed by the preparer and a second individual for 
accuracy and signed/dated by both individuals.  To avoid sample mix-ups or 
misidentification, the samples in the shipment will be sorted by patient number and sample 
time using segmented cartons. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Table D-2 PK Sampling Time Points (Dose Escalation Phase and Cohort A of Dose 
Expansion Phase) 
Visit Cycle 
Time Point 
Cycle 1, Day 1 
Pre-dose (≤10 minutes) 
Post-dose 1 hour ±±(± 5 minutes)  
Post-dose 2 hours ±±(± 15 minutes)  
Post-dose 4 hours ±±(± 30 minutes)  
Post-dose 8 hours ±±(± 60 minutes)  
Cycle 1, Day 2 
Pre-dose (≤10 minutes) 
Cycle 1, Day 14 
Pre-dose (≤10 minutes) 
Post-dose 1 hour ±±(± 5 minutes)  
Post-dose 2 hours ±±(± 15 minutes)  
Post-dose 4 hours ±±(± 30 minutes)  
Post-dose 8 hours ±±(± 60 minutes)  
Cycle1, Day 15 
Pre-dose (≤10 minutes) 
Cycle1, Day 21 
Pre-dose (≤10 minutes) 
Post-dose 1 hour ±±(± 5 minutes)  
Post-dose 2 hours ±±(± 15 minutes)  
Post-dose 4 hours ±±(± 30 minutes)  
Post-dose 8 hours ±±(± 60 minutes)  
Cycle 1, Day 22 
Post-dose 24 hours ±±(± 60 minutes) on Day 21 
 
 
Table D-2 PK Sampling Time Points (Cohort B, C, D, and E of Dose Expansion 
Phase) 
Visit Cycle 
Time Point 
Cycle 1, Day 1 
Pre-dose (≤10 minutes) 
Post-dose 1 hour ±±(± 5 minutes)  
Post-dose 2 hours ±±(± 15 minutes)  
Post-dose 4 hours ±±(± 30 minutes)  
Post-dose 8 hours ±±(± 60 minutes)  
Cycle 1, Day 2 
Pre-dose (≤10 minutes) 
Cycle 1, Day 14 
Pre-dose (≤10 minutes) 
Post-dose 1 hour ±±(± 5 minutes)  
Post-dose 2 hours ±±(± 15 minutes)  
Post-dose 4 hours ±±(± 30 minutes)  
Post-dose 8 hours ±±(± 60 minutes)  
Cycle1, Day 15 
Pre-dose (≤10 minutes) 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix E  
Prohibited Concomitant Medications that Have a Known Risk of QT 
prolongation and/or Torsades des Pointes (TdP) 
The list is continuously updated online at www.crediblemeds.org or www.qtdrugs.org  
Generic Name 
Brand Names (Partial List) 
Drug Class 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anticancer 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / Antiemetic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Cocaine 
Cocaine 
Local anesthetic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Domperidone 
Motilium, Motillium, Motinorm Costi, Nomit 
Antinausea 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic / Antiemetic 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-Tab, 
Eryc Ranbaxy, Erypar, Eryped, Erythrocin 
Stearate Filmtab, Erythrocot, E-Base, 
Erythroped, Ilosone, MY-E, Pediamycin, 
Zineryt, Abboticin, Abboticin-ES, Erycin, PCE 
Dispertab, Stiemycine, Acnasol, Tiloryth 
Antibiotic 
Escitalopram 
Cipralex, Lexapro, Nexito,  
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Fluconazole 
Diflucan, Trican 
Antifungal 
Haloperidol 
Haldol  
Antipsychotic 
Ibutilide 
Corvert 
Antiarrhythmic 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Methadone 
Dolophine, Symoron, Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, Emetron, 
Ondavell, Emeset, Ondisolv, Setronax 
Antiemetic 
Oxaliplatin 
Eloxatin 
Antineoplastic Agent 
Papaverine HCl 
(Intra-coronary) 
none 
Vasodilator, Coronary 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, Quinact, Quinidex, Cin-
Quin, Quinora 
Antiarrhythmic 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anticancer 
Source: www.crediblemeds.org or www.qt.drugs.org 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix F  
Fruquinitinib and Concomitant Medication 
Fruquintinib is not a substrate of efflux transporters.  Fruquintinib showed dose-
dependent inhibition on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). 
Based on the data for digoxin transport (mediated by P-gp) and estrone-3-sulfate transport 
(mediated by BCRP), the IC50 on P-gp and BCRP was estimated to be 4.60 and 1.29 µM, 
respectively. 
According to the present metabolism data, cytochrome P450 enzymes CYP3A4/5 play an 
important role in the metabolism of fruquintinib.  Fruquintinib had no marked reversibly 
inhibitory effects on CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 (IC50 >10 µM) and 
no induction of CYP1A2, 
 and CYP3A4 at the tested concentration of 10 µM.  
No marked time-dependent inhibition was observed for CYP1A2, 2B6, 2C8, 2C9, 2C19, 
2D6, and 3A4/5. 
A series of CYP3A4 strong inducers and strong inhibitors are listed in Tables F-1 and F2 
below.  Patients who received a CYP3A4 strong inducer or strong inhibitor within 
2 weeks (3 weeks for hyperforin perforatum treatment) prior to the first dose of the study 
drug will not be allowed to participate in the study. 
Typical substrates of P-gp and BCRP are listed in Table F-3 below.  During the study, 
substrates of P-gp and BCRP, and strong inducers and inhibitors of CYP3A4/5 are avoided 
to be administered concomitantly with fruquintinib, unless investigators consider it 
necessary.  In this case, efficacy reduction and toxicity increases resulting from the 
interaction should be closely monitored. 
Not all the medications are listed in the following tables.  Other drugs known to possibly 
affect CYP3A4 activity and to be substrates of P-gp and BCRP should be used with 
cautions.  When combining fruquintinib with other drugs the prescription information of 
all concomitant medications should be reviewed. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Table F-1 
Typical Strong Inhibitors of CYP3A4 
Strong Inhibitors of CYP3A4 
Boceprevir 
Clarithromycin 
Conivaptan 
Elvitegravir/Ritonavir 
Fluconazole 
Grapefruit juicea,b 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir/Ritonavir 
Mibefradil 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Tipranavir/Ritonavir 
Troleandomycin 
Voriconazole 
a 
Super-concentrated grapefruit juice 
b 
During the study, patients should not consume large amounts of grapefruit or lime (or products that 
include these fruits, such as grapefruit juice and orange jam). No more than one cup (120 mL) of 
grapefruit juice, half a grapefruit or a spoon full (15 g) of orange jam should be consumed each day. 
 
Table F-2 
Typical Strong Inducers of CYP3A4 
Strong Inducers of CYP3A4 
Avasimibe 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenobarbital 
Phenytoin 
Rifabutin 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Rifampicin 
Enzalutamide 
St. John’s wort 
 
Table F-3: Typical Substrates of P-gp and BCRP 
Substrates of P-gp 
Substrates of BCRP 
Aliskiren  
Ambrisentan  
Colchicine 
Dabigatran etexilate  
Digoxin  
Everolimus  
Fexofenadine  
Imatinib  
Lapatinib  
Maraviroc  
Nilotinib  
Posaconazole  
Ranolazine  
Saxagliptin  
Sirolimus  
Sitagliptin  
Talinolol  
Tolvaptan  
Topotecan 
Methotrexate  
Mitoxantrone  
Imatinib  
Irrinotecan  
Lapatinib  
Rosuvastatin  
Sulfasalazine  
Topotecan 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix G  
Guideline to Interpreting the Causality Question 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
• Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties? 
• Dechallenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug without treatment of the reported event? 
• No alternative cause.  The AE cannot be reasonably explained by another etiology, 
such as the underlying disease, other drugs, other host or environmental factors. 
• Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  HMPL would not normally recommend or support a 
rechallenge. 
• Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where 1 or more of these 
factors exist.   
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause 
of the AE. 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the drug? 
• Is there a known mechanism? 
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. 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix H  Clinical Evaluation of Possible Drug-Induced Liver Injury (DILI) 
If ALT or AST is elevated to higher than 3 x ULN and bilirubin is elevated to higher than 
2 X ULN, fruquintinib treatment should be discontinued immediately, and supportive 
treatment should be given. T his combination of lab abnormalities meets the biochemical 
criteria for Hy’s law, which is associated with a markedly increased possibility of severe 
drug-induced liver injury (DILI), and may progress to liver transplantation or death (FDA 
Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation.  
FDA, 2009). 
If the biochemical criteria for Hy’s law are met, fruquintinib should be immediately 
discontinued, and patients need to be very closely monitored (bilirubin, ALP, AST, and 
ALT measured 2-3 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. 
If the biochemical criteria for Hy’s Law have been met, expedited reporting is required 
(see Section 7.1.2), before waiting for the evaluation of other causes to be completed.  
 
Recommended Data Collection for Suspected DILI 
The investigator is recommended to obtain the following information, so as to further 
evaluate and follow up and complete the clinical data.  Data should be recorded on CRFs 
where possible, and supplemented by investigator reporting as text in the clinical database: 
• 
Medical history of the patient 
o Detailed history of current symptoms, diagnosis of complications and medical 
history 
o Previous medical history (viral hepatitis, alcoholic hepatitis, autoimmune 
disease, biliary tract disease and cardiovascular disease, etc.) 
o History of concomitant medication (including OTC and prescription drugs, 
herbal medicine and dietary supplements), alcohol consumption, recreational 
drugs and special diet 
o History of exposure to potentially hepatotoxic chemicals 
• 
Complete the following laboratory tests: 
o Haematology 
o Clinical biochemistry: ALT, AST, bilirubin (including total bilirubin and 
direct bilirubin), ALP, albumin, prothrombin time or INR, amylase, fasting 
blood glucose, cholesterol and triglycerides 
o Other Serum Tests: Hepatitis A (Anti-IgM and Anti-IgG), hepatitis B (HbsAg, 
Anti-HBs and HBV DNA), hepatitis C (Anti-HCV, and HCV RNA test is 
required for any patient with positive test result), hepatitis D (Anti-IgM and 
Anti -IgG), hepatitis E (Anti-HEV and Anti-HEV IgM). 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
• 
Complete appropriate auxiliary examination: 
o Patients with confirmed elevation of ALT/AST combined with TBili are 
required to receive abdominal ultrasonography or other clinically applicable 
imaging examination within 48 hours (to exclude biliary tract, pancreatic, or 
intrahepatic causes, such as new or worsening hepatobiliary metastases or 
biliary calculi) and obtain the liver imaging result as soon as possible. If an 
alternative cause (such as biliary tract, pancreatic, or intrahepatic causes) of 
abnormal hepatic results cannot be confirmed by imaging, paracentesis is 
recommended for pathological examination after obtaining consent of the 
patient;  
o If suspected cardiovascular causes exist, cardiac ultrasonography is 
recommended to exclude cardiovascular dysfunction (ie, right heart failure); 
Long-term follow-up: Perform close monitoring on the patient through repetitive tests of 
ALT, AST and bilirubin (including total bilirubin and direct bilirubin) two to three times 
weekly until the laboratory ALT and/or AST abnormality becomes stable or recovers, and 
then proceed according to the protocol.  
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix I 
Management of Hypertension in Patients Receiving Fruquintinib 
Hypertension is a common AE that has been reported in patients taking angiogenesis 
inhibitors (Izzedine, et al 2009[15]), including fruquintinib.  Grade 3 AEs have been 
reported in 16% of patients treated with fruquintinib; no Grade 4 events have been reported 
to date.  It appears that hypertension is a class-effect of VEGFR inhibitors (either 
antibodies or small molecules). 
There is no standard therapy for angiogenesis inhibitor-induced hypertension because there 
have not been any published controlled clinical trials with specific agents.  Therefore, one 
can take an approach based on the clinical characteristics of particular patients.  Calcium 
channel blockers and angiotensin converting enzyme inhibitors (ACEI) are a reasonable 
first choice in most cases.  For patients with proteinuria, chronic renal disease or 
metabolic disease, an ACE inhibitor or angiotensin II receptor blockers (ARB) may be 
preferred; for elderly patients, dihydropyridine calcium channel blockers may be preferred.  
In this appendix is a summary of the most recent American Heart Association 
(AHA)/American College of Cardiology (ACC) hypertension treatment guidelines.  A 
cardiologist may be consulted if appropriate. 
The objective of antihypertensive therapy in general is to control the blood pressure to a 
target level <140/90 mmHg.  For high-risk populations, such as patients with chronic 
renal disease and/or diabetes, it may be appropriate to aim for a target blood pressure < 
130/80 mmHg.  On the following two pages, please see a summary of the most recent 
AHA/ACC hypertension treatment guidelines. 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
 
 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Hypertension Guidelines From: Go A, Bauman M, Coleman King S, et al. An Effective Approach to High 
Blood Pressure Control. A Science Advisory from the American Heart Association, the American College of 
Cardiology, and the Centers for Disease Control and Prevention. J Am Coll Cardiol 2014; 63:1230-8 
 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix J 
Clinical Management of Severe or Serious Hemorrhagic Events  
If hemorrhagic events are evaluated as severe (CTCAE Grade ≥3) or serious adverse events, 
fruquintinib treatment should be discontinued or interrupted immediately, and appropriate 
treatment measures initiated to control bleeding (e.g. transfusion, radiologic, endoscopic, 
or elective operative intervention as indicated).  When the patient is not well enough to 
tolerate an invasive procedure or operation, best supportive care is given (see 
Section 5.2.2.1, Table 13, Dose Adjustment for Hemorrhage at any Site).  Patients need 
to be very closely monitored, both clinically (continuously), and by relevant laboratory 
testing (INR, aPTT, platelet count, hemoglobin) every 2-3 days until the results return to 
baseline or normal).  During the initial assessment, a focused history and physical 
examination, with collection of vital signs and laboratory evaluation and imaging 
evaluation should be obtained, aimed at determining the time of onset, location, severity of 
bleeding, and whether bleeding is ongoing.  Clinicians should be mindful of 
comorbidities 
and 
concomitant 
treatments 
(eg. 
anti-platelet 
therapy 
and/or 
thrombocytopenia, or liver disease) that could also contribute to bleeding and manage them 
as appropriate.  Consultation with other department clinicians should be considered when 
necessary. 
The investigator should closely monitor patients receiving anti-platelet and/or anti-
thrombotic drugs during study drug treatment and make a timely decision on whether to 
continue or stop such drugs in patients that report Grade ≥2 hemorrhagic events at any site, 
based on an individual assessment of the risk-benefit balance. 
If a hemorrhagic event is evaluated as a severe (CTCAE Grade ≥3) or serious adverse event 
after taking fruquintinib, the investigator is required to report the event in an expedited 
fashion (within 24 hours of first awareness) to sponsor (see Table 12 and Section 7.2 
Expedited Reporting Requirements).  
See the Management Flowchart below for guidance on the management of severe or 
serious hemorrhage at any site. 
Recommended Data Collection for Severe or Serious Hemorrhagic Events: 
The investigator is recommended to obtain the following information, so as to further 
evaluate and follow up and complete the clinical data.  Data should be recorded on 
SAE/AESI report form where possible, and supplemented by Bleeding Event Follow-Up 
Questionnaire: 
• Medical history of the patient 
o Detailed history of current symptoms, diagnosis of complications and medical 
history  
o Previous medical history  
o History of concomitant medication ( 
 Vitamin K antagonists (e.g. warfarin) 
 NSAIDs (e.g. aspirin) 
 Anti-platelet drugs (e.g. clopidogrel/glycoprotein GPIIb/IIIa 
inhibitors/dipyridamole) 
 Other anticoagulants (e.g. heparin/thrombolytics/SSRIs) 
 Food and herbal supplements with anticoagulant property 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
 Immunosuppressants 
 alcohol consumption 
 Recreational drugs and special diet  
o Family history of bleeding events 
• Complete the following laboratory tests: 
o Hematology: hemoglobin, platelet, hematocrit, reticulocyte count 
o Clinical biochemistry: bleeding time, prothrombin time, aPTT, INR  
• Complete appropriate auxiliary examination: 
o Patients with confirmed bleeding are required to receive upper or lower GI 
endoscopy, bronchoscopy or other clinically applicable procedure or 
radiologic imaging within 48 hours, to confirm the site of bleeding.  
o If suspected cardiovascular causes exist, cardiac ultrasonography is 
recommended to exclude cardiovascular dysfunction (ie, right heart failure).


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Protocol Number: 2015-013-00US1                                                                                                          Version 4.0 
Severe or Serious Hemorrhagic Events Management Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•
Closely monitor 
•
Interrupt study drug 
•
Initiate appropriate measures 
to control bleeding if 
necessary 
•
Closely monitor patients 
receiving anti-platelet and/or 
anti-thrombotic drugs during 
study drug treatment, and 
make a timely decision on 
whether to continue or stop 
such drugs in patients that 
t G
d ≥2 h
h
i
•
Fill in SAE/AESI form and expedited reporting of this hemorrhagic event to sponsor 
•
Complete the bleeding event follow up questionnaire when received from sponsor 
•
Continue monitoring 
•
Expedited reporting to 
sponsor if upgraded to 
severe or serious 
hemorrhagic event 
Hemorrhagic event meeting any of the criteria below: 
•
CTCAE grade ≥ 3 (severe AE) 
•
Serious adverse event 
•
CTCAE grade ≥2 and receiving anti platelet and/or anti thrombotic drugs during study drug treatment
Hemorrhage is severe (CTCAE grade ≥3) (regardless of 
whether or not it meets “serious” criteria) 
Hemorrhage is non-severe (CTCAE grade ≤ 2)  
Does the hemorrhagic event meet SAE criteria? 
•
Discontinue study drug immediately 
•
Initiate appropriate measures to control 
bleeding 
•
Closely monitor laboratory tests (INR, 
aPTT, platelet count, hemoglobin and 
blood pressure) every 2-3 days 
•
A focused history and physical 
examination, with collection of vital signs, 
and laboratory evaluation as appropriate 
•
Closely monitor patients receiving anti-
platelet and/or anti-thrombotic drugs 
during study drug treatment, and make a 
timely decision on whether to continue or 
stop such drugs in patients that report 
G
d
2 h
h
i
i
Grade=
Grade=
Yes 
No 
•
Closely monitor 
•
Initiate appropriate measures to control 
bleeding if necessary 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Appendix K  
Protocol Amendment History 
Amendment 3, Version 3: 
The protocol was amended on July 2, 2018 to add a cohort of 30 patients with metastatic 
colorectal cancer (mCRC) to the expansion phase of this study.  At the time of writing the 
Amendment 3, the Safety Review Committee (SRC) had determined that the recommended 
Phase 2 dose (RP2D) of fruquintinib is 5 mg QD (3 weeks on/1 week off each 28-day 
cycle).  The study population in the expansion phase therefore included both the 
originally planned cohort of 6 patients with advanced solid tumors of any type (Cohort A) 
and a new cohort of 30 patients with metastatic colorectal cancer mCRC (Cohort B).  The 
basis for adding 30 patients with mCRC was the positive Phase 3 study FRESCO 
conducted in China that demonstrated a significantly increased overall survival in patients 
with mCRC treated with fruquintinib compared to placebo, and led to approval of 
fruquintinib for this indication by the CFDA.  Another reason for Amendment 3 was to 
correct the terminology used in the original protocol to describe the dose escalation phase 
of the study as a safety run-in phase.  The correct terminology was changed to “dose 
escalation phase” because the study was not prospectively designed as the safety-run in 
phase in a Phase 2 trial. 
The changes in Amendment 3 are summarized in the table below. 
Section Number 
Section Title 
Description of Changes 
Not applicable 
Signature page, 
Declaration of 
Sponsor 
Personnel changes:  
1. 
 has replaced 
 
 as the signatory on behalf of Hutchison 
MediPharma (US) Inc. 
2. 
, 
and 
of Hutchison 
MediPharma Limited, has replaced 
 
 as the signatory on behalf of Hutchison 
MediPharma, Limited (Shanghai, China) 
Not applicable 
Protocol title 
Changed Protocol of Clinical Trials to Clinical Study 
Protocol in keeping with industry terminology. 
Not applicable 
Title page; 
Declaration of 
Investigator; 
Synopsis, Study 
Title 
Title change: A Multi-Center, Open-Label, Phase 1/1b 
Clinical Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Anticancer Activity of fruquintinib 
in Patients with Advanced Solid Tumors of any Type, and 
in Patients with Refractory Metastatic Colorectal Cancer 
Section 1.3.2 
 
Clinical Safety 
Added Table 3, Identified Risks in Patients Treated with 
Fruquintinib, and Table 4, Potential Risks in Patients 
Treated with Fruquintinib, with cross-reference to 
fruquintinib IB edition 10 (finalized November 22, 2018) 


Date:   0 9 Ja n 2 0 2 0                                                      C o nfi de ntial                                                               1 1 8 / 1 4 4 
Pr ot oc ol N u m ber : 2 0 1 5- 0 1 3- 0 0 U S 1                                                                                                               Versi o n 4 . 0 
Secti o n N u m ber  
Secti o n Title  
Descri pti o n of C h a n ges  
S y n o psis  
Secti o n 1. 3. 3  
Secti o n 1. 4  
S y n o psis  
Cli nical Efficac y  
St u d y Rati o nale  
 
A d de d a d ose e x p a nsi o n p h ase c o m prisi n g 6  p atie nts wit h 
s oli d t u m ors of a n y t y pe ( C o h ort A) a n d 3 0 p atie nts wit h 
refr act or y met ast atic c ol orect al c a ncer ( m C R C).  
A d de d t hat t he r ati o n ale f or e nr olli n g 3 0 p atie nts wit h 
refr act or y m C R C i n t he d ose e x p a nsi o n p h ase ( C o h ort B) 
is t he o utc o me of a pl ace b o-c o ntr olle d, P hase 3 (st u d y 
2 0 1 3 -0 1 3 -0 0 C H 1 [ F R E S C O]) of fr u q ui nti ni b as t hir d -li ne 
or hi g her tre at me nt f or p atie nts wit h m C R C. F R E S C O 
de m o nstr ate d a si g nific a ntl y l o n ger O S a n d P F S f or 
fr u q ui nti ni b c o m p are d t o pl ace b o a n d a n acce pt a ble 
s afet y pr ofile. T he C F D A a p pr o ve d fr u q ui nti ni b f or 
t hir d-li ne or hi g her tre at me nt of p atie nts wit h m C R C. 
Details are pr o vi de d i n t he trac ke d -c ha n ges versi o n of 
A me n d me nt 3.  
Secti o n 2  
S y n o psis  
St u d y O bjecti ves 
a n d E n d p oi nts 
To cre ate a ne w first -le vel he a di n g title d St u d y O bjecti ves 
a n d E n d p oi nts a n d s pecif y t he o bjective s a n d t he 
ass oci ate d e n d p oi nts of t he d ose esc al ati o n p h ase a n d t he 
d ose e x p a nsi o n p h ase u n der a si n gle sec o n d -le vel he a di n g 
f or e ac h of t he res pecti ve p h ases. 
Secti o n 2. 1  
D ose Escalati o n 
P hase  
To a d d a he a di n g u n der w hic h t he o bjecti ves a n d 
e n d p oi nts of t he d ose esc al ati o n p h ase are s pecifie d.  
Secti o n 2. 1. 1  
Pri mar y O bjecti ve  
T he pri m ar y o bjecti ve of t he d ose esc al ati o n p h ase is t o 
e v al u ate t he s afet y a n d t oler a bilit y of fr u q ui nti ni b i n 
p atie nts wit h a d v a nce d s oli d t u m ors a n d t o deter mi ne t he 
rec o m me n de d P h ase 2 d ose ( R P 2 D).  
Secti o n 2. 1. 2  
Pri mar y E n d p oi nt  
To s pecif y t h at t he pri m ar y e n d p oi nt of t he d ose 
esc al ati o n p h ase is t he i nci de nce of D L T i n e ac h c o h ort. 
D L T is defi ne d i n Secti o n 2. 1. 2  
Secti o n 2. 1. 3  
Sec o n dar y 
O bjecti v es 
A d de d t hat t he sec o n dar y o bjecti ves are:  
•  
To e v al u ate t he P K c h ar acteristics of m ulti ple -d ose 
fr u q ui nti ni b a n d t o i n vesti g ate t he met a b olite pr ofile 
of fr u q ui nti ni b i n t he pl as m a of p atie nts wit h s oli d 
t u m ors.  
•  
To e v al u ate t he a ntic a ncer acti vit y of fr u q ui nti ni b i n 
p atie nts wit h s oli d t u m ors acc or di n g t o R E CI S T 
Versi o n 1. 1.  
 
Secti o n 2. 1. 4  
Sec o n dar y 
E n d p oi nts  
A d de d t hat t he sec o n dar y e n d p oi nts are:  
•  
T he pri m ar y P K p ar a meters: m a xi m u m pl as m a 
c o nce ntr ati o n ( C m a x ), ti me t o re ac h m a xi m u m 
c o nce ntr ati o n ( T m a x ), ter mi n al h alf-life (t1/ 2), are a 
u n der t he c o nce ntr ati o n -ti me c ur ve i n a selecte d 
ti me i nter v al ( A U C0-t), are a u n der t he 
c o nce ntr ati o n -ti me c ur ve i n t he ti me i nter v al 
fr o m 0 t o i nfi nit y ( A U C0- ), a p p are nt cle ar a nce 
( C L/ F), a p p are nt v ol u me of distri b uti o n ( Vz/ F) 
d uri n g t he ter mi n al p h ase acc or di n g t o C L/ F/ Ke, 
a n d t he acc u m ul ati o n i n de x b ase d o n A U C.  
•  
T he o bjecti ve res p o nse r ate ( O R R), dise ase 


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Section Title 
Description of Changes 
control rate (DCR), duration of response (DoR), 
PFS overall survival (OS) and percentage change 
in tumor size from baseline according to RECIST 
V. 1.1 
 
Section 2.2 
Dose Expansion 
Phase 
To add a heading under which the objectives and 
endpoints of the dose expansion phase are specified 
Section 2.2.1 
Primary Objective 
To add that the primary objective of the dose expansion 
phase is to evaluate the anticancer activity of fruquintinib 
at the recommended Phase 2 dose (RP2D) from the dose 
escalation phase, in patients with advanced solid tumors 
and in patients with metastatic colorectal cancer mCRC 
who have either progressed on, or had intolerable toxicity 
from at least 1 FDA-approved third-line therapy 
(trifluridine/tipiracil or regorafenib). Progression is 
assessed according to the Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 
Section 2.2.2 
Primary Endpoint 
To specify that progression free survival (PFS) at 12 weeks 
is the primary endpoint of the dose expansion phase. 
 
Section 2.2.3 
Secondary 
Objective 
To specify that the secondary objectives of the dose 
expansion phase are: 
• 
To evaluate anticancer efficacy (ORR, DCR, 
DoR, PFS, and OS) 
• 
To evaluate the pharmacokinetic (PK) 
characteristics of multiple dose fruquintinib and 
to investigate the metabolite profile of 
fruquintinib in the plasma of patients with 
advanced solid tumors and in patients with 
mCRC.  
To evaluate the safety of fruquintinib in patients with 
advanced tumors and in patients with mCRC. 
Section 2.2.4 
Secondary 
Endpoints 
To specify that the secondary endpoints of the dose 
expansion phase are: 
• 
The objective response rate (ORR), disease 
control rate (DCR), duration of response (DoR), 
PFS overall survival (OS) and percentage change 
in tumor size from baseline according to RECIST 
V. 1.1 
• 
The primary PK parameters include: maximum 
plasma concentration (Cmax), time to reach 
maximum concentration (Tmax), terminal half-
life (t1/2), area under the concentration-time 
curve in a selected time interval (AUC0-t), area 
under the concentration-time curve in the time 
interval from 0 to infinity (AUC0-∞), apparent 
clearance (CL/F), apparent volume of distribution 
(Vz/F) during the terminal phase according to 
CL/F/Ke, and the accumulation index based on 
AUC. 
• 
Safety: AEs, physical examinations, vital signs, 
laboratory test results, 12-lead electrocardiogram, 


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Section Title 
Description of Changes 
and echocardiogram. 
 
Section 3.1 and 
Section 3.1.2 
Description of the 
Study; Dose 
Expansion Phase 
Changed description to read as follows: This is an open-
label study of fruquintinib comprised of a dose escalation 
phase in patients with advanced solid tumors of any type, 
and a dose expansion phase in patients with advanced 
solid tumors of any type and in patients with refractory 
mCRC. Patients with refractory mCRC have progressed 
on, or had intolerable toxicity from, at least 1 FDA-
approved third-line therapy (trifluridine/tipiracil or 
regorafenib). 
Section 3.2 
Sample Size 
To specify that approximately 50 patients will be enrolled in 
this 2-phase study: 14 in the dose escalation phase and 36 in 
the dose expansion phase (6 patients with advanced solid 
tumors of any type and 30 patients with mCRC). 
Section 3.4 
Safety Review 
Committee 
To define the role of the Safety Review Committee as 
follows: safety monitoring and evaluation for dose 
escalation decisions SRC upon completion of the of the 
DLT observation period of the last patient in each cohort. 
The SRC is chaired by the Sponsor’s fruquintinib 
Clinical Program Leader, members will include the 
principal investigators (PIs), the Sponsor’s PK scientist, 
medical monitor, and the CRO’s medical monitor.  
 
Section 3.6 
Patient 
Discontinuation 
To modify the criteria for the discontinuation of study 
drug treatment and to add criteria for early 
discontinuation of study drug treatment. Details are 
provided in the tracked-changes version of Amendment 3. 
Section 4 
Patient Selection 
Changed patient population as follows: ”patients with locally 
advanced or metastatic solid tumors” to “patients with 
locally advanced or metastatic solid tumors of any type, 
and patients with refractory mCRC”.  
Section 4.1 
Inclusion Criteria 
(Criterion 4) 
Specified that the criterion for enrollment in the dose 
escalation phase is histologically or cytologically 
documented, locally advanced or metastatic solid malignancy 
of any type (except squamous NSCLC) that has progressed 
on approved systemic therapy and for which no effective 
therapy or standard of care exists.  
Section 4.1 
Inclusion Criteria 
(Criterion 4) 
Added the dose expansion phase and specified that patients 
will be enrolled in 1 of 2 cohorts. For Cohort A, the entry 
criterion is identical to that of the dose escalation phase.  
For Cohort B, the entry criterion is defined as 
histologically or cytologically documented mCRC in 
patients who have progressed on, or had intolerable 
toxicity with at least 1 FDA-approved third-line systemic 
therapy (trifluridine/tipiracil or regorafenib.  
A definition of treatment failure was also added and can 
be found in the tracked-changes version of Protocol 
Amendment 3. 
Section 4.2 
Exclusion Criteria 
(Criterion 8) 
Changed text as follows: Risk International Normalized 
Ratio (INR) >1.5 or activated partial thromboplastin time 
(aPTT) >1.5 X ULN, unless the patient is currently 


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Section Title 
Description of Changes 
receiving or intending to receive anticoagulants for 
prophylactic purposes. 
Section 4.2 
Exclusion Criteria  
(Criterion 9) 
Changed text as follows: Risk of, active hemorrhage; history 
or presence of active gastric/duodenal ulcer or ulcerative 
colitis, active hemorrhage of an unresected gastrointestinal 
tumor, history of perforation of fistulas; or any other 
condition that could possibly result in gastrointestinal tract 
hemorrhage or perforation within 6 months prior to 
screening. 
Section 4.2 
Exclusion Criteria 
(Criterion 16) 
Changed text as follows: Patients who have ever received a 
VEGFR inhibitor, except for patients with mCRC enrolled 
in the dose expansion phase. 
Section 4.2 
Exclusion Criteria 
(Criterion 23) 
Changed text as follows: Any unresolved toxicities from a 
previous antitumor treatment greater than CTCAE v.4.03 
Grade 1 (except for alopecia) 
Section 4.2 
Exclusion Criteria 
(Criterion 25) 
Changed exclusion of patients with liver disease as follows: 
Known clinically significant history of liver disease, 
including cirrhosis, current alcohol abuse or active viral 
hepatitis. For patients with evidence of chronic hepatitis 
B ((HBV), the HBV viral load must be undetectable on 
suppressive therapy, if indicated. Patients with a history 
of hepatitis C virus (HCB) must have been treated and 
cured. Patients with HCV who are currently on treatment 
are eligible if they have an undetectable HCV viral load.  
Section 4.2 
Exclusion Criteria 
(Criterion 29) 
Changed text as follows: Brain metastases and/or spinal 
cord compression untreated with surgery and/or 
radiotherapy, and without clinical imaging evidence of 
stable disease for 14 days or longer/ patients requiring 
steroids within 4 weeks prior to start of study treatment 
will be excluded. 
5.1.3 
Packaging and 
Drug Labeling 
Removed expiry date from description of product labeling 
because this information is not required by the US FDA. 
5.1.6 
Dose and 
Administration 
(Declaration of 
RP2D) 
Added the following paragraph (note: text refers to dose 
escalation phase): After the SRC review of Cohort 2, the 
RP2D was declared as 5 mg QD, 3 weeks on/1 week off 
each 28-day cycle. Patients from Cohort 1 who remain in 
the study may have their fruquintinib dose escalated to 
5 mg QD at the discretion of the investigator and with the 
agreement of the Sponsor. 
5.1.6 
Dose and  
Administration 
(Foods and/or 
drugs to avoid on 
PK sampling days) 
Added the following test to the paragraph beginning with 
“On the days of PK sampling:” The patient is encouraged 
to avoid, or minimize the use of caffeine-containing foods 
or drinks, tobacco, tobacco products, and alcohol during 
the entire study. If the patient cannot avoid taking any of 
the above-listed substances during the study, it should be 
regarded as a habit and documented as demographic 
data. 
Also added: 
The following substances are prohibited during the study: 
grapefruit or grapefruit juice, illegal drug use, or 
excessive (>1 drink/day) alcohol use. 
Section 5.2.2.1 
Dose Modification 
• 
Changed title of Section 5.2.2.1 to read as follows: Dose 


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Section Title 
Description of Changes 
Sequence by 
Starting Dose and 
for General 
Hematologic and 
Non-hematologic 
Toxicity 
Modification Sequence by Starting Dose and for 
General Hematologic and Non-Hematologic Toxicity  
• 
Added Table 7, Dose Modification by Starting Dose, 
and Table 8, Dose Modification for Hematologic and 
Non-hematologic Toxicity, 
Added the following text: 
• 
Patients starting at 5 mg QD are allowed to have two 
dose reductions: one reduction from 5 mg QD to 4 mg 
QD, and if not tolerated, then a second reduction 
from 4 mg QD to 3 mg QD. Patients starting at 3 mg 
QD are allowed to have one reduction, ie, from 3 mg 
QD to 2 mg QD. The lowest dose level permitted in 
the study is 2 mg (see Table 7). 
5.3.1 
Concomitant 
Therapies 
The following text was changed:  
• 
Patients who are receiving low-dose warfarin or 
Coumadin-like products should have their INR 
monitored and maintained at the lower third of the 
therapeutic range (ie, 2.0-2.3) unless a higher INR is 
required for anti-thrombotic efficacy. 
Section 6.1.2 
Physical 
Examination 
Added the following text to the paragraph describing the 
limited physical examination: In order to assess changes 
from baseline and screen for new abnormalities, the 
limited physical examination should assess for new or 
changed skin lesions, enlarged nodes, palpable masses, 
hepatomegaly, and splenomegaly. Patient-reported 
symptoms should be directed to address the symptoms. 
Synopsis 
 
Section 6.2 and 
Appendix A, 
Study Flowchart 
(Table and 
Footnote 4) 
Synopsis 
 
Tumor Assessment 
and assessment of 
specific tumor 
markers in each 
phase  
Specified in Section 6.2 that the schedule of tumor 
assessments is different in the dose escalation and dose 
expansion phases of the study.  
Added to the text of Section 6.2 and to Appendix A, Study 
Flowchart, the schedule of tumor assessments in the dose 
escalation phase assessments and specific tumor markers 
in the dose escalation phase (Screening, then every 8 (±1) 
weeks thereafter: C3D1, C5D1, C7D1, etc). 
Added to the text of Section 6.2 and to Appendix A, Study 
Flowchart, the schedule of tumor assessments and specific 
tumor markers in the dose expansion phase (Screening, 
then every 8 (±1) weeks thereafter: C2D1, C3D1, C4D1, 
etc) 
Added the following text: Response assessments will be 
performed by the investigator using physical and image-
based evaluation. 
Section 7.1.2 
Reporting of Dose 
Limiting Toxicity 
The following paragraph has been added to Section 7, 
Safety Plan:  
7.1.2 Investigators are required to report DLT events to 
the Sponsor within 48 hours of first awareness. The 
communication must include an email that describes the 
event and indicates which DLT criterion was met (see 
Section 3.1.1 c, Definition of a Dose-Limiting Toxicity). 
The Sponsor’s medical monitor must confirm that the 
event meets the DLT definition and communicate this 


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Section Number 
Section Title 
Description of Changes 
back to the investigator by email. A notification of each 
DLT event will be distributed by email to all investigators 
shortly after confirmation. DLT events are again reviewed 
together with other safety data and PK data, at the SRC 
meeting upon completion of the DLT window of each dose 
cohort. 
Section 7.1.8 
Recording of 
Adverse Events 
(Hospitalization, 
Prolonged 
Hospitalization, or 
Surgery) 
Changed the text to read as follows: The investigator must 
document any AE that results in hospitalization unless the 
patient is hospitalized for 1 or more of the following 
reasons:  
• 
To undergo an efficacy measurement for the study 
• 
To undergo a diagnostic or elective surgical procedure 
for a preexisting medical condition that has not changed 
• 
To receive scheduled therapy for the target disease of the 
study 
Section 8.1 
Analysis 
Populations 
Added text to define the Efficacy Analysis Set (EAS) as all 
patients who have received at least 1 dose of fruquintinib 
and have had at least 1 post-baseline tumor assessment. 
All efficacy endpoints will be analyzed will based on this 
analysis set. 
Section 8.5 
Efficacy Analysis 
• 
Added text to identify the efficacy endpoints, 
including the objective response rate (ORR), 
duration of response (DoR), progression free survival 
(PFS), and overall survival (OS).  
• 
Added text to specify that efficacy data will be listed 
and summarized by dose cohort and disease type.  
• 
Added text to specify that ORR and DCR will be 
summarized with percentages and 95% exact 
confidence intervals. The PFS rate at 12 weeks and its 
95% confidence intervals will be estimated by the 
Kaplan-Meier method. PFS, DoR, and OS will be 
summarized descriptively using Kaplan-Meier 
medians and quartiles. Percentage change in tumor 
size from baseline will be determined for patients 
with measurable disease at baseline and derived at 
each visit by the percentage change in the sum of the 
diameters of target lesions (TLs) compared to 
baseline. Best percentage change in tumor size will be 
summarized using descriptive statistics and presented 
using a waterfall plot. 
• 
Added text to stipulate that a best overall response of 
PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments no less than 4 weeks 
after the criteria for response are first met. 
• 
Added the definitions of best overall response (BOR), 
disease control rate (DCR) PFS at 12 weeks, and 
analysis of median PFS using all data available up to 
the analysis cut-off point. Details are provided in the 
tracked-changes version of Protocol Amendment 3. 
Section 8.6 
Determination of 
Sample Size 
Dose Escalation Phase: 
Added text to specify that the total number of patients 
enrolled will depend on the number of dose escalations 


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Section Number 
Section Title 
Description of Changes 
and the need to further characterize individual cohorts 
treated with single-agent fruquintinib at the RP2D. 
 
Dose Expansion Phase: 
Added text to specify that the PFS rate is the primary efficacy 
endpoint for Cohort B (patients with refractory mCRC). 
Thirty patients will be recruited to have at least 25 evaluable 
patients in Cohort B. The true positive PFS rate and the 
true negative PFS rate at 12 weeks in a cohort of at least 
25 evaluable patients. Determination is based on the PFS 
rates in the FRESCO study. 
Appendix A 
Study Flowchart 
(Footnote 7) 
Added details of physical examination to be completed as 
part of the tumor assessment. 
To correct various grammatical and typographical errors in the previous version of the protocol 
(Amendment 2) and to add the date of 3 December 2018 to the footers. 
 
Amendment 2, Version 2: 
This amendment to protocol 2015-013-00US1 was written for the following reasons: (1) 
to provide updated safety information and additional guidance to the investigator on the 
management of severe or serious hemorrhagic events; (2) inclusion and exclusion 
clarifications/modifications as discovered during the conduct of the study; and (3) many 
minor changes were made to improve clarity and consistency within the protocol.  The 
minor changes in the protocol text, which may include punctuation, grammar corrections 
or text edited for greater clarity or detail are not included in this document, however, these 
changes are captured in the accompanying tracked changes document. Header and/or footer 
changes are mentioned once but are throughout the document. 
The changes in Amendment 2 are summarized in the table below. 
Prior version: v1.1 
Current version: v2.0 
Reason for Amendment 
1 
Page 1 and page footer: 
Amendment 1; Version 1.1; 
Date: 31 July 2017 
Page 1 and page footer: 
Version 2.0; Date: 2 July 
2018 
Protocol version and date 
change. This is a major 
amendment; therefore, the 
version number increases 
from 1.1 to 2.0. It is also 
called Amendment 2. 
2 
Page 3: 
Sponsor Medical Monitor for 
the Trial: 
 
Clinical Development and 
Regulatory Affair Department 
Hutchison MediPharma 
Limited 
 
 
Page 4: 
Sponsor Medical Monitor for the 
Trial: 
 
Clinical Development and 
Regulatory Affair Department 
Hutchison MediPharma Limited 
 
 
 
Personnel change. Moved 
the information page after 
the signature page. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Prior version: v1.1 
Current version: v2.0 
Reason for Amendment 
3 
Page 5: Study Design 
1. Safety monitoring and 
evaluation for dose 
escalation will be carried 
out by the Safety Review 
Committee (SRC) which 
is comprised of the site 
PIs, the CRO’s medical 
monitor, and the sponsor’s 
medical monitor. 
2. If 2 or more patients at the 
5 mg QD dose level 
experience DLT, study 
will be terminated and the 
expansion phase of the 
study will not be 
conducted. 
Page 6: Study Design 
1. Safety monitoring and 
evaluation for dose escalation 
will be carried out by the 
Safety Review Committee 
(SRC) upon completion of the 
DLT observation period of 
each cohort. The SRC is 
comprised of the site principal 
investigators (PIs), a PK 
scientist, the CRO’s medical 
monitor and the sponsor’s 
medical team member, safety 
scientist. Adverse event (AE) 
and PK data will be evaluated 
together when determining 
fruquintinib dose escalation 
with reference to fruquintinib 
PK and safety characteristics 
in Chinese patients in trials 
conducted previously. 
2.  If 2 or more patients at the 
5 mg QD dose level 
experience DLT, the SRCwill 
discuss the next dose 
1. Clarification as to the 
timing of the SRC 
review. 
Update to include a PK 
scientist and safety 
scientist into SRC 
membership. 
Delete duplicated 
information and 
combine to a 
paragraph. 
2. SRC discussion instead 
of terminating the 
study, if 2 or more 
DLTs happen at 5 the 
mg QD dose level. 
4 
Page 7: Study Treatment 
…until disease progression, 
death, intolerable toxic reaction, 
or at investigator’s discretion 
that the patient can no longer 
benefit from the study 
treatment. 
Page 7: Study Treatment 
… until disease progression, death, 
intolerable toxicities, or at 
investigator’s discretion that the 
patient can no longer benefit from 
the study drug. 
Consistency in the use of 
the term “study drug” as 
an alternative to the term 
“fruquintinib.” Other 
alternative terms (e.g., 
“study treatment,” “study 
medication” or “IP”) are 
removed. 
5 
Page 7-8 and 36: Inclusion 
Criteria 
1. 18-75 years of age 
2. Body weight ≥ 45kg 
4. … the last dose of prior 
systemic anti-cancer therapy 
must have been administered 
≥ 4 weeks prior to initiation of 
study treatment, and for whom 
no effective therapy or 
standard of care exists. 
5. Have measurable disease per 
RECIST Version 1.1 
(expansion phase only) 
Page 7-8 and 35: Inclusion 
Criteria 
1. ≥ 18 years of age; 
2. Body weight ≥ 40kg; 
4. … the last dose of prior 
systemic anti-cancer therapy 
must have been administered 
≥ 4 weeks (unless specifically 
noted in exclusion criteria) prior 
to initiation of study drug, and for 
whom no effective therapy or 
standard of care exists. 
Have measurable disease per 
RECIST Version 1.1 (expansion 
phase only). Lesions that received 
radiotherapy are not measurable 
per RECIST v 1.1. 
1. Remove the upper age 
limit to include adult 
subjects of any age that 
otherwise meet all 
inclusion no exclusion 
criteria. . 
2. Reduce lower limit of 
body weight for inclusion 
4. Clarification of prior 
anti-cancer therapy 
washout: ≥ 4 weeks with 
reference to exceptions in 
exclusion criteria 
Clarification of RECIST 
v. 1.1 criteria for lesions 
treated with radiotherapy. 


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Reason for Amendment 
6 
Page 8 and 37: Exclusion 
Criteria 
1. 
Page 8 and 36: Exclusion 
Criteria 
1. Blood transfusion within 1 
week before enrollment for the 
purpose of increasing the 
likelihood of eligibility is not 
allowed; 
1. Clarification to exclude 
patients with blood 
transfusion during the 
week before enrollment to 
avoid a temporary 
measure to meet the 
minimum hemoglobin 
concentration (9.0 g/dL). 
7 
Page 8 and 37: Exclusion 
Criteria 
5. Serum creatinine clearance 
< 60 mL/min; 
Page 8 and 36: Exclusion 
Criteria 
5. Creatinine > 1.5 ULN or 
Creatinine clearance < 60 
mL/min. Creatinine clearance 
can either be measured in a 
24-hour urine collection or 
estimated by the Cockraft- 
Gault equation as follows: 
Clcr (ml/min) = [(140 - age) x 
(weight in kg) x 0.85 if 
female] ÷ [72 x (serum 
creatinine in mg/dL)]. 
5. Specifies the methods 
by which creatinine 
clearance can be measured 
or estimated and indicates 
the upper limit of serum 
creatinine permitted at 
screening. 
8 
Page 8 and 37: Exclusion 
Criteria 
6. Urine dipstick for proteinuria 
> 2 +. Patients discovered to 
have ≥ 1 + proteinuria on 
dipstick urinalysis at baseline 
should undergo a 24-hour urine 
collection and must demonstrate 
≤ 1 g of protein in 24 hours; 
Page 8 and 36: Exclusion 
Criteria 
6. 
Urine dipstick protein 
≥2+ and 24-hour urine protein 
≥1.0 g/24-h. Patients with 
greater than 1+ proteinuria on 
urinalysis must undergo a 24- 
hour urine collection; 
6. Clarification of 
exclusion criteria for 
proteinuria by semi- 
quantitative (urinalysis) 
and quantitative (24-hour 
urine) methods. 
9 
Page 8 and 37: Exclusion 
Criteria 
8. International Normalized 
Ratio (INR) > 2 or activated 
partial thromboplastin time 
(aPTT) > 1.5 ULN, except if the 
patient is currently receiving or 
intending to receive anti-
coagulants for therapeutic 
purposes (prophylactic use is 
allowed). 
Page 9 and 36: Exclusion 
Criteria 
8. International Normalized 
Ratio (INR) >1.5 or activated 
partial thromboplastin time 
(aPTT) > 1.5 × ULN. 
8. Decrease the upper 
limit of INR at screening 
from 2.0 to 1.5. 
Clarification of indications 
for anti-thrombotic 
therapy permitted at study 
entry. Both measures are 
to reduce the risk of 
hemorrhagic events on 
study. 
10 
Page 9 and 37-38: Exclusion 
Criteria 
9. 
Page 9 and 37: Exclusion 
Criteria 
9. History of perforation or 
fistulas; 
9. Exclusions for GI 
disorders broadened to 
include patients with a 
history of GI perforation 
or fistulas. 


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Prior version: v1.1 
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Reason for Amendment 
11 
Exclusion Criteria 
This criterion was added. 
Page 9 and 37: Exclusion 
Criteria 
16. Patients who have ever 
received a VEGFR inhibitor. 
16. Such drugs are excluded 
because they target the same 
molecule as fruquintinib. 
Patients treated with VEGFR 
inhibitors previously are 
unlikely to respond to 
fruquintinib 
12 
Page 9 and 38: Exclusion 
Criteria 
16. Systemic anti-neoplastic 
therapies within 4 weeks prior 
to the initiation of 
investigational treatment, 
including chemotherapy, radical 
radiotherapy, hormonotherapy, 
biotherapy and immunotherapy; 
Page 9 and 37: Exclusion 
Criteria 
17. Systemic anti-neoplastic 
therapies (except for those 
described in Exclusion 18) or other 
investigational therapies within 4 
weeks prior to the first dose of 
study drug, including 
chemotherapy, radical 
radiotherapy, hormonotherapy, 
biotherapy and immunotherapy; 
Note: Original Exclusion 
Criteria #16 is now #17. 
17. Now includes a reference 
to exceptions to the exclusion 
criteria based on prior 
systemic anticancer therapy. 
13 
Exclusion Criteria 
This criterion was added. 
Page 10 and 37: Exclusion 
Criteria 
18. Systemic small molecule 
targeted therapies (e.g., tyrosine 
kinase inhibitors) within 5 half-
lives or 4 weeks (whichever is 
shorter) prior to the first dose of 
study drug; 
Note: Original Exclusion 
Criteria #18 is now #21 due 
to added criteria. 
18. Small molecule tyrosine 
kinase inhibitors are an 
exception to the standard 4-
week washout period for prior 
systemic anti-cancer therapies. 
Tyrosine kinase inhibitors 
usually wash out in < 2 weeks; 
5 half-lives is expected to be < 
4 weeks. 
14 
Exclusion Criteria 
This criterion was added. 
Page 9 and 37: Exclusion 
Criteria 
20. Brachytherapy (i.e., 
implantation of radioactive seeds) 
within 60 days prior to the first 
dose of study drug. 
20. This criterion is added 
because of the potentially 
increased risk of severe or 
serious hemorrhage after 
brachytherapy. 
15 
Page 9 and 38: Exclusion 
Criteria 
18. Use of strong inducers or 
inhibitors of CYP3A4 within 2 
weeks before the first dose of 
study treatment (3 weeks for St 
John’s Wort). See Appendix F 
for a list of such medications 
Page 10 and 37: Exclusion 
Criteria 
21. Use of strong inducers or 
inhibitors of CYP3A4 within 2 
weeks before the first dose of 
study drug (3 weeks for St John’s 
Wort); P-glycoprotein (P-gp) or 
breast cancer resistance protein 
(BCRP) substrate within 2 weeks 
before the first dose of study 
drug. See Appendix F for a list of 
such medications. 
2. Drugs affected by P-gp and 
BCRP transporters are added 
to the list of excluded drugs 
because of the potential for 
fruquintinib increasing the 
exposure to the drugs by 
affecting the absorption and 
disposition of the drugs. 


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16 
Page 9 and 38: Exclusion 
Criteria 
19. Surgery prior to enrollment 
within 28 days prior to the 
initiation of study treatment or 
unhealed surgical incision; 
Page 10 and 38: Exclusion 
Criteria 
22. Surgery or invasive procedure 
(i.e., procedure that includes a 
biopsy) within 60 days prior to the 
first dose of study drug or unhealed 
surgical incision; 
Note: Original Exclusion 
Criteria #19 is now #21 due 
to added criteria. 
21. Invasive procedures 
with biopsy are added to 
surgery as exclusions; the 
duration is set at 60 days 
for invasive procedures and 
extended to 60 days for 
surgery. These exclusions 
are to reduce the risk of 
severe or serious 
hemorrhagic events while 
on study drug. 
17 
Page 10 and 38: Exclusion 
Criteria 
21. Known human 
immunodeficiency virus 
(HIV), hepatitis A, B or C 
infection except for fully 
recovered Hepatitis A. 
Previous medical history of 
hepatitis B virus (HBV) 
infection regardless of drug 
control, HBV DNA ≥104 
×copy number or ≥2000 IU/mL; 
Page 10 and 38: Exclusion 
Criteria 
24. Known human 
immunodeficiency virus 
(HIV) infection; 
Known clinically significant 
history of liver disease, including 
cirrhosis or known hepatitis A, B 
or C infection except for fully 
recovered Hepatitis A. Previous 
medical history of hepatitis B virus 
(HBV) infection regardless of drug 
control, HBV DNA ≥104 × copy 
number or ≥2000 IU/mL; current 
alcohol abuse; 
Exclusion criteria were broken 
up into two separate criteria 
18 
Exclusion Criteria 
This criterion was added. 
Page 10 and 38: Exclusion 
Criteria 
27. Tumor invades large vascular 
structure, e.g., 
pulmonary artery, superior or 
inferior vena cava. 
27. Exclusion added because 
of the increased risk of severe 
(Grade ≥ 3) or serious (SAE) 
hemorrhage. 
19 
Page 10 and 38: Exclusion 
Criteria 
25. Central nervous system 
(CNS) metastatic disease or 
prior cerebral metastasis; 
Page 10 and 38: Exclusion 
Criteria 
29. History or presence of Central 
nervous system (CNS) metastatic 
disease; 
Note: Original Exclusion 
Criteria #25 is now #29 due 
to added criteria. 
29. Clarifies that either 
current or past CNS 
metastatic disease is an 
exclusion. 
20 
Exclusion Criteria 
This criterion was added. 
Page 10 and 38: Exclusion 
Criteria 
30. No other malignancy, except 
for non-melanoma skin cancer, 
during the 5 years prior to 
screening; 
30. More than one invasive 
malignancy in the same 
patient could lead to 
confusion about which 
disease is active and 
interfere with efficacy 
assessment. 


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21 
Page 10 and 38: Exclusion 
Criteria 
27. Received investigational 
treatment in another clinical 
study within 4 weeks prior to 
the initiation of 
investigational treatment; 
This criterion was deleted. 
This was deleted, and more 
specific criteria were added for 
clarification (see #16,17 & 18). 
22 
Exclusion Criteria 
This criterion was added. 
Page 10 and 38: Exclusion 
Criteria 
33. Known hypersensitivity 
to fruquintinib or any of its 
excipients.  
33. This was erroneously 
omitted in prior versions of the 
protocol. 
23 
Page 11: Statistical Analysis 
All variables obtained at each 
observation time point will be 
summarized descriptively by 
dose cohort, except for certain 
time points for which a 
description is not required by 
the protocol. For continuous 
variables, summary statistics 
will include the number of 
patients (n), mean, standard 
deviation (SD), minimum and 
maximum. For categorical 
variables, summary statistics 
will include the number and 
percentage of patients in each 
category. 
Page 11: Statistical Analysis 
By-subject listings will be created 
for important variables from each 
CRF module. Summary tables for 
continuous variables will contain at 
least the following statistics: N 
(number in population), mean, 
standard deviation, median, 
minimum, and maximum. 
Summary tables for categorical 
variables will include: N, n, and 
percentage. 
The revised description 
clarified only important 
variables rather than all 
variables will be listed in 
by-subject listings. 
For continuous variables, 
an additional statistic 
“median” as added to 
summary statistics. For 
categorical variables, both 
total N and non-missing n will 
be presented 
24 
Page 12: Safety Assessment 
AE severity will be graded 
according to the NCI CTCAE 
(version 4.03). AEs will be 
coded using the Medical 
Dictionary for Drug 
Regulatory Activities 
(MedDRA). The frequency of 
treatment-emergent AEs 
(TEAEs) will be summarized 
by MedDRA System Organ 
Class (SOC) as well as 
Preferred Term (PT). The 
incidence of TEAEs, SAEs, 
AEs of special interest, AEs 
leading to dose interruption, 
reduction, or treatment 
discontinuation will be 
presented by a system organ 
class and preferred term; by 
relationship to investigational 
product and by toxicity grade 
for each dose level in both 
study phases. 
Page 12: Safety Assessment The 
severity of all AEs will be graded 
by the investigator according to 
the NCI CTCAE, version 4.03. 
AEs will be coded using the 
Medical Dictionary for Drug 
Regulatory Activities (MedDRA). 
Treatment- emergent AEs 
(TEAEs) will be classified by 
MedDRA System Organ Class 
(SOC) and specified by Preferred 
Term (PT). The incidence of 
TEAEs, SAEs, AEs of special 
interest, AEs leading to dose 
interruption, reduction, or study 
drug discontinuation will be 
summarized for each dose level in 
both study phases. 
For the laboratory assessments, 
such as hematological, serum 
biochemistry, and urine data will 
be programmatically graded 
according to CTCAE severity 
grade. Summary tables will be 
This section was re- written 
to specify that the 
investigator grades the 
severity of AEs 
The description of how 
laboratory assessments will be 
handled is presented in more 
detail, including those 
parameters where a CTCAE 
scale does not exist. This was 
not included in such detail 
previously. 


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Shifts in laboratory test results 
will be summarized 
hierarchically according to the 
NCI CTCAE (version 4.03) 
grade or normal ranges if no 
CTCAE grade is provided for a 
particular analyte. When 
abnormal laboratory results are 
counted at the patient level, the 
worst value reported during 
study treatment will be chosen. 
presented to show the number of 
subjects by CTCAE severity 
grade with corresponding 
percentages. For parameters for 
which a CTCAE scale does not 
exist, the frequency of subjects 
with values below, within, and 
above the normal ranges will be 
summarized. 
Shift tables for hematology and 
serum biochemistry will also be 
presented showing change in 
CTCAE severity grade from 
baseline to worst 
grade post-baseline. 
25 
Page 13: Efficacy 
All patients who receive at 
least one dose of fruquintinib 
and have at least one post- 
baseline tumor assessment 
will be included in the 
evaluable for respone set 
(ERS). 
The overall response rate 
(ORR) and disease control rate 
(DCR) will be summarized by 
dose cohort with percentages 
and 95% exact confidence 
intervals for ERS. If the sample 
size permits, duration of 
response in the ERS and 
progression free survival (PFS) 
in the SAS will be summarized 
by the dose cohort descriptively 
using Kaplan-Meier medians 
and quartiles. 
Page 12-13: Efficacy 
All SAS patients who have at 
least one post-baseline tumor 
assessment will be included into 
the response evaluable analysis 
set (REAS). 
The overall response rate (ORR) 
and disease control rate (DCR) 
will be summarized by dose 
cohort with percentages and 95% 
exact confidence intervals for 
REAS. If sample size permits, 
PFS and DoR will be summarized 
by dose cohort descriptively 
using Kaplan- Meier medians and 
quartiles. Percentage change in 
tumor size will be determined for 
patients with measurable disease 
at baseline and is derived at each 
visit by the percentage change in 
the sum of the diameters of TLs 
compared to baseline. 
This section was edited for 
grammar and content. 
The patient population REAS 
was defined in a simpler way 
when treating it as a subset of 
SAS. The change in tumor size 
for those patients with 
measurable baseline disease 
will be characterized to 
provide a metric by which to 
measure possible efficacy. 
26 
 
Page 18-19: Abbreviations and 
Definitions 
The following were added to this 
table: ALP, APTT, BUN, DBil, 
EC, FDG-PET, IEC- IRB, INR, 
CTCAE, PFS, PT, RECIST, TBil, 
TLs, TSH, ULN, VEGF, VEGRF 
These abbreviations and 
definitions are added in this 
amendment. 
27 
Page 33: Section 3.1 
Description of the study. The 
study is comprised of 2 phases 
Page 31: Section 3.1 Description 
of the study. The study is 
comprised of 2 phases: the Safety 
run-in phase and the Expansion 
phase. 
Elaboration of the names of 
the two phases. 


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28 
Page 33: Section 3.1, 5th 
bullet. 
• 
If 2 or … will not be 
conducted. If 2 or more 
patients at the 5mg QD dose 
level experience DLT, the 
study will be terminated the 
expansion phase of the study 
will not be conducted. 
Page 31: Section 3.1, 5th 
bullet. 
If 2 or … will not be conducted. 
If 2 or more patients at the 5mg 
QD dose level experience DLT, 
the SRC will discuss the next 
dose level. 
Verbiage was added to 
indicate the next step in the 
study if the conditions in 
the 5th bullet item are met. 
Previously it stated the 
study will end, which is not 
correct the next step will be 
discussed by the 
SRC. 
29 
Page 34: Section 3.1, 1th 
bullet on the page. 
• 
At the discretion of the 
investigators, patients who 
have completed the DLT 
observational window (Cycle 
1, Days 1-28) and are deemed 
to be benefiting from 
fruquintinib treatment may 
continue fruquintinib 
treatment at the assigned dose 
until disease progression, death, 
or intolerable toxicity. 
Page 32: Section 3.1. 
Bullet deleted. 
This bullet point duplicates 
bullet point 10 on page 42; 
therefore, it is deleted. 
30 
Page 35: Section 3.3 
It is planned to have about 3 
sites to participate in the study. 
Page 34: Section 3.3 
It is planned to have up to 5 sites 
to participate in the study. 
Sponsor may increase the 
number of participating sites to 
5 if enrollment targets are not 
met. 
31 
Page 35: Section 3.4, Safety 
Review Committee 
safety data review and to 
determine the next step for dose 
escalation or de- escalation 
Page 34: Section 3.4, Safety 
Review Committee 
…safety data review and to 
determine the next step for dose 
escalation or dose expansion. 
There is no “de- escalation” of 
dose in the study. The term is 
corrected to “dose expansion.” 
32 
Page 35: Section 3.4, Safety 
Review Committee 
Regular safety data review will 
be conducted at pre- defined 
intervals and at the end of the 
first treatment cycle of a dose 
cohort. 
Page 34: Section 3.4, Safety 
Review Committee 
Regular safety data review will be 
conducted at pre- defined 
intervals and at the end of the 
DLT observation period (i.e., first 
treatment cycle) of a dose cohort. 
Clarification that safety data 
review should be done at the 
end of the DLT observation 
period for all patients in a 
particular dose cohort. 
33 
Page 39: Section 5.1.4 Drug 
Storage 
… under appropriate storage 
conditions. 
Page 39: Section 5.1.4 Drug 
Storage 
… under appropriate storage 
conditions (10-30 º C). 
The temperature range for 
drug storage was added for 
completeness. 


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34 
Page 40: Section 5.1.5 Drug 
Accountability, 2nd 
paragraph 
…standard operating procedure 
or returned to Hutchison 
MediPharma with appropriate 
documentation… 
Page 39: Section 5.1.5 Drug 
Accountability, 2nd paragraph 
…standard operating procedure or 
returned to Hutchison MediPharma 
or a Hutchison identified entity 
with appropriate documentation… 
Verbiage added to indicate that 
study drug may be returned 
either directly to an HMP 
employee, or to a person or 
organization designated by 
Hutchison to receive drug for 
destruction. 
35 
Page 40: Section 5.1.6 Dose 
and Administration, 3rd 
paragraph 
On the days of PK sampling, 
patients should avoid high-fat 
meals for the entire day and 
avoid consumption of any 
liquids other than water (up to 
200ml) within the period of 1 
hour before and after drug 
administration. No caffeine 
containing foods or drinks, no 
grapefruit or grapefruit juice, or 
recreational drugs will be 
allowed during the PK 
assessment period (Cycle 1). 
Page 40: Section 5.1.6 Dose 
and Administration, 3rd 
paragraph 
On the days of PK sampling, 
patients should avoid high-fat 
meals for the entire day and avoid 
consumption of any liquids other 
than water (up to 200ml) within 1 
hour before or after drug 
administration. No grapefruit, 
grapefruit juice, or recreational 
drugs will be allowed during the 
PK assessment period (Cycle 1), 
and no caffeine-containing foods 
or drinks may be taken on the days 
that PK samples are drawn. 
It was clarified that caffeine 
containing foods should be 
avoided only on days PK 
samples are to be drawn. 
Previously it was indicated 
that no caffeine was to be 
consumed during the entire 1st 
cycle which was incorrect. 
36 
Page 41: Section 5.2.2.1 
Dose Modification for 
general….4th & 5th sentence. 
A patient is allowed to have 
dose reduction no more than 
twice, i.e., from 3mg QD to 2 
mg QD for patients taking the 
3mg QD regimen, and from 
5mg QD to 4 mg QD for 
patients escalated to 5 mg QD. 
Patients that were reduced from 
5mg to 4mg QD can have a 
second dose reduction to 3mg 
QD. 
Page 41: Section 5.2.2.1 
Dose Modification for 
general…., 4th & 5th 
sentence. 
A patient is allowed to have dose 
reduction no more than twice, 
i.e., from 3mg QD to 2 mg QD 
for patients taking 3mg QD 
regimen, and from 
5mg QD to 4 mg QD for patients 
taking 5 mg QD regimen. Patients 
that were reduced from 5mg to 
4mg QD can have a second dose 
reduction to 3mg QD. Patients 
taking 3mg QD regimen can only 
have dose reduction once (from 
3mg to 2mg QD). 
Dose reduction directions for 
subjects with toxicities are 
clarified. Directions for dose 
reduction for patients receiving 
the 3 mg dose are now 
included. 
37 
Page 42: Section 5.2.2.2 
Dose Modification and 
Treatment…., 
Title of section now reads: 
Dose Modification and 
Treatment Suggestions for 
selected AEs 
Page 41: Section 5.2.2.2 
Dose Modification and 
Treatment…., 
Title of section now reads: 
Dose Modification and 
Treatment Suggestions for 
selected identified risks 
The term “identified risks” is 
more accurate than “selected 
AEs”. 


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38 
Page 42-43, Table 8, Dose 
Modification for Proteinuria 
No foot note 
Page 42, Table 8, Dose 
Modification for 
Proteinuriaa 
The following note was 
added to the end of the 
table: a: If protein ≥ 2+ 
during the period of study 
treatment, a 24-hour urine 
test should be conducted 
within 1 week, and dose 
modification will be done 
by the result of 24-hour 
urine protein quantitation. 
The conditions under which a 
24-hour urine test should be 
conducted are clarified. 
39 
Page 43, Table 9, Dose 
Modification for 
Hypertension, AE Grading 
and Definitions, Grade 3 
Grade 3: SBP ≥ 160mm Hg 
or DBP ≥ 100mm Hg; or 
symptomatic increase in DBP 
by >20mmHg 
Page 43, Table 9, Dose 
Modification for 
Hypertension, AE Grading 
and Definitions, Grade 3 
Grade 3: SBP ≥ 160mmHg 
or DBP ≥ 100mmHg; or 
more than one drug or more 
intensive therapy are used 
Another criterion is added to 
define a Grade 3 AE of 
hypertension, i.e. more than 
one drug or more intensive 
therapy are used to manage the 
AE. 
40 
Page 44, Table 11, Dose 
Adjustment for 
Hemorrahage at any site. 
Page 44, Table 11, Dose 
Adjustment for Hemorrahage 
at any site. 
The following notes were 
added to the end of the table 
for Grade 3 events: 
a: Refer to Appendix J for 
clinical management of 
severe or serious 
hemorrhage. 
b: The investigator should 
closely monitor patients 
receiving anti-platelet 
and/or anti-thrombotic 
drugs during study drug 
treatment and make a 
timely decision on whether 
to continue or stop such 
drugs in patients that report 
Grade ≥2 hemorrhagic 
events at any site, based on 
an individual assessment of 
the risk-benefit balance 
(See section 5.3.1 
Concomitant therapy). 
Elaboration of instructions 
is added to guide the 
investigator on the 
management of 
hemorrhagic AEs, which 
are associated with this 
class of drugs (VEGF or 
VEGFR inhibitors) 


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41 
Page 45, Section 5.3.1 
Concomitant Therapies, 1st 
paragraph. 
Last sentence of the section 
was moved to the end of the 
first paragraph. 
Page 45, Section 5.3.1 
Concomitant Therapies, 1st 
paragraph. 
The following sentence was added 
to the end of the paragraph: All 
concomitant medications should 
be reported to the investigator and 
recorded on the appropriate CRF. 
This sentence was added to the 
1st paragraph and deleted from 
below. 
42 
Page 45, Section 5.3.1 
Concomitant Therapies, 1st 
bullet. 
• 
Patients who are 
receiving low-dose warfarin 
or coumadin-like products 
should have their INR 
monitored and maintained at 
≤1.5 
Page 45, Section 5.3.1 
Concomitant Therapies, 1st 
bullet. 
• 
Patients who are receiving 
low-dose warfarin or coumadin-
like products should have their 
INR monitored and maintained 
at ≤2.0 
Upper limit of INR changed to 
≤2.0 for prophylactic use of 
anticoagulation, which is at the 
lower end of the therapeutic 
range for prevention and 
treatment of thrombosis, in 
order to minimize the risk of 
hemorrhage. 
43 
Page 46, Section 5.3.1 
Concomitant Therapies, 1st 
paragraph. 
Page 46, Section 5.3.1 
Concomitant Therapies, 1st 
paragraph. 
The investigator should closely 
monitor patients receiving anti-
platelet and/or anti-thrombotic 
drugs with INR, aPTT and platelet 
count during study drug treatment 
and make a timely decision on 
whether to continue or stop such 
drugs in patients that report Grade 
≥2 hemorrhagic events at any site, 
based on an individual assessment 
of the risk-benefit balance (See 
Appendix J for additional 
information on the clinical 
management of severe or serious 
hemorrhagic AEs). 
This paragraph was added 
to instruct investigators to 
closely 
monitor 
coagulation-related 
lab 
results 
and 
consider 
whether anti-platelet and/or 
anti-thrombotic 
concomitant 
medications 
should be continued in the 
event 
of 
Grade 
≥2 
hemorrhagic events at any 
site. This is designed to 
mitigate the risk of severe 
(Grade ≥ 3) and serious 
(SAEs) hemorrhagic AEs 
44 
Page 47, Section 6.1, Safety 
Assessments, Vital Signs 
Assessment, 1st paragraph, 
3rd sentence. 
For patients with a baseline 
history of antihypertensive 
medications, blood pressure 
should be monitored at 3 
hours (±2 hours) after the 
daily doses of anti- 
hypertensive medication. 
Page 47, Section 6.1, Safety 
Assessments, Vital Signs 
Assessment, 1st paragraph, 3rd 
sentence. 
For patients with a baseline history 
of hypertension, or those who 
develop hypertension during the 
study, blood pressure should be 
monitored daily by the patient at 
home, at 3 hours (±2 hours) after 
the daily doses of anti- 
hypertensive medication, and the 
results recorded in a blood pressure 
diary. Patients monitoring their 
blood pressure should bring their 
Clarification that patients with 
hypertension must monitor 
their blood pressure at home 
and keep a diary of the results. 


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diary to each study visit. 
45 
Page 48, Cardiac 
Monitoring, 1st paragraph, 
1st sentence. 
Left ventricular ejection 
fraction (LVEF) assessed via 
ultrasonic cardiogram and 12- 
lead. 
Page 48, Cardiac Monitoring, 
1st paragraph, 1st sentence. 
Left ventricular ejection fraction 
(LVEF) assessed via 
echocardiogram and 12- lead… 
The more appropriate term in 
the U.S. for this cardiac 
imaging modality is 
“echocardiogram.” 
46 
Page 48, Section 6.2 Efficacy 
Assessment 
The baseline tumor 
assessment can be comleted 
within 28 days prior to first 
administration of study drug. 
All measurable and evaluable 
lesions should be assessed and 
documented at this visit, 
using physical… 
Page 49, Section 6.2 Efficacy 
Assessment 
The section was titled “Tumor 
Assessment” and the window of 
± 7 days was added. 1st sentence 
of the 1st paragraph now reads: 
The baseline tumor assessment 
can be completed within 28 days 
prior to first administration of 
study drug. All measurable and 
evaluable lesions should be 
assessed and documented at this 
visit ± 7 days, using physical… 
The window of assessment 
was added for procedural 
clarification. 
47 
Page 61, Section 6.2 Efficacy 
Assessment, paragraph 4 
Disease status will be assessed 
using RECIST version 1.1 (see 
Appendix C). At the 
investigator’s discretion, other 
methods of assessment of 
measurable disease as per 
RECIST may be used. 
Includes assessment of PSA 
levels for patients who have 
prostate cancer at each cycle. 
Includes assessment of CA- 
125 levels for patients who 
have ovarian cancer at each 
cycle. The same imaging 
procedure used to define 
measurable lesions at baseline 
must be used throughout the 
study for each patient. 
Page 49, Section 6.2 Efficacy 
Assessment, now paragraphs 
4&5 
Disease status will be assessed 
using RECIST version 1.1 (see 
Appendix C). The same imaging 
procedure used to define 
measurable lesions at baseline 
must be used throughout the 
study for each patient. 
At the investigator’s discretion, 
other methods of assessment of 
measurable disease as per 
RECIST may be used. Examples 
of other assessment methods 
include tumor markers, such as 
PSA and CA-125 levels for 
patients with prostate and ovarian 
cancer, respectively. However, 
tumor markers alone cannot be 
used to assess response. If 
markers are initially above the 
upper normal limit, they must 
normalize for a patient to be 
considered in complete response. 
Paragraph 4 was broken up 
into two separate 
paragraphs. It was clarified 
that tumor assessment 
methods in addition to 
standard imaging, e.g., 
tumor markers, may be 
used as part of the 
assessment, as described in 
RECIST v 1.1. 
It is clarified that tumor 
markers alone cannot be used 
to assess a tumor response, and 
additional detail is provided to 
describe how tumor markers 
can be considered in the 
overall assessment of tumor 
responses. 


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48 
Page 50, Section 7.1.1 Adverse 
Events and Serious Adverse 
Events (SAEs) 
Page 51, Section 7.1.1 
The section was renamed to 
7.1.1 Adverse Events and 
broken up to distinguish 
between SAEs and AEs. The 
following section was added: 
7.1.2 SAEs and other 
Expedited Reporting of 
Adverse Events. Section 
7.1.2. was subdivided into the 
following sections: 7.1.2.1 SAE 
definition, 7.1.2.2 Potential 
Drug-Induced Liver Injury 
(DILI), and 
7.1.2.3 Severe Hemorrhagic 
Events 
This section was divided to 
improve the organization of 
content, and to add a specific 
section for Severe 
Hemorrhagic Events. 
49 
Page 50-51, Section 7.1.1, 
bullet list: A serious adverse 
event is any AE that is any of 
the following: 
Page 51, 7.1.2.1 SAE 
definition 
The following bullet point was 
added to the end of the list: 
If AEs meet any of the above 
serious criteria, the AEs should be 
reported to sponsor as an SAE no 
more than 24 hours after 
awareness of the SAE. 
The bullet point was added to 
specify the time window for 
reporting SAEs to the Sponsor. 
50 
Not applicable, section added. Page 52, 7.1.2.3 Severe 
Hemorrhagic Events 
When hemorrhagic events meet 
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. 
The management of severe or 
serious hemorrhagic events will 
be conducted according to 
Appendix J. 
This section instructs 
investigators to report any 
hemorrhagic event with Grade 
≥ 3, regardless of whether it 
is serious or non-serious, 
within the same time window 
as all SAEs. 
51 
Page 52, Section 7.1.3 
Adverse Events Reporting 
Period. 
After initiation of study 
medications, all AEs and SAEs 
regardless of attribution will be 
collected until 30 days 
following the last dose of study 
treatment or a new treatment of 
anti-tumor therapy, whichever 
is earlier. 
Page 53, Section 7.1.4 Adverse 
Events Reporting Period. 
2nd paragraph, first sentence: After 
initiation of study drug, all AEs 
and SAEs (including non-serious 
potential DILI and non-serious 
severe hemorrhagic events), 
regardless of attribution…. 
This modification specifies 
that non-serious drug-induced 
liver injury (DILI) AEs and 
non- serious severe (grade ≥ 3) 
hemorrhagic events are 
reported according to the same 
schedule as SAEs. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
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Current version: v2.0 
Reason for Amendment 
52 
Page 55, Pregnancy section, 
1st paragraph, 2nd sentence. 
The investigator should report 
all pregnancies within 24 hours 
to the sponsor. 
Page 56, Pregnancy section, 1st 
paragraph, 2nd sentence. 
The investigator should report all 
pregnancies within 24 hours to the 
sponsor (the reporting period for 
pregnancy continues up to 30 days 
after completion of the study drug). 
Clarification of the duration of 
the reporting period for 
pregnancy. 
53 
Page 55, Section 7.2 
Expedited Reporting 
Requirements for Serious 
Adverse Events 
· 
Serious adverse events 
· 
Potential Drug-
Induced Liver Injury 
regardless of seriousness 
· 
Pregnancies 
SAEs occurring beyond the 
abovementioned time limit, if 
considered related to the study 
investigational drug, should also 
be reported to the sponsor. 
Page 57, 7.2 Expedited 
Reporting Requirements, bullet 
points clarified and added: 
· 
Serious adverse events 
(from informed consent to 30 
days following the last dose of 
study drug or a new treatment of 
anti-tumor therapy) 
· 
Potential Drug-Induced 
Liver Injury regardless of 
seriousness 
· Severe hemorrhagic events 
(NCI CTCAE grade ≥ 3), 
regardless of seriousness 
· 
Pregnancies 
SAEs occurring beyond the 
abovementioned time limit (30 
days after the discontinuation of 
the study drug), if considered 
related 
The group of AEs for which 
Expedited Reporting is 
required is expanded 
beyond SAEs and 
pregnancies to include non-
serious DILI events, and 
non-serious severe (grade ≥ 
3) hemorrhagic events. 
In addition, the duration of 
time after the last dose of 
study drug is extended to 30 
days (if not related) or 
longer than 30 days (if 
related) for reporting all of 
these events. 
. 
54 
Page 56, Section 8, 
Statistical 
Analysis. 
The final analysis will be based 
on patient data collected 
through study discontinuation 
or study termination. All 
summaries will be presented by 
assigned dose level. 
Page 58, Section 8, Statistical 
Analysis. The introduction to 
this section was rewritten: 
All statistical analysis will be 
performed under the direction of 
Hutchison MediPharma 
personnel. Any data analysis 
carried out independently by the 
investigator should be submitted 
to Hutchison MediPharma prior to 
publication or presentation. 
The final analysis of study data 
will be based on all patient data 
up to the time when either all 
patients have discontinued the 
study or the study has been 
terminated. Details of the 
statistical analysis and data 
reporting will be provided in the 
Statistical Analysis Plan (SAP) 
document finalized prior to 
database lock. 
Data will be summarized using 
descriptive statistics (continuous 
The introduction to this 
section was rewritten to 
specify that all statistical 
analyses should be 
performed under the 
direction of Hutchison 
MediPharma personnel. 
In addition, more information 
is provided on how the data 
will be summarized and 
finalized, on the requirement 
of completion of the SAP 
before database lock, and on 
the description of how missing 
data will be treated in the 
statistical analyses. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Prior version: v1.1 
Current version: v2.0 
Reason for Amendment 
data) and/or contingency tables 
(categorical data) for 
demographic and baseline 
characteristics, efficacy 
measurements, safety 
measurements, and 
pharmacokinetic measurements. 
Information regarding 
compliance with efficacy testing 
and data missingness will be 
documented. Graphical 
techniques (eg, waterfall plots, 
Kaplain-Meier curves) will be 
used when such methods are 
appropriate and informative. 
The baseline value used in each 
analysis will be the last (most 
recent) pre-treatment value. 
Analyses will be based upon the 
observed data unless methods for 
handling missing data are 
specified. 
Analyses will be performed using 
SAS® (Version 9.1 or higher). 
55 
Page 56, Section 8.1, 
Analysis Populations. 3rd 
bullet. 
 
Evaluable for Response Set 
(ERS): This population 
includes all dosed tpatients 
who have measurable tumor 
lesions at baseline. Tumor 
evaluation related endpoints 
other than PFS will be 
summarized based on this 
specific population. 
Page 59, Section 8.1, Analysis 
Populations. 3rd bullet. 
Response Evaluable Analysis Set 
(REAS): All SAS patients who 
have at least one post-baseline 
tumor assessment will be 
included in the REAS. Tumor 
evaluation related endpoints will 
be summarized based on this 
analysis set. 
A better description of the 
REAS was provided. It was 
made clear that all patients that 
have at least one post baseline 
assessment will be included. 
This was not clear previously. 
56 
Page 56, Section 8.2, 
Analysis of the Conduct of 
the Study. This entire 
section was rewritten. 
Enrollment, major protocol 
violations, and 
discontinuations from the 
study will be summarized by 
dose level. 
Demographic and baseline 
characteristics, such as age, 
sex, race/ethnicity, weight, 
type of malignancy, duration 
of malignancy, site of 
metastatic disease, and 
baseline ECOG performance 
status, will be summarized 
Page 59, Section 8.2, Analysis 
of the Conduct of the Study. 
This entire section was 
rewritten. 
A patient listing of all treated 
patients will be generated to 
describe site, subject number, 
screening date, first dosing date, 
duration of study treatment, 
analysis set in which the patient 
included and disposition. In the 
patient disposition listing, reason 
for study drug discontinuation 
will be included. A table will be 
created to summarize these 
categories in terms of number 
and percent for each of the 
A more detailed description of 
this section was provided with 
a more accurate description of 
listings to be generated for the 
study conduct analysis. 


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Current version: v2.0 
Reason for Amendment 
using means, standard 
deviations, medians, and 
ranges for continuous 
variables, and proportions for 
categorical variables. All 
summaries will be presented 
overall and by dose level.  
Study drug administration 
data will be listed by dose 
level, and any dose 
modifications will be flagged. 
Means and standard 
deviations will be used to 
summarize the total dose of 
fruquintinib received. 
 
analysis set defined above. 
Patient demographics and 
baseline characteristics, such as 
age, sex, race/ethnicity, weight, 
type of malignancy, duration of 
malignancy, site 
of metastatic disease, and 
baseline ECOG performance 
status, will be listed and 
summarized. All summaries will 
be presented overall and by dose 
level. 
Major protocol deviations related 
to study inclusion or exclusion 
criteria, conduct of the trial, 
subject management, or subject 
assessment will be listed. 
Study drug administration data 
will be listed by dose level, and 
any dose modifications will be 
flagged. Descriptive information 
will be provided regarding 
number of initialized cycles, 
total days of study drug 
exposure, actual days of study 
drug taken, cumulative dose of 
study drug, dose intensity and 
relative dose intensity and the 
number and timing of prescribed 
dose reductions and 
interruptions. 
57 
Page 57, Section 8.3, Safety 
Analysis. 
AE severity will be graded 
according to the NCI CTCAE 
(version 4.03). AEs will be 
coded with Medical 
Dictionary for Drug 
Regulatory Activities 
(MedDRA). The frequency of 
AEs will be summarized by 
MedDRA System Organ 
Class (SOC) as well as 
Preferred Term (PT). The 
incidence of TEAEs, SAEs, 
AEs of special interest, AEs 
leading to dose interruption, 
reduction, or treatment 
discontinuation will be 
presented by a system organ 
class and preferred term; by 
relationship to investigational 
product and by toxicity grade 
for each dose level in both 
Page 59, Section 8.3, Safety 
Analysis. Paragraph 2 and 3. 
AE severity will be graded by the 
investigator according to the NCI 
CTCAE (version 4.03). If a 
CTCAE criterion does not exist, 
the grade corresponding to the 
appropriate adjective will be used 
by the investigator to describe the 
maximum intensity of the 
adverse event: Grade 1 (mild), 
Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life 
threatening), or Grade 5 (fatal). 
All AEs will be coded with 
Medical Dictionary for Drug 
Regulatory Activities 
(MedDRA). 
All AEs will be listed. The focus 
of safety data summarization will 
be on treatment-emergent 
adverse events (TEAEs), which 
are defined as adverse event that 
Paragraph 2 of the original 
section was revised. The 
paragraph was split into two 
paragraphs and edited for 
content. The 2nd paragraph 
now includes the process by 
which investigators are to 
grade AEs in the event there is 
not a CTCAE criterion for the 
AE intensity observed. Details 
regarding AE listings and 
TEAEs were provided and 
edited for content. 


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Current version: v2.0 
Reason for Amendment 
study phases. Changes in 
laboratory data will be 
summarized by grade using 
the NCI CTCAE, v4.03. 
When counting abnormal 
laboratory results at patient 
level, the worst value during 
study treatment will be 
chosen. 
occurs or worsen in the period 
extending from the first dose of 
study drug to 30 days after the 
last dose of study drug in this 
study. 
TEAEs will be summarized as 
the number of patients and 
corresponding percentage by 
MedDRA System Organ Class 
(SOC) as well as Preferred Term 
(PT). 
58 
Page 58, Section 8.5, Tumor 
Assessment 
Tumor-assessment related 
endpoints, ORR, DCR and 
DoR will be summarized 
based on ERS. PFS will be 
summarized for SAS. 
Objective Response Rate 
(ORR) 
The objective response rate 
(ORR) will be estimated only 
for patients with disease that 
is measurable by RECIST 
(v.1.1, see Appendix C). The 
ORR is defined as the number 
(%) of patients with at least 
one response of CR or PR at a 
study visit that is confirmed at 
least 
4 weeks later. Data obtained 
up until progression, or the last 
evaluable assessment in the 
absence of progression, will be 
included in the assessment of 
ORR. However, any CR or PR 
which occurs after the patient 
has received an anticancer 
therapy other than fruquintinib 
anticancer 
will not be included in 
numerator of the ORR 
calculation. 
Progression Free Survival (PFS) 
Progression free survival (PFS) 
is defined as the time from date 
of first dosing until the date of 
an objective disease progression 
as defined by RECIST 1.1 or 
death (by any cause in the 
absence of progression) 
regardless of whether the 
patient withdraws from the 
fruquintinib therapy. Patients 
Page 61, Section 8.5, Tumor 
Assessment 
Objective Response Rate (ORR) 
The objective response rate (ORR) 
is defined as the percentage of 
patients with at least one best 
overall response of CR or PR 
according to RECIST 1.1. 
ORR will be calculated based on 
the REAS. Proportions of subjects 
with ORR will be presented by 
dose group along with exact 
confidence intervals. 
Progression Free Survival (PFS) 
Progression free survival (PFS) is 
defined as the time from date of 
first dose of study drug until the 
date of an objective disease 
progression as defined by 
RECIST 1.1 or death for any 
reason. Patients who have not 
progressed or died at the time of 
analysis will be censored at the 
time of the last tumor assessment. 
The censoring rule for PFS will 
be detailed in the Statistical 
Analysis Plan (SAP). 
PFS will be summarized by dose 
cohort 
descriptively 
using 
Kaplan-Meier 
medians 
and 
quartiles. 
Duration of Response (DoR) 
Duration of response (DoR) is 
defined as the time from date of 
the first objective response 
complete response (CR) or 
partial response (PR), which 
evever comes first, until the 
occurene of documented disease 
progression or of death in the 
absence of disease progression.  
If a patient does not progress 
following a response, then the 
This section was edited and 
rewritten for clarity and 
simplification. In addition, 
provided more details on the 
statistical analysis methods for 
the endpoints. 


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Current version: v2.0 
Reason for Amendment 
who have not progressed or 
died at the time of analysis will 
be censored at the time of the 
latest date of assessment from 
their last evaluable RECIST 
assessment. However, if the 
patient progresses or dies after 
two or more consecutive missed 
tumor assessment visits, the 
patient will be censored at the 
time of the latest evaluable 
RECIST assessment. If the 
patient has no evaluable tumor 
assessment visits after first dose 
of study treatment or does not 
have evaluable baseline tumor 
assessment data the patient will 
be censored on the date of first 
dosing unless they die within 
two tumor assessment visits of 
baseline. Patients who start new 
anticancer treatment initiated 
prior to documented disease 
progression or death on study, 
will be censored at the date of 
last evaluable tumor assessment 
prior to or on date of new 
anticancer treatment. 
Duration of Response (DoR) 
Duration of response (DoR) 
will be defined as the time from 
the date of the first documented 
response, (that is subsequently 
confirmed) until the date of the 
documented progression or of 
death in the absence of disease 
progression. Then, the end of 
response should coincide with 
the date of progression or death 
from any cause used for the 
PFS endpoint. 
duration of response will be 
censored at the same time of 
PFS. 
 
59 
Page 58, Section 8.5, Tumor 
Assessment 
Not applicable, section added. 
Page 61, Section 8.5, Tumor 
Assessment 
Change in Tumor Size. 
Percentage change in tumor size 
will be determined for patients 
with measurable disease at 
baseline and is derived at each 
visit by the percentage change in 
the sum of the diameters of target 
lesions compared to baseline. Best 
percentage change in tumor size 
will be 
summarized using descriptive 
The methodology in RECIST 
v 1.1 for assessing thechange 
in tumor size is added. 


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Protocol Number: 2015-013-00US1                                                        Version 4.0 
Prior version: v1.1 
Current version: v2.0 
Reason for Amendment 
statistics and waterfall plot. 
60 
Page 61-62, Section 12, Data 
Quality. 3rd paragraph and 
5th paragraph. 
3rd paragraph: The Sponsor 
will be responsible for data 
management of this study, 
including quality checking of 
the data. Data entered 
manually will be collected via 
EDC with use of eCRFs. Sites 
will be responsible for data 
entry into the EDC system. In 
the event of discrepant data, 
the Sponsor or its agent will 
request data clarification from 
the sites, which the sites will 
resolve electronically in the 
EDC system. 
5th paragraph deleted/rewritten: 
A comprehensive validation 
check program will verify the 
data and discrepancy reports 
will be generated accordingly 
for resolution by the 
investigator. 
Throughout the study the Study 
Management Team will review 
data according to the Data 
Validation Manual (Any 
decision to use the CRF as a 
source document must be stated 
in the Data Validation Manual 
and the investigator 
must be advised of this 
decision). 
Page 64-65, Section 12, Data 
Quality. 3rd paragraph. 
The Sponsor or its agent will be 
responsible for data management 
of this study according to data 
management documents. Any 
decision to use the CRF as a 
source document must be stated 
in the Data Validation Manual 
and the investigator must be 
advised of this decision. A 
comprehensive validation check 
program will verify the data and 
discrepancy will be generated 
accordingly. In the event of 
discrepant data, the Sponsor or its 
agent will issue data queries to 
the site and request data 
clarification. Site 
are required respond to all queries 
and promptly enter date into the 
EDC system. 
The 3rd and 5th paragraphs 
were combined and edited for 
content and rewritten more 
succinctly and for clarity. 
61 
Page 67, Notes to Study 
Flow Chart, Note #4. 
All measurable and evaluable 
lesions should be assessed and 
documented at this visit, using 
physical examination and 
image-based evaluation. 
Page 69, Notes to Study Flow 
Chart, Note #4. 2nd sentence & 
the following sentence was 
added to the end of the note. 
2nd sentence: All measurable 
and evaluable lesions should be 
assessed and documented at this 
visit +/- 7 days, using physical 
examination and image-based 
evaluation. 
Added sentence: At the 
investigator’s discretion, other 
methods of assessment of 
measurable disease as per RECIST 
Lesion assessment 
windows are added to 
specify when they should 
be done in relation to the 
study visit schedule. The 
sentence added to note #4 
provides guidance to 
investigators on the 
optional use of tumor 
assessment methods other 
than imaging, e.g., tumor 
markers, that are described 
in RECIST v 1.1. 


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Current version: v2.0 
Reason for Amendment 
may be used. 
Examples of other assessment 
methods include tumor markers, 
such as PSA and CA-125 levels 
for patients with prostate and 
ovarian cancer, respectively. 
However, tumor markers alone 
cannot be used to assess response. 
If markers are initially above the 
upper normal limit, they must 
normalize for a patient to be 
considered in complete response. 
Many of the footnotes were 
edited for clarity and grammar. 
62 
Page 68, Notes to Study 
Flow Chart, Note #15. 
Adverse Events and 
Concomitant Medications 
are collected continuously 
from the time of informed 
consent until 30 days after 
study completion, but 
represented at study visits 
on this study flow chart. 
Page 70, Notes to Study 
Flow Chart, Note #15. 
After informed consent, all SAEs 
and concomitant medications 
will be collected. After initiation 
of study drug, all AEs and SAEs 
will be collected until 30 days 
following the last dose of study 
drug or a new treatment of anti-
tumor therapy, whichever is 
earlier. After this period, 
investigators should report only 
SAEs that are considered to be 
related to the study drug. 
Changed the AE reporting 
period from first dose of study 
instead of informed consent, 
and keep it consistent with 
Section 7.1.4. 
63 
 
 
Page 77, Table PK Sampling 
Time Points. 
Cycle 1, Day 1 
Pre-dose 10 
minutes 
Cycle 1, Day 2 
Pre-dose 
10 minutes 
Cycle 1, Day 14 
Pre-dose 
10 minutes 
Cycle1, Day 15 
Pre-
dose 10 minutes 
Cycle1, Day 21 
Pre-dose 
10 minutes 
Cycle 1, Day 22 
Pre-dose 
10 minutes 
Page 79, Table PK Sampling 
Time Points. 
Windows to the sampling 
time points were adjusted. 
Cycle 1, Day 1 
Pre-dose (≤ 10 minutes) 
Cycle 1, Day 2 
Pre-dose 
(≤ 10 minutes) 
Cycle 1, Day 14 
Pre-dose 
(≤ 10 minutes) 
Cycle1, Day 15 
Pre-dose 
(≤ 10 minutes) 
Cycle1, Day 21 
Pre-dose 
(≤ 10 minutes) 
Cycle 1, Day 22 
Post-dose 
24 hours (± 60 minutes) on 
Day 21 
The modifications provide 
specific windows to those time 
points in the sample schedule 
that did not have a window 
defined. 


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Current version: v2.0 
Reason for Amendment 
64 
Page 78, Appendix E. 
Prohibited Concomitant 
Medications that have a 
Known Risk of QT 
prolongation and/or 
Torsades des Pointes (TdP). 
The list is continuously updated 
online at 
www.crediblemeds.org or 
www.qtdrugs.org. The 
investigator should consult both 
the list below and one of the 
above referenced web sites to 
be sure none of the concomitant 
medications are prohibited 
because of a known risk of QT 
prolongation and/or TdP. 
Page 80, Appendix E Prohibited 
Concomitant Medications that 
have a Known Risk of QT 
prolongation and/or Torsades 
des Pointes (TdP). 
The list is continuously updated 
online at www.crediblemeds.org or 
www.qtdrugs.org 
The second sentence was 
deleted for brevity. It is clear 
from the section title what this 
list is intended for. 
65 
Page 80, Appendix F 
Fruquintinib and Potential 
Drug-Drug Interactions 
Page 84, Appendix F 
Fruquintinib and Concomitant 
Medication 
The section was renamed. 
66 
Not applicable, Appendix J 
was added. 
Page 91-93, Appendix J, 
Clinical Management of severe 
or serious hemorrhagic events. 
This appendix was added to 
provide detailed guidance 
to investigators on the 
management of severe 
(Grade ≥ 3) or serious 
(SAE) hemorrhagic events 
to mitigate the risk and 
impact of such events on 
study patients. A flow chart 
is included. 
 

SAP_001.pdf: 
 
 
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Statistical Analysis Plan 
 
 
 
2015-0013-00US1 
A MULTI-CENTER, OPEN-LABEL, PHASE 1/1B CLINICAL STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
ANTICANCER ACTIVITY OF FRUQUINTINIB IN PATIENTS WITH ADVANCED 
SOLID TUMORS 
 
 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
 
Statistical Analysis Plan V2.5 (Dated 18Feb2021) for Protocol 2015-013-00US1. 
 
 
 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
 
 
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MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
0.1 
10Jan2018 
 
Not Applicable – First Version 
0.2 
15Mar2018 
 
Revise 3.1 section according to protocol 
version 2 
Revise the REAS according to protocol 
version 2 
Add the FAS according to the 
requirement for analysis 
Delete the shift table for low, high, 
normal according to protocol 
0.3 
24Jan2019 
 
Add the definition of OS and PFS at 12 
weeks 
Revise the population set of REAS to 
EAS. 
Add the definition of subsequent anti-
cancer therapy. 
Delete the shift from baseline analysis of 
ECOG PS. 
Global changes according to protocol 
version 3. 
1.0 
30Jan2019
 
Upgrade version, no updates. 
1.0 
17Jan2020 
 
Updating SAP & Shell according to 
sponsor’ comments 
1.1 
11Feb2020 
 
Updating SAP & Shell according to 
sponsor’ comments 
 
03Mar2020 
 
Update Table 14.1.1.1, Table 14.1.6.1, 
source listing of Table 14.1.6.2,  
 
09Mar2020
 
Update shell of “ Listing 16.2.7.2” 
 
12Mar2020
 
 
Revise source listing of Table 14.1.3, 
update section 7.3 
 
16Mar2020 
 
Update notes to programmer of  Listing 
16.2.7.3 
Update layout of Listing 16.2.1.1, 
16.2.1.2 and 16.2.6.5 
 
17Mar2020 
 
Updating Source of Table 14.1.2 and 
notes to programmer of  Listing 
16.2.9.1.1 


 
 
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07Apr2020 
 
- Updating Listing 16.2.1.2, 16.2.3.1, 
16.2.4.2, 16.2.5.1.1, 16.2.5.2, 16.2.5.1.3, 
16.2.5.6, 16.2.7.2, 16.2.6.4, 16.2.7.7; 
Table 14.1.4.3.2, 14.3.1.2, 14.3.1.3.2  
- Updating footnote of Listing 16.2.4.2, 
16.2.5.1.2, 16.2.5.2, 16.2.5.3;  Table  
14.3.1.6.2, 14.3.1.7.3, 14.3.1.8.3,  
- Updating note to programmer of Table 
14.3.1.11.3, 14.3.1.12.3,   
- Typo:  Listing 16.2.4.2, 16.2.5.1.2,  
- Revision of table caption: 14.2.1.1, 
14.2.2.1, 14.2.3.1, 14.2.4.1, 14.2.5.1  
- Adding Table 14.2.1.2, 14.2.2.2, 
14.2.3.2, 14.2.4.2, 14.2.5.2, 14.4.1, 
14.4.2 
- Adding Figure 14.2.1.2, 14.2.2.2, 
14.2.3.2, 14.2.4.2, and 14.4.1 
- SAP update: 18.2.1 
1.2 
15Oct2020 
 
- Revision done for amended protocol 
V.4.0 
-Wording change on replacing ‘subject’ 
with ‘patient’  
-Typos 
-Output Conventions 
-Revisions were done in almost all 
sections except for section 4.2, 6, 7.1, 
7.2,  7.3.3-7.5, 8, and 14. 
2.0 
23Nov2020 
 
Revision according to sponsor’s 
comments  
 
30Nov2020 
 
- Revisions of format and typos 
- Remove one blank page 
 
04Dec2020 
 
- Remove section 2.3 to Appendix 1 
- Re-number all appendices 
- Revisions of section 3, 5.7, 6.2, 6.3.1, 
6.3.2, 7-12, 13.2, 14, 15.1, 16.1.5, 16.2    
- Changes on wording according to 
sponsor’s comments 
 
08Dec2020 
 
Revise SI unit of: Alkaline Phosphatase, 
Aspartate Aminotransferase, Alanine 
Aminotransferase 
 
09Dec2020
 
Update Appendix 4 
 
10Dec2020
 
Update section 2.4 and 17.4.4 


 
 
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16Dec2020 
 
- Section 17.7 and corresponding shell 
- Update some inconsistencies based on 
shell 
- Specify cut-off date on header 
- Separate Table 14.1.1.1 into 2 tables 
and update footnote separately 
- Footnote update for some tables 
- Update Appendix 4 
- typo correction 
 
18Dec2020
 
Date update 
2.2 
02Jul2021 
 
Update Appendix 2:  Presentation of 
Treatment Groups 
2.3 
16Nov2021 
  
Date update 
2.4 
13Dec2021 
  
- Version and date updated 
- Updated format of Appendix 4, 5 and 6 
- Updated table 2 and AESI description 
in section 17.2.6 
- Removed additional blank 
- Updated listing 16.2.9.6 
Pharmacokinetic Blood Sample 
(Pharmacokinetic Analysis Set) to listing 
16.2.9.6 COVID-19 Visit Impact (Safety 
Analysis Set) 
2.5 
18Feb2022 
 
- Version and date updated 
- Update the AESI list of table in 
Appendix 5, the old list is the MedDRA 
24.0, and the updated list is using 
MedDRA 24.1. 


 
 
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TABLE OF CONTENTS 
Statistical Analysis Plan Signature Page ............................................................................................................ 2 
Output Templates Signature Page ...................................................................................................................... 3 
Table of Contents .................................................................................................................................................. 7 
1. 
Introduction ............................................................................................................................................ 12 
1.1. 
Primary Objective ............................................................................................................................. 12 
1.1.1. 
Dose Escalation Phase ...................................................................................................................... 12 
1.1.2. 
Dose Expansion Phase ...................................................................................................................... 12 
1.2. 
Secondary Objectives ....................................................................................................................... 12 
1.2.1. 
Dose Escalation Phase ...................................................................................................................... 12 
1.2.2. 
Dose expansion Phase ....................................................................................................................... 12 
2. 
Study Design ............................................................................................................................................ 13 
2.1. 
Dose Escalation Phase ...................................................................................................................... 13 
2.2. 
Dose Expansion Phase ...................................................................................................................... 14 
2.3. 
Study Endpoints ................................................................................................................................ 15 
2.3.1. 
Dose Escalation Phase ...................................................................................................................... 15 
2.3.2. 
Dose Expansion Phase ...................................................................................................................... 15 
2.4. 
Changes to Analysis from Protocol .................................................................................................. 16 
3. 
Planned Analyses .................................................................................................................................... 16 
3.1. 
Interim Analysis ................................................................................................................................ 16 
3.2. 
Final Analysis ................................................................................................................................... 17 
4. 
Analysis Sets ............................................................................................................................................ 17 
4.1. 
All Patients Enrolled Set [ENR] ....................................................................................................... 17 
4.2. 
Safety Analysis Set [SAS] – (All Treated Population) ..................................................................... 17 
4.3. 
Dose-Limiting Toxicity Evaluable Set [DLT] .................................................................................. 17 
4.4. 
Efficacy Analysis  Set [EAS] ............................................................................................................ 17 
5. 
General Considerations .......................................................................................................................... 18 
5.1. 
Reference Start Date and Study Day ................................................................................................ 18 
5.2. 
Baseline ............................................................................................................................................ 18 
5.3. 
Unscheduled Visits and Early Termination Data .............................................................................. 18 
5.4. 
Windowing Conventions .................................................................................................................. 19 
5.5. 
Statistical Tests ................................................................................................................................. 19 
5.6. 
Common Calculations....................................................................................................................... 19 
5.7. 
Software Version .............................................................................................................................. 19 
6. 
Statistical Considerations ....................................................................................................................... 19 
MODIFICATION HISTORY ................................................................................................. 4 
LIST OF ABBREVIATIONS ............................................................................................... 10 


 
 
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6.1. 
Adjustments for Covariates and Factors to be Included in Analyses ................................................ 19 
6.2. 
Multicenter Studies ........................................................................................................................... 20 
6.3. 
Missing data ...................................................................................................................................... 20 
6.3.1. 
Missing Dates Information of Study Treatment ............................................................................... 20 
6.3.2. 
Missing or Incomplete Date Information for Adverse Event Date ................................................... 20 
6.3.3. 
Missing or Incomplete Date Information for concomitant Medication/ Procedure .......................... 22 
6.3.4. 
Missing or Incomplete Date Information for Primary Diagnosis Date and Metastatic Diagnosis Date
 
22 
6.3.5. 
Missing or Incomplete Date Information for Efficacy Data ............................................................. 22 
6.4. 
Multiple Comparisons/ Multiplicity ................................................................................................. 22 
6.5. 
Examination of Subgroups ................................................................................................................ 22 
7. 
Output Presentations .............................................................................................................................. 23 
8. 
Disposition and Withdrawals ................................................................................................................. 23 
8.1. 
Enrollment ........................................................................................................................................ 23 
8.2. 
Patient status at treatment and study completion .............................................................................. 24 
9. 
Protocol Deviation .................................................................................................................................. 24 
10. 
Demographic and other Baseline Characteristics ................................................................................ 25 
10.1. 
Derivations ........................................................................................................................................ 25 
11. 
Surgical and Medical History ................................................................................................................ 25 
12. 
Oncology History .................................................................................................................................... 25 
12.1. 
Derivations ........................................................................................................................................ 26 
13. 
Oncological Therapies ............................................................................................................................ 26 
13.1. 
Prior oncological therapy .................................................................................................................. 26 
13.2. 
Subsequent Oncology Therapy ......................................................................................................... 27 
14. 
Medications and Procedures .................................................................................................................. 27 
14.1. 
Prior and Concomitant Medication ................................................................................................... 28 
14.2. 
Concomitant procedures ................................................................................................................... 28 
15. 
Study Medication Exposure ................................................................................................................... 28 
15.1. 
Exposure to study medication ........................................................................................................... 29 
15.2. 
Study Medication Compliance .......................................................................................................... 29 
15.3. 
Derivations ........................................................................................................................................ 29 
16. 
Efficacy Outcomes .................................................................................................................................. 30 
16.1. 
Primary Efficacy Variable(s) & Derivation(s) .................................................................................. 30 
16.1.1. 
Best Overall Response (BOR) .......................................................................................................... 30 
16.1.2. 
Objective Response Rate (ORR) ...................................................................................................... 31 
16.1.3. 
Duration of Response (DoR) ............................................................................................................ 31 
16.1.4. 
Duration Control Rate (DCR) ........................................................................................................... 31 
16.1.5. 
Progression Free Survival (PFS) ....................................................................................................... 31 
16.1.6. 
Overall Survival (OS) ....................................................................................................................... 33 
16.1.7. 
Tumor Shrinkage .............................................................................................................................. 33 
16.2. 
Analysis of Efficacy Variable(s) ....................................................................................................... 33 


 
 
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17. 
Safety Outcomes ..................................................................................................................................... 34 
17.1. 
DLTs ................................................................................................................................................. 34 
17.2. 
Adverse Events ................................................................................................................................. 35 
17.2.1. 
All TEAEs ........................................................................................................................................ 35 
17.2.2. 
TEAEs Leading to Dose Interruption or Reduction .......................................................................... 36 
17.2.3. 
TEAEs Leading to Discontinuation of Study Drug .......................................................................... 36 
17.2.4. 
Serious Adverse Events .................................................................................................................... 36 
17.2.5. 
Adverse Events Leading to Death ..................................................................................................... 36 
17.2.6. 
Adverse Events Of Special Interest (AESI) ...................................................................................... 36 
17.3. 
Deaths ............................................................................................................................................... 37 
17.4. 
Laboratory Evaluations ..................................................................................................................... 37 
17.4.1. 
Laboratory Specific Derivations ....................................................................................................... 38 
17.4.2. 
CTCAE Grading for Laboratory Data .............................................................................................. 39 
17.4.3. 
Laboratory Reference Ranges ........................................................................................................... 39 
17.4.4. 
Potential Drug-Induced Liver Injury (DILI) ..................................................................................... 39 
17.5. 
ECG Evaluations .............................................................................................................................. 40 
17.5.1. 
ECG Specific Derivations ................................................................................................................. 41 
17.5.2. 
Markedly Abnormal Criteria ............................................................................................................ 41 
17.6. 
Vital Signs ........................................................................................................................................ 42 
17.6.1. 
Vital Signs Specific Derivations ....................................................................................................... 42 
17.6.2. 
Vital Signs Markedly Abnormal Criteria .......................................................................................... 42 
17.7. 
Physical Examination ....................................................................................................................... 43 
17.8. 
Other Safety Assessments ................................................................................................................. 43 
17.8.1. 
ECOG Performance Status ............................................................................................................... 43 
17.8.2. 
Echocardiogram ................................................................................................................................ 43 
17.8.3. 
Pregnancy Test .................................................................................................................................. 43 
17.8.4. 
Tumor Marker ................................................................................................................................... 43 
17.8.5. 
Impact of COVID-19 ........................................................................................................................ 44 
18. 
References ................................................................................................................................................ 44 
APPENDIX 1. Schedule of Events..................................................................................................................... 45 
APPENDIX 2. Programming Conventions for Outputs .................................................................................. 47 
APPENDIX 3. Best Overall Response When Confirmation of CR and PR are Required ........................... 49 
APPENDIX 4. Visit-Window Mapping ............................................................................................................ 51 
APPENDIX 5. MedDRA (Version 24.1) Preferred Term List for AESI Categories .................................... 54 
APPENDIX 6. Clinical Laboratory Parameters CTCAE Criteria ................................................................ 72 
 
 
 


 
 
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LIST OF ABBREVIATIONS 
Terms and 
Abbreviations  
Definition 
AE  
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase/Glutamic-Pyruvic Transaminase 
APTT 
Activated Partial Thromboplastin time 
AST 
Aspartate Aminotransferase/Glutamic-Oxalacetic Transaminase 
ATC 
Anatomical Therapeutic Classification 
BC 
Breast Cancer 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CEA 
Carcino-Embryonic Antigen 
CR 
Complete Response 
CS 
Clinically Significant 
CTCAE  
Common Terminology Criteria for Adverse Event 
CTMS 
Clinical Trial Management System 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
DoR 
Duration of Response 
DILI 
Drug Induced Liver Injury 
ECG  
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF  
Electronic Case Report Form 
ENR 
All Patients Enrolled Set 
HR 
Hormone Receptor 
INR 
International Normalized Ratio 
LLQ 
Lower Limit of Quantification 
mCRC 
Metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multi-Gated Acquisition 
NCI 
National Cancer Institute 


 
 
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NCS 
Not Clinically Significant 
NE 
Not Evaluable 
NSCLC 
Non˗Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD  
Progressive Disease 
PFS 
Progressive Free Survival 
PID 
Percentage Intended Dose 
PLT 
Blood platelet count 
PR2D 
Recommended Phase 2 Dose 
PR 
Partial Response 
RD 
Relative Dose 
PT 
Preferred Term 
QD 
Quaque Die/ Once Daily 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE  
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Stable Disease  
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
STD 
Standard Deviation 
TEAE 
Treatment-Emergent Adverse Event 
TEAESI 
Treatment-Emergent Adverse Event of Special Interest 
TNBC 
Triple-Negative Breast Cancer 
TSH 
Thyroid stimulating hormone 
ULN 
Upper Limit of Normal 
ULQ 
Upper Limit of Quantification 
VEGF 
Vascular Endothelial Growth Factor 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 


 
 
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1.  INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and 
safety data for Protocol 2015-013-00US1. It describes the data to be summarized and analyzed, including specifics 
of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol Version 4.0 (Amendment 4), dated 09 Jan 2020. The 
Pharmacokinetics (PK) and pharmacodynamics analyses will not be performed by IQVIA Biostatistics (BIOS) 
and therefore are not documented in this SAP. 
1.1. 
PRIMARY OBJECTIVE 
1.1.1. DOSE ESCALATION PHASE 
The primary objective of the dose escalation phase is to evaluate the safety and tolerability of fruquintinib in 
patients with advanced solid tumors and to determine the recommended Phase 2 dose (RP2D). 
1.1.2. DOSE EXPANSION PHASE 
The primary objective of the dose expansion phase is to evaluate the anticancer activity of fruquintinib at the 
recommended RP2D from the dose escalation phase, in patients with advanced solid tumors.  
1.2. 
SECONDARY OBJECTIVES 
1.2.1. DOSE ESCALATION PHASE 
The secondary objectives of the dose escalation phase are: 
1.2.2. DOSE EXPANSION PHASE 
The secondary objectives of the dose expansion phase are: 
 
To evaluate the PK characteristics of multiple dose fruquintinib and to investigate the metabolite profile of 
fruquintinib in the plasma of patients with solid tumors (The detailed analysis method will not be 
documented in this document). 
 
To evaluate anticancer activity of fruquintinib in patients with solid tumors according to the Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Eisenhauer et al., 2009).  
 
To evaluate anticancer efficacy of fruquintinib, as assessed by Objective response rate (ORR), disease 
control rate (DCR), duration of response (DoR), progression free survival (PFS) and overall survival (OS). 
 
To evaluate the PK characteristics of multiple dose fruquintinib and to investigate the metabolite profile of 
fruquintinib in plasma. 
 
To evaluate the safety of fruquintinib. 


 
 
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2. STUDY DESIGN 
The study is an open-label phase 1/1b study of fruquintinib comprised of a dose escalation phase that will enroll 
patients with advanced solid tumors of any type, and a dose expansion phase that will enroll patients with advanced 
solid tumors of any type (Cohort A) and in patients with refractory metastatic colorectal cancer (mCRC, Cohort 
B and C), or breast cancer (BC, Cohort D and E) (see study schema below). 
 
 
Approximately 128 patients will be enrolled in this dose escalation/dose expansion study. Approximately 12 
patients will be enrolled in the dose escalation phase, and approximately 116 additional patients (6 with advanced 
solid tumors of any type and 40 with refractory mCRC who progressed on TAS-102 and/or regorafenib, 40 with 
mCRC who had not received TAS-102 or regorafenib, 15 with refractory HR+/HER2- mBC, and 15 with 
advanced, refractory triple-negative breast cancer (TNBC) will be enrolled in the dose expansion phase. 
2.1. 
DOSE ESCALATION PHASE 
Approximately 12 evaluable patients will be enrolled. The actual number of patients will depend on the occurrence 
of dose-limiting toxicities (DLTs) as well as the Maximum Toxicity Dose (MTD) level reached in this trial. MTD 
is the highest dose at which no more than 1 of the 6 patients in each cohort of the dose escalation phase develops 
a DLT. If 2 or more of 6 patients in each cohort of the dose escalation phase develop DLT at a particular dose 
level, that dose has exceeded the MTD. The dose levels to be investigated are 3 mg and 5 mg once daily (QD), 3 
weeks on/1 week off. 
 


 
 
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The definition of DLTs and the DLT assessment window is provided in section 17.1 and the definition of a DLT 
evaluable patient is provided in section 4.3. 
 
To investigate DLT, 6 DLT-evaluable patients will be firstly enrolled in the phase and will be treated with 
fruquintinib 3 mg QD (3 weeks on/ 1 week off) orally. If no more than 1 DLT occurs during the DLT observational 
window (i.e. from Day 1 – 28 in Cycle 1) among the 6 patients, the trial will continue to enroll another 6 patients 
in the next dose cohort in which fruquintinib 5 mg QD (3 weeks on / 1 week off) will be tested. Safety monitoring 
and evaluation for the dose escalation phase will be carried out by the Safety Review Committee (SRC). If no 
more than 1 patient at the dose level of 5 mg QD experiences a DLT, the dose escalation phase is completed, and 
the expansion phase of the study will be conducted. Upon the completion of the dose escalation phase, the SRC 
will review aggregated safety and PK data and then select a fruquintinib dose as the RP2D for the expansion phase 
of the trial.  Prior to confirmation of a DLT, if a patient has received any prophylactic medical intervention or 
missed 4 or more fruquintinib dose during the DLT observational window, the patient is not DLT evaluable and 
will be replaced. If a patient does not meet the definition of DLT evaluable patient criterion during the DLT 
observation period, the patient will be replaced. Patients who have completed the DLT observation period (Days 
1 – 28, Cycle 1) and are deemed to be benefiting from the fruquintinib treatment at the investigator’s discretion 
may continue the fruquintinib treatment until disease progression, death, intolerable toxicity, or at investigator’s 
discretion that the patient can no longer benefit from the study drug.  
Patients will be followed until death or study completion, which is defined as the CRF form “End of Study” is 
filled.  
2.2. 
DOSE EXPANSION PHASE 
Once the RP2D is determined, patients may enroll into one of the following cohorts and will receive fruquintinib 
at the RP2D. 
 
Cohort A: Patients with advanced, refractory solid tumors of any type. 
 
Cohort B: Patients with refractory mCRC who have progressed on all standard chemotherapies and relevant 
biologics and have also progressed on, or had intolerable toxicity with, at least 1 FDA-approved third-line 
therapy (TAS-102 or regorafenib). 
 
Cohort C: Patients with refractory mCRC who have progressed on all standard chemotherapies and relevant 
biologics and have not received prior TAS-102 or regorafenib. 
 
Cohort D: Patients with hormone-receptor positive (ER+ and/or PR+)/Her2-metastatic breast cancer who 
have progressed on at least two line of prior systemic therapy. 
 
Cohort E: Patients with advanced TNBC who have progressed on at least one cytotoxic therapy in the 
metastatic setting 


 
 
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The safety of all enrolled patients will be closely monitored from the first day of fruquintinib dosing until 30 days 
after the last dose. All serious adverse events (SAEs) should be reported from the day the informed consent form 
(ICF) is signed through 30 days after last dose regardless of relationship to study drug. All AEs will be graded in 
accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
V4.03.  
In the dose expansion phase, tumor response will be assessed according to RECIST Version 1.1 (Eisenhauer et 
al., 2009) at screening, and at study visits according the Schedule of Events (Appendix A in the protocol).  
Confirmation of complete response (CR) and partial response (PR) is required at no less than 4-week intervals 
between the date of initial response and the confirmation assessment date.  
Patients will be followed until death or study completion. 
2.3. 
STUDY ENDPOINTS 
2.3.1. DOSE ESCALATION PHASE 
2.3.2. DOSE EXPANSION PHASE  
 
Primary Endpoints: The primary endpoint of the dose escalation phase is the incidence of DLT in each 
cohort. 
 
Secondary endpoints: The objective response rate (ORR), disease control rate (DCR), duration of response 
(DoR), and progression free survival (PFS) according to RECIST Version 1.1 (Eisenhauer et al., 2009), 
overall survival (OS) and percentage change from baseline in tumor size.  
 
Primary endpoint: PFS 
 
Secondary endpoints:  
o 
Efficacy analysis: ORR, DCR, DoR, PFS according to RECIST Version 1.1 (Eisenhauer et 
al., 2009), OS and percentage change in tumor size from baseline. 
o 
Safety analysis: the incidence and severity of adverse events (AEs), physical examinations, 
vital signs, laboratory test results, 12-lead electrocardiogram, and echocardiogram. 


 
 
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2.4. 
CHANGES TO ANALYSIS FROM PROTOCOL 
3. PLANNED ANALYSES 
The timing of analysis for each cohort may be different depending on completion of each cohort, and the final 
analysis of the study will be conducted at the time of analysis of the last cohort. No formal interim analysis is 
planned for the study. However, the accrued data from any cohort may be analyzed for internal decision-making 
purposes; for example, to provide information for a future trial or external data disclosures. Then, the Database 
Lock (DBL) authorized by sponsor will be planned depending on the purpose of the analysis.  
The final analysis will be planned to be carried out after a DBL. The DBL of final analysis is performed according 
to the study termination criteria (but not limited to) as below: 
OR 
3.1. 
INTERIM ANALYSIS  
No formal interim analysis is planned for the study. However, the accrued data from any cohort may be analyzed 
for internal decision-making purposes; for example, to provide information for a future trial or external data 
disclosures. During the analysis, selected summary for safety and anticancer activity of fruquintinib will be 
performed. 
 
Change in definition of efficacy analysis set (EAS), in section 4.4. 
 
Analysis to be performed based on EAS has been revised to exclude PFS and OS in section 4.4.  
 
Subsequent oncology therapy was not defined in the protocol. The definition and analysis has been added 
in section 13 of SAP 
 
Changes on criteria of Hy’s Law; “Serum AST or ALT ≥3 × ULN and ALP < 2x ULN and total bilirubin 
≥2 × ULN” is changed to be “Hy’s Law: Serum AST or ALT > 3 × ULN and ALP < 2x ULN and total 
bilirubin > 2 × ULN”, in section 17.4.4. 
 
Changes on criteria of drug-induced liver injury (DILI); “Serum AST or ALT ≥3 × ULN together with total 
bilirubin ≥2 × ULN” is changed to be “Serum AST or ALT > 3 × ULN together with total bilirubin > 2 × 
ULN”, in section 17.4.4. 
 
The study is completed when all patients have discontinued study drug or the last enrolled patient have 
completed 1 year of treatment 
 
If the study is terminated early for reasons including but not limited to: 
o 
The incidence or severity of adverse events (AEs) in this or other studies indicates a potential 
health hazard to patients. 
o 
Patient enrollment is unsatisfactory. 


 
 
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3.2. 
FINAL ANALYSIS 
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor 
Authorization of this Statistical Analysis Plan and Database Lock for this study.  
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to 
database lock.  
4.1. 
ALL PATIENTS ENROLLED SET [ENR] 
The analysis set contains all patients who provide the informed consent form for this study. 
4.2. 
SAFETY ANALYSIS SET [SAS] – (ALL TREATED 
POPULATION) 
The analysis set includes all patients who have received at least one dose of fruquintinib. Patients in the SAS will 
be analyzed by their actual dose initially received. If patients have dose reduction during the study, all data will 
be summarized/analyzed on the initial dose of study drug received.  
All safety analyses except for DLT summaries, along with PFS and OS will be based on the SAS.   
If there is any doubt whether a patient was treated or not, they will be assumed treated for the purpose of analysis. 
4.3. 
DOSE-LIMITING TOXICITY EVALUABLE SET [DLT]  
The analysis set comprises all SAS patients who are evaluable for DLT assessment. DLT evaluable patients are 
identified if [Yes] is ticked as the response to “DLT Evaluable Patients” on CRF. DLT set and summaries will 
only apply to dose escalation phase.  
4.4. 
EFFICACY ANALYSIS  SET [EAS] 
This analysis set includes all patients who have received at least 1 dose of fruquintinib, have a measurable lesion 
(target lesions ≥ 10 mm) at the baseline tumor assessment, and either (i) have had at least one post-baseline tumor 
assessment, or (ii) do not have post-dose tumor assessment but have clinical progression as noted by the 
investigator, or have died due to disease progression before their first post-baseline tumor scan. All efficacy 
endpoints (i.e. BOR, ORR, DCR, DoR, and best percentage change from baseline in tumor size), not including 
PFS and OS, will be summarized based on this analysis set.  
4. ANALYSIS SETS 


 
 
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5.1. 
REFERENCE START DATE AND STUDY DAY 
Reference start date is defined as the day of the first dose of study medication. Study Day will be calculated from 
the reference start date and will be used to show start/ stop day of assessments and events. Study day will appear 
in every listing where an assessment date or event date appears.  
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
If the date of the event is prior to the reference date then: 
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, 
but Study Day and any corresponding durations will be presented based on the imputations specified in section 
6.3. 
5.2. 
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference start 
date (including unscheduled assessments). In the case where the last non-missing measurement and the reference 
start date coincide, that measurement will be considered baseline, unless additional information collected on eCRF 
indicate otherwise.  
For example, ECG will be considered being performed post-baseline if assessment date coincides with the 
reference start date but “Time Point” on “ECG (ECG)” form indicates the assessment was performed “Post-dose 
3 hours (± 15 minutes)”. Adverse Events (AEs) onset on the reference start date and with “Did the adverse event 
occur prior to the start of study treatment?” in “Adverse Events (AE)” form answered as “No” or not being 
answered will be considered as post-baseline. Medications commencing the reference start date will be considered 
post-baseline. 
5.3. 
UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the best/ worst case value where 
required (e.g., shift table).  
Listings will include scheduled, unscheduled, and early discontinuation data. 
5. GENERAL CONSIDERATIONS 


 
 
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5.4. 
WINDOWING CONVENTIONS  
The visit-window mapping is described in APPENDIX 4. Visit-based summaries will be based on the windowed 
visits. All data, whether or not within the visit windows, will be presented in listings.  
For windowed visits during the treatment cycles,  
For the post-treatment visit, the last assessment in the window will be included in the summary. The window for 
the post-treatment visit will be "from the last dose date + 8 days to the last dose date + 37 days".   
For a patient who prematurely discontinues the study, the premature visit will be slotted accordingly.   
5.5. 
STATISTICAL TESTS 
No formal statistical hypotheses will be tested in this study.  
Two-sided 95% confidence intervals will be calculated and two-sided, unless otherwise specified in the 
description of the analyses. 
5.6. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
Test Value at Visit X – Baseline Value 
5.7. 
SOFTWARE VERSION 
All analyses will be conducted with SAS version 9.4 or higher based on Enterprise Guide version 7.1.  
6.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
No adjustment will be performed. 
 
If more than 1 assessment occurs during a visit window, the assessment closest to the scheduled day will 
be assigned to the windowed visit.  
 
If two assessments are equidistant from the scheduled day, the later assessment will be assigned to the 
windowed visit.  
 
If there are multiple assessments on the same day, the worst case will be used.   
6. STATISTICAL CONSIDERATIONS 


 
 
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6.2. 
MULTICENTER STUDIES 
This study is planned to be carried out at up to 10 sites. However, no adjustment in aspect of site effect will be 
performed. Data from all centers will be pooled for the analysis. 
6.3. 
MISSING DATA 
Generally, the missing efficacy and safety data will not be imputed except for the critical missing and partial dates 
which will be handled as described in this section. In the situation where partial or missing date are imputed, the 
date will appear partial or missing in the listings, while imputed date will only be used for calculation. 
6.3.1. MISSING DATES INFORMATION OF STUDY TREATMENT 
When the date of the last dose of study treatment is missing for a patient, all efforts should be made to obtain the 
date from the investigator. If it is still missing after all efforts, the last dose date collected from the [Study Drug 
Administration] page of or data cut-off date (if applicable) will be used in the calculation of treatment duration.   
6.3.2. MISSING OR INCOMPLETE DATE INFORMATION FOR ADVERSE EVENT DATE 
For the purpose of determining whether an adverse event (AE) is treatment emergent (see section 17.2.1), 
incomplete start dates and/or stop dates will be imputed. Start date will be imputed first when the start date and 
stop date are both incomplete for a patient. If the field of year is missing or start date of an AE is completely 
missing, then no value will be imputed. The following rules will be applied to impute the incomplete start date, 
assuming year is available. 
Missing or incomplete start date 
Here are some examples. 
Incomplete Date of Onset  
(DD MMM YYYY) 
Reference Start Date  
(DD MMM YYYY) 
Imputed Date  
(DD MMM YYYY) 
--------- 
10Apr2017 
--------- 
 
In case the start date of an AE is in the same year as reference start date (when only year is recorded), or 
the start date is in the same month and year (if only the day is missing) as the reference start date, then the 
start date of the AE will be imputed by the reference start date or the AE resolution date, whichever occurs 
earlier.  
 
If the day and month parts of the AE onset date are missing and occur in the same year as the first dose of 
study drug, the date of the first dose of study drug will be used as the onset date of the AE. If an AE is 
observed on different year of first dose, January 1st will be used to complete the onset date of the AE. 
 
If only the day part of the AE onset date is missing and occurs in the same month and year as the first dose 
date of study drug, the date of first dose of study drug will be used as the onset date of the AE. Otherwise, 
the first day of the month will be used to complete the onset date of the AE.   
 
In all other cases, imputation will not be performed.  


 
 
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Incomplete Date of Onset  
(DD MMM YYYY) 
Reference Start Date  
(DD MMM YYYY) 
Imputed Date  
(DD MMM YYYY) 
-----2017 
10Apr2017 
10Apr2017 
-----2018 
10Apr2017 
01Jan2018 (because the AE 
onsets after the reference 
date) 
--Apr2017 
10Apr2017 
10Apr2017  
--Oct2017 
10Apr2017 
01Oct2017 
05---2017 
10Apr2017 
05---2017 
 
Missing or incomplete stop date 
Incomplete stop dates will be imputed to the last possible date: 
Here are some examples: 
Incomplete AE End Date 
(DD MMM YYYY) 
Date of Death/ End of Study  
(DD MMM YYYY) 
Imputed Date  
(DD MMM YYYY) 
--May2017 
Not Available/ Not Available 
31May2017 
--Sep2017 (known part the SAME as 
date of death/ end of study) 
---------/ 09Sep2017 
09Sep2017 
-----2017 (known part the SAME as 
date of death/ end of study) 
09Sep2017/ 09Sep2017 
09Sep2017 
--Jun2017 (known part DIFFERENT 
from date of death/ end of study) 
09Sep2017/ 09Sep2017 
30Jun2017 
--------- 
---------/ 09Sep2017 
--------- 
31Dec----- 
09Sep2017/ 09Sep2017 
31Dec---- 
-----2018 
09Oct2019/ 09Oct2019 
31Dec2018 
 
If the known part(s) of the AE end date is (are) the same as the death date/ end of study date, the AE end 
date will be imputed by the death date/ end of study date, whichever occurs earlier.  
 
In all other cases, the AE end date will be imputed to the last day of the month if only the day is missing 
or imputed to with 31st December if both day and month are missing.  
 
If the imputed stop date is before the start date (imputed or non-imputed start date), then the stop date will 
be imputed using start date.  
 
If the end date is completely missing or the year part is unknown, the end date will not be imputed.  


 
 
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6.3.3. MISSING OR INCOMPLETE DATE INFORMATION FOR CONCOMITANT 
MEDICATION/ PROCEDURE 
The imputation rule is the same as described for adverse event. 
6.3.4. MISSING OR INCOMPLETE DATE INFORMATION FOR PRIMARY DIAGNOSIS 
DATE AND METASTATIC DIAGNOSIS DATE 
Imputation will only be applied in case the field of year is available. If year and month are known but the day is 
unknown, day will be imputed as 15. If only year is known, month and day will be imputed to July 1st. If the 
diagnosis date is completely missing or the year part is unknown, the diagnosis date will not be imputed. 
6.3.5. MISSING OR INCOMPLETE DATE INFORMATION FOR EFFICACY DATA 
When a partial new anticancer therapy starting date is reported, every effort will be made to identify the 
precedence relationship of starting date of new anticancer therapy relative to last dosing date of study drug and 
the date of disease progression (if happened). According to the confirmed precedence relationship, partial new 
anticancer therapy date will be imputed to the earliest possible date:  
However, the imputed anticancer start date will be adjusted based on corresponding date in different scenario as 
shown below, the imputed date will be set to the date according to which it will be adjusted if the originally 
imputed date is earlier than the corresponding date: 
6.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
There are no requirements for multiplicity adjustments in this study. 
6.5. 
EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
 
Day will be imputed as 1 if year and month are known; month and day will be imputed as Jan 1st if only 
year is known.  
 
In rare case, if year and month of death date are known but the day is unknown, day will be imputed as 15. 
For example, if a patient is reported to die on Dec2017, the death date will be imputed as 15 Dec2017. 
 
Adjust based on the date of first dose in case that anticancer therapy starts earlier than both last dosing date 
and disease progression. 
 
Adjust based on the last dosing date/the date of disease progression which occurs earlier in case that 
anticancer therapy is initiated after last dosing date but before disease progression date or vice versa. 
 
Adjust based on the last dosing date/the date of disease progression which occurs later in case that 
anticancer therapy is initiated after both last dosing and disease progression. 


 
 
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Appendix 2 shows conventions for presentation of data in outputs.  
Format and content of summary tables, figures, and listings are presented as mock shells for TFLs and provided 
by IQVIA Biostatistics.  
Continuous variables will be summarized using descriptive statistics including, number of patients (n), mean, 
median, standard deviation (STD), 25% and 75% quantiles, minimum and maximum. Categorical variables will 
be summarized with number and percentage and presented in frequency tables. All results will be presented by 
dose cohort (only in dose escalation phase) or tumor specific cohorts (only in dose expansion phase). 
Qualitative variables will be summarized by count(s) and percentages (%). 
Percentages will be reported with 1 decimal point; if the count is 0, no percentage will be presented. Value of 
percentage less than 1% will be presented as “<1%.” Value of percentage less than 100% but >99% will be 
presented as “>99%.” Any rounding will be done after all calculations are made.  
8.1. 
ENROLLMENT 
Information of all patients who provided informed consent (that is the ENR) will be included in the summary of 
disposition and withdrawals for this study. A summary table will be generated to provide the following:  
A separate table will be presented to show the patients included in each analysis set and reason for exclusion 
from an analysis set. 
7. OUTPUT PRESENTATIONS 
8. DISPOSITION AND WITHDRAWALS 
 
Number of patients who signed the informed consent  
 
Number of screen failures 
 
Reason for screen failure 
 
Number of patients who passed screening  
 
Number of patients who withdrew consent before study treatment 
 
Number of patients who received treatment 


 
 
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8.2. 
PATIENT STATUS AT TREATMENT AND STUDY 
COMPLETION 
Patient status at treatment and study completion will be listed and summarized for SAS. The listing will include 
individual information (i.e. site and patient number, informed consent information), whether patients discontinued 
from the treatment and the reasons for the discontinuation, along with the date of first/ last dose, duration of 
treatment, and the date of discontinuation from the treatment. The same information will be provided for patients 
who discontinued from the study.  The following summaries will be presented: 
A flowchart for disposition will be presented. 
9. PROTOCOL DEVIATION 
Protocol deviations are recorded as critical, major or minor in Clinical Trial Management System (CTMS) and 
are classified into 10 categories:  
 
Major protocol deviations are those recorded as critical or major.  
All subject-level protocol deviations will be presented in listing including deviation date and severity.  
 
Patients still on treatment  
 
Reason for study drug discontinuation (for study drug) 
 
Number of patients going into Survival follow-up  
 
Number and percentage of patients who discontinue the study 
 
Reason for study discontinuation 
 
Administrative Criteria 
 
Eligibility and Entry Criteria 
 
Informed Consent Criteria 
 
IP Compliance 
 
Laboratory Assessment Criteria 
 
Regulatory or Ethics Approvals Criteria 
 
Serious Adverse Event Criteria 
 
Study Procedures Criteria 
 
Visit Schedule Criteria 
 
Other Criteria 


 
 
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Demographic data and other baseline characteristics will be presented for the SAS. Data listing will also be 
provided. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
10.1. 
DERIVATIONS 
BMI (kg/ m2) = weight (kg)/ height (m)2 
Medical and surgical history will be coded by MedDRA Version 23.1 or higher and summarized separately for 
SAS; results will be expressed by system organ class (SOC) and preferred term (PT) in descending order of the 
frequency in total. For SOCs or PTs with the same frequency, results will be sorted alphabetically. 
Individual patient listings of and medical/surgical history will also be provided for the SAS. 
Oncology history information will be presented for the SAS. The following oncology history information will be 
summarized: 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
 
Age (years) – calculated relative to date of consent; summarized as both continuous variable and categorical 
variable (< 65 vs. ≥ 65 years) 
 
Gender 
 
Race  
 
Ethnicity 
 
Weight (kg) 
 
Height (cm) 
 
BMI (kg/m2): summarized as both continuous and categorical variable (<18.5, ≥18.5 and <24, ≥24 kg/m2) 
 
Baseline ECOG performance status (0, 1, 2, 3, 4, 5) 
11. SURGICAL AND MEDICAL HISTORY 
12. ONCOLOGY HISTORY  


 
 
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12.1. 
DERIVATIONS 
13.1. 
PRIOR ONCOLOGICAL THERAPY 
Prior oncological therapy information are recorded as following: Prior oncology medication information, Prior 
oncology radiotherapy information, Prior oncology surgery and procedure information. 
 
Prior oncology medication will be coded using World Health Organization Drug Dictionary Enhanced (WHO 
DDE) Version SEP2020. Prior oncology surgery and procedures will be coded using MedDRA Version 23.1 or 
higher.  
 
Primary diagnosis of malignancy 
 
Time since primary diagnosis to first dose of study treatment (months) 
 
Primary site 
 
Diagnosis of malignancy at enrollment 
 
Metastatic status (yes, no) 
 
Number of metastatic sites: both continuous variable and categorical variable (0, 1, 2, >=3) 
 
Time since first metastasis diagnosis to first dose of study treatment (months) 
 
TNM stage at enrollment  
 
Disease stage at enrollment 
 
Histological classification at enrollment (Adenocarcinoma, Adenosquamous Carcinoma, Carcinoid, Clear 
Cell Carcinoma, Indeterminate, Sarcoma, Squamous (except squamous non˗small cell lung cancer 
[NSCLC], Other) 
 
Prior use of VEGF-R inhibitor (yes, no) 
 
Prior use of VEGF inhibitor (yes, no) 
 
Time since last systemic anti-neoplastic therapies to first dose of study treatment (months)  
 
Liver metastasis (yes, no): obtained based on whether the liver organ was involved in the target and non-
target lesion tumor scan assessment at the baseline. 
 
Time since primary diagnosis to first dose of study treatment (months) = (Date of first dose of study 
treatment – Date of primary diagnosis)/ 30.4375 
 
Time since first metastasis diagnosis to first dose date (months) = (Date of first dose of study treatment – 
Date of first metastasis diagnosis)/ 30.4375 
 
Time since last systemic anti-neoplastic therapies to first dose of study treatment (months) = (Date of first 
dose of study treatment – Date of last systemic anti-neoplastic therapies)/ 30.4375 
13. ONCOLOGICAL THERAPIES 


 
 
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Prior oncology medications will be presented by Anatomical Therapeutic Classification (ATC)-2nd-level term 
(ATC level 2) and by PTs for each dose and/ or disease cohort in each phase. ATC class and PT will be sorted in 
descending frequency of the total number of patients with at least one condition in the corresponding category; 
ATCs/PTs will be presented alphabetically for ATCs/PTs of the same total frequency. In addition, number and 
percent of patients who have received prior oncology medication, regimen number, and category of regimen 
number will be summarized for prior oncology medication. 
 
Prior oncology surgery and procedures will be presented by SOC and PT for each cohort in each phase. SOC and 
PT will be sorted in descending frequency of the total number of patients with at least one condition in the 
corresponding category, SOCs/PTs will be presented alphabetically for SOCs/PTs of the same total frequency. 
Corresponding listings will be provided. 
13.2. 
SUBSEQUENT ONCOLOGY THERAPY 
Subsequent oncology therapies taken after end of treatment will be collected in below forms:  
Subsequent oncology therapies are defined as therapies started after the last dose of study medication. The 
following information will be summarized and listed for subsequent therapy:  
 
Subsequent oncology (or anti-tumor) medications will also be presented by ATC level 2 and by PTs for each dose/ 
disease cohort in each phase. 
Subsequent anti-tumor therapy will be flagged in the listing of oncology medication/ radiotherapy/ surgery. 
Medications and procedures information are recorded as following: 
 
“Oncology Medication (CHEMO1)”  
 
“Oncology Radiotherapy”  
 
“Oncology Surgery and Procedure”  
 
Number of subsequent oncology medications 
 
Number of subsequent regimen 
 
Category of number of subsequent regimen 
 
 
14. MEDICATIONS AND PROCEDURES 
 
Prior and concomitant medication information  
 
Prior and concomitant procedure information 


 
 
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‘Prior’ medications/procedures are medications/procedures which started prior to the first dose of study 
medication.  
‘Concomitant’ medications/procedures except for oncology therapies are medications which ended on or after the 
date of first dose of study medication or were ongoing at the end of the study, and start no later than 37 days 
following last dose administration. 
A medication may be both prior and concomitant if it meets 2 above-mentioned definitions. 
14.1. 
PRIOR AND CONCOMITANT MEDICATION 
Medications will be coded using World Health Organization Drug Dictionary Enhanced (WHO DDE), Versions 
SEP2020 or higher. See section 6.3.3 for handling of partial dates for medications, in the case where it is not 
possible to define a medication as prior and concomitant, the medication will be classified by the worst case, i.e. 
concomitant.  
Concomitant medications will be presented by ATC level 2 and by PTs for each dose and/ or disease cohort in 
each phase. ATC class and PT will be sorted in descending frequency of the total number of patients with at least 
one condition in the corresponding category, ATCs/PTs will be presented alphabetically for ATCs/PTs of the 
same total frequency.  
 
Prior and concomitant medications will be presented in listings with flag to differentiate whether the medication 
is prior medication or concomitant medication.  
14.2. 
CONCOMITANT PROCEDURES 
Surgery and procedures will be coded using MedDRA Version 23.1 or higher. Concomitant procedures will be 
presented by SOC and PT for each dose and/ or disease cohort in each phase.  
SOC and PT will be sorted in descending frequency of the total number of patients with at least one condition in 
the corresponding category, SOCs/PTs will be presented alphabetically for SOCs/PTs of the same total frequency. 
Prior and concomitant surgery will be listed and flagged like the listing of prior and concomitant medication. 
15. STUDY MEDICATION EXPOSURE 
Exposure to study medication and compliance will be presented for the SAS. 
The planned treatment is given at either 3mg QD or 5mg QD in the corresponding study phase and dose and/ or 
disease cohort. In each 28-day cycle, a patient will take medication in the first 3 weeks followed by 1 week off 
treatment. Study drug administration and derived exposure information will be summarized and listed. 
 


 
 
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15.1. 
EXPOSURE TO STUDY MEDICATION 
Below variables will be summarized: 
15.2. 
STUDY MEDICATION COMPLIANCE  
The study medication compliance is quantified with relative dose (RD, %) of study medication. RD is calculated 
as the cumulative dose taken divided by the planned total dose in the corresponding period, expressed as a 
percentage, see section 15.3 for more details. RDI (%) and RD (%) will be categorized as stated above in Section 
15.1. 
15.3. 
DERIVATIONS 
Algorithms for calculating parameters relevant to the dose exposure and intensity are listed in Table below:   
 
Number of cycle(s) received: the number of cycles in which at least one dose of Fruquintinib or placebo is 
taken. The number of cycles could be further categorized into:  
o 
1, 2, 3, 4, 5, 6 and > 6 
 
Total duration of exposure (days)  
 
Cumulative dose (mg) 
 
Dose intensity (mg/day) 
 
Relative dose intensity (RDI, %): both continuous variable and categorical variable (< 50%; 50 - < 70%; 
70 - < 90%; 90 - < 110%;  ≥ 110%)  
 
Actual duration of study treatment (days) 
 
Percentage intended dose (PID) 
 
Number of patients with any dose modification (including both drug interruption, dose increase, and dose 
reduction) 
 
Frequency of dose modification: 0, 1, 2, 3, 4, 5, 6, >6 
 
Number of patients experienced drug interruption   
 
Frequency of drug interruptions: 0, 1,  ≥ 2 
 
Number of patients with any dose reduction  
 
Reduction from 5mg to 4mg  
 
Reduction from 4mg to 3mg  
 
Frequency of dose reduction: 0, 1, 2  
 
Total duration of exposure (days) is calculated from the first dose date of study drug in Cycle 1 to the last 
dose date of study drug + 8 days or death date, whichever comes earlier if treatment is discontinued, or to 
the cut-off date. if treatment is still ongoing.  
 
Actual duration of exposure (days) = Sum of the days with study drug administered 


 
 
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Parameter 
Description/ Formula [a] 
Dosing schedule per 
protocol# 
5 mg PO QD between Days 1 and Day 21, followed by 1-week off  
Cumulative dose (mg) [b] 
∑ [5 × (all dispensed 5-mg tablets – total returned 5-mg tablets - total lost 5-mg 
tablets in a cycle) + 1 × (all dispensed 1-mg tablets – total returned 1-mg tablets 
– total lost 1-mg tablets in a cycle)] 
Dose intensity (mg/day) 
Cumulative dose (mg) / Total duration of exposure (day) 
Relative dose intensity 
(RDI, %) # 
100 * [Dose intensity (mg/day) / (5 × 21/28, mg/day)]   
Relative Dose (RD, %)# 
100 * [Cumulative dose (mg) / (5 × 21 × number of cycles received (mg)]  
Percentage intended dose 
(PID, %) [c] 
100 * [(total number of days with any recorded doses) / total duration of 
exposure (days)] 
[a]In the study, there are the other dose level of "3mg QD” used.  
[b]In the study, both 1-mg and 5-mg fruquintinib are provided for oral administration. When dose adjustment is required, 1- 
    mg fruquintinib is always used. Before calculating the cumulative dose, total number of 1-mg and 5-mg tablets taken should  
    be counted separately. 
[c]Given the dose schedule of a 4-week cycle in the protocol, 3 weeks on/ 1 week off, the reference value is 0.75. 
# indicates 5 (mg) should be replaced with 3 (mg) for calculation in Cohort “3 mg QD”. 
16. EFFICACY OUTCOMES  
Analyses of efficacy outcomes are based on EAS except PFS and OS, which are estimated based on SAS. 
16.1. 
PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S) 
16.1.1. 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 (Eisenhauer et al., 2009) or death; or (ii) withdrawal 
of consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. 
 
The timing of an overall TPR will always be derived based on scan dates not response assessment dates. For a 
scheduled tumor scan assessment, it is expected that there may be a variation for the actual timing of scans among 
target, non-target, and new lesions. In assigning a date for the overall response assessment at a visit, the earliest 
date collected at that visit will be used. Within a grouped timepoint, if there are multiple assessments on different 
dates for the same target lesions, the last assessment will be used.  
A patient’s BOR will be determined based on APPENDIX 3.   


 
 
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There are two ways of assigning BOR for a patient when the minimum interval for confirmation of CR and PR is 
not satisfied or if there are no confirmatory scans for CR and PR: 
Both ways of assigning BOR will be implemented.  
The number and percentage of patients in each category of derived BOR (Confirmed CR, Confirmed PR, SD, 
PD, or NE) will be summarized.  
16.1.2. OBJECTIVE RESPONSE RATE (ORR) 
Objective response rate (ORR) will be calculated using two different ways: 
16.1.3. DURATION OF RESPONSE (DOR) 
The DoR is defined as the time from the date of the first objective response (CR or PR which is subsequently 
confirmed) until the date of the documented progression or of death, whichever comes first. DoR will only be 
analyzed for patients whose BOR is either CR or PR. Censoring will follow the rules outlined below for PFS in 
Section 16.1.5. 
16.1.4. DURATION CONTROL RATE (DCR) 
The DCR is defined as the percentage of patients in EAS with a BOR of confirmed CR, confirmed PR or SD for 
7 weeks.  
16.1.5. PROGRESSION FREE SURVIVAL (PFS)  
The PFS is defined as the time from date of first dosing until the date of an objective disease progression as defined 
by RECIST Version 1.1 (Eisenhauer et al., 2009) or death due to any cause, whichever comes first. More 
specifically, PFS will be determined using all the assessment data up until the last evaluable visit prior to or on 
 
Adding two more response categories as: unconfirmed CR, unconfirmed PR. 
 
Assigning BOR as SD, that is, both the unconfirmed CR and unconfirmed PR will be SD. 
 
Scenario #1: ORR will be calculated using a strict interpretation of RECIST Version 1.1. Objective 
response will be derived as no/yes variable. Patients with a BOR of confirmed CR or PR will be assigned 
‘Yes’. Patients not having a BOR of confirmed CR or PR will be assigned ‘No’. Hence, ORR is defined as 
the proportion of patients with objective response being “Yes”.  
 
Scenario #2: ORRUNCONFIRMED will be calculated using all responses regardless of confirmation. Objective 
response will be derived as no/yes variable.  Patients with a BOR of confirmed CR, confirmed PR, 
unconfirmed CR or unconfirmed PR will be assigned “Yes”.  All patients with other BOR values will be 
assigned “No”.  Hence, ORRUNCONFIRMED is defined as the proportion of patients with objective response 
being “Yes”.  


 
 
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the date of (i) disease progression as defined by RECIST Version 1.1 or death; or (ii) withdrawal of consent; or 
(iii) receiving subsequent anti-cancer therapy, whichever is earlier.  
 
The rule of censoring/ event is summarized in Table 1.  
The PFS time will always be derived based on scan dates not tumor assessment dates. If PD is documented 
between scheduled visits, the actual date of documented progression will be used as an uncensored value in the 
analysis of PFS. 
RECIST assessments/scans contributing towards a particular visit may be performed on different dates. The 
following rules will be applied: 
 
Table 1 Progression free survival 
Description 
Event/ 
Censor 
Date of Event/Censor 
Documented progression before starting use of 
new anticancer treatment and without missing 
two consecutive tumor assessment visits 
Event 
Date of first documented disease progression 
Death without progression  
Event 
Date of death 
Progression or death after two or more 
consecutive missed tumor assessments 
Censor 
Date of last adequate tumor assessment before 
two consecutive missed tumor assessment visits 
No evaluable baseline tumor assessment  
Censor 
Date of first dosing of study treatment 
No evaluable tumor assessment after first dose 
of study treatment  
Censor 
Date of first dosing of study treatment 
New anticancer treatment started prior to 
documented disease progression or death on 
study 
Censor 
Date of last evaluable tumor assessment before 
start use of new anticancer treatment/two 
consecutive missed tumor assessment visits 
No progression and no death before end of 
study or data cut-off 
Censor 
Date of last evaluable tumor assessment 
Note: An adequate radiologic assessment is defined as an assessment where the Investigator determined radiological response  
          is CR, PR, SD, or PD. If PD and new anti-cancer therapy occur on the same day, will assume that the progression was  
          documented first, e.g. outcome is progression and the date is the date of the assessment of progression. 
 
Date of progression will be determined based on the earliest of the dates of the component that triggered 
the progression.  
 
When censoring a patient for PFS the patient will be censored at the latest of the dates contributing to a 
particular overall visit assessment. 


 
 
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Note: Two consecutive scheduled tumor assessments is equal to 126 days (=2* (8 weeks *7+ 7 days)) since previous evaluable  
          RECIST 1.1 or baseline assessment if there is no post baseline tumor assessment.  
16.1.6. OVERALL SURVIVAL (OS) 
The OS (in months) refers to the time interval between the first dose date and the date of death (any cause). The 
last known alive date (i.e. the last follow-up date in patients on study or the date of EOS in patients withdrawn 
from the study) will be used as the censoring date for patients who have not died at the time of the statistical 
analysis. Patients lacking data beyond the first dose date will have their survival time censored at the first dose 
date.  
16.1.7. TUMOR SHRINKAGE  
Tumor shrinkage will be estimated using data on sum of diameters of target lesion based on EAS. Percentage 
change in tumor size will be determined for patients with measurable disease at baseline and will be derived for 
each tumor assessment. 
16.2. 
ANALYSIS OF EFFICACY VARIABLE(S) 
The efficacy endpoints include ORR, DCR, DoR, PFS and OS. Efficacy data will be listed and summarized by 
dose cohort (only in dose escalation phase) or tumor specific cohorts (only in dose expansion phase) and disease 
type if applicable.  
ORR, DCR, and DoR 
The ORR and DCR will be summarized with percentages and 95% exact Clopper-Pearson confidence interval 
based on EAS.  
DOR will be summarized using Kaplan-Meier method, and the descriptive statistics of median, 25% and 75% 
percentiles along with their 95% CIs will be calculated. It will be based on the EAS. The supportive data listings 
will also be provided.  
PFS, OS, and Duration to Follow-Up 
 PFS and OS will be similarly summarized as DOR, and in addition to the quartile summary from Kaplan-Meier 
method, Kaplan-Meier estimates will be provided for the rates at 12, 16, 20, and 24 weeks along with their 95% 
CIs based on the Brookmeyer and Crowley method (1982).  
In addition, duration (months) to follow-up for overall survival would be summarized by Kaplan-Meier method. 
Duration to follow-up refers to the time interval between date of first study drug administration and last date 
known to be alive for subjects who have not yet been reported to have died by the time of analysis, i.e. (date of 
last known to be alive – date of first study drug administration + 1)/ 30.475. Subjects who are reported to have 
died would be censored at death date.  
Tumor Shrinkage 


 
 
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Percentage change in tumor size from baseline will be determined for patients with measurable disease at baseline 
and derived at each visit by the percentage change in the sum of the diameters of target lesions (TLs) compared 
to baseline. Best (minimum) percentage change from baseline (PCFB) in tumor size will be summarized using 
descriptive statistics and a waterfall plot will be presented also. Best post-baseline sum of diameter is defined as 
the sum of diameter with either the largest decrease or smallest increase from baseline sum of diameter at a single 
post-baseline evaluable tumor assessment visit before RECIST progression of disease. More details please refer 
to section 16.1.7.  
17. SAFETY OUTCOMES 
Unless otherwise specified, the overall safety evaluation period is from the first date of study drug administration 
to no later than 37 days after the date of last study treatment administration. All outputs for safety outcomes will 
be based on the SAS.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section.  
Safety will be assessed through summaries of adverse events, changes in laboratory test results, changes in vital 
signs and change in ECG. Safety data will be listed and summarized. Incidence of DLTs will be listed by dose 
cohort for dose escalation phase only. 
17.1. 
DLTS 
A DLT is defined as one of the following toxicities occurring during the DLT assessment window (Cycle 1) and 
determined by the investigator to have a reasonable possibility of being related to fruquintinib. All DLT analysis 
will be performed for dose escalation phase only. In addition to summarizing the proportion of patients with DLTs, 
the DLT categories will also be summarized as follows:  
The individual data of DLTs will also be listed by dose and/ or disease cohort and by patient. 
 
Any Grade 4 non-hematologic toxicity; 
 
Any Grade 3 non-hematologic toxicity related to study drug except for nausea/vomiting, diarrhea, 
constipation, hypertension and electrolyte imbalances downgraded within 3 days with appropriate supportive 
treatment; 
 
Grade 4 neutropenia lasting > 3 days; 
 
Grade 3 febrile neutropenia (absolute neutrophil count < 1.0 x 109/L with a single temperature of > 38.3 °C 
or a sustained temperature of ≥38 °C for more than 1 hour; 
 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; 
 
DLT leading to dose interruption for > 14 days due to toxicity 


 
 
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17.2. 
ADVERSE EVENTS 
AEs will be coded using Medical Dictionary for Drug Regulatory Activities (MedDRA) central coding dictionary, 
Version 23.1 or higher. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after 
the first dose of study medication and no later than 37 days after the date of last study treatment. In case that the 
AE onset date coincide with the first dose date of study treatment, AE will be considered as TEAE if the response 
of question “Did the adverse event occur prior to the start of study treatment?” in AE form is “No”. 
See section 6.3.2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment emergent or not, (i.e., the required imputed dates are missing or partial) the AE will be classified by the 
worst case, i.e. treatment emergent.  
An overall summary of number of patients within each of the categories described in the sub-section below, will 
be provided.  
Listings will include all the AEs being reported during the study with flag to distinguish TEAEs and Non-TEAEs. 
Imputed AE dates will not be presented in the listings. 
17.2.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also broken 
down further by maximum severity for each phase, each dose and disease cohort and overall. The study drug 
related TEAEs will also be summarized in the similar way.  
17.2.1.1. 
Severity 
AE severity will be graded to 5 grades (Grade 1 to Grade 5) according to the national cancer institute common 
terminology criteria for adverse event (NCI CTCAE) V4.03.  
TEAEs starting after the first dose of study medication with a missing severity will be classified as Grade 3. If a 
patient reports a TEAE more than once within that SOC/ PT, the AE with the worst-case severity will be used in 
the corresponding severity summaries. A summary table for TEAE with grade >= 3 will also be presented by dose 
or disease cohort. 
17.2.1.2. 
Relationship to Study Drug 
The relationship, as indicated by investigator, is classed as “Unrelated” and “Related”. A study drug “related” 
TEAE is defined as a TEAE with response of “Yes” to the field “Possible causality to study drug?” on the 
“Adverse Event (AE)” form of the eCRF. TEAEs with a missing causality to study drug will be regarded as 
“Related” to study drug. If a patient reports the same AE more than once within that SOC/ PT, the AE with the 
worst case relationship to study drug will be used in the corresponding relationship summaries.  


 
 
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17.2.2. TEAES LEADING TO DOSE INTERRUPTION OR REDUCTION 
TEAEs leading to dose interruption or reduction will be identified as those TEAEs with a response of either “Drug 
Interrupted” or “Dose Reduced”. 
For TEAEs leading to dose interruption or reduction, summaries of incidence rates (frequencies and percentages) 
by SOC and PT will be prepared. Summaries for TEAEs leading to dose interruption or reduction by SOC and PT 
will be further limited to study medication-related TEAE and broken down by maximum severity. 
17.2.3. TEAES LEADING TO DISCONTINUATION OF STUDY DRUG 
TEAEs leading to permanent discontinuation of study drug will be identified as those TEAEs with a response of 
“Drug Withdrawal”.  
For TEAEs leading to discontinuation of study drug, summaries of incidence rates (frequencies and percentages) 
by SOC and PT will be prepared. Summaries for TEAEs leading to discontinuation of study drug by SOC and PT 
will be further broken down by maximum severity and strongest relationship to study drug. 
TEAEs leading to discontinuation of study drug will also be listed. 
17.2.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded with a response of “Yes” for the field “Is the adverse 
event serious?” on the “Adverse Events (AE)” form of eCRF. A summary of serious TEAEs by SOC and PT will 
be prepared. In addition, summaries for serious TEAEs by SOC and PT will be further broken down by maximum 
severity. 
Listing of serious TEAE will also be provided. 
17.2.5. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events with response of “Fatal. A summary of TEAEs leading to death by SOC 
and PT will be prepared.  
TEAEs leading to death will also be listed. 
17.2.6. ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
According to the IB Version 13.0 (dated 08 November 2021), treatment emergent adverse events of special interest 
(TEAESI) for fruquintinib are defined to include 10 categories: 
 
hepatic function abnormal  
 
haemorrhages  
 
hypertension 
 
infections   
 
thyroid dysfunction   
 
proteinuria   
 
dermatological toxicity   
 
gastrointestinal perforation 


 
 
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 
embolic and thrombotic events 
 
left ventricular ejection fraction decreased 
The MedDRA terms used to define AESIs categories are listed in Table 2, for AESI categories (i.e. 
“haemorrhages”, “hepatic function abnormal”, “hypertension”, “proteinuria”, “thyroid dysfunction”, “embolic 
and thrombotic events” “gastrointestinal perforation” and “left ventricular ejection fraction decreased”), the PTs 
to be included in these AESI categories are included in Appendix 5. These terms were selected by subjecting 
standardized MedDRA queries (SMQ) lists (narrow and/or broad scope depending on the category) for each 
category and had been used in the fruquintinib clinical development program for pharmacovigilance. TEAESI 
will be summarized by AESI category and PTs. Incidence rates (frequencies and percentages) will be presented 
by treatment arm. Similar by severity and by relationship summary tables will also be provided separately.   
Table 2: MedDRA Terms Used for Adverse Events of Special Interest 
AESIs Category 
Search terms/strategy 
Dermatological toxicity 
MedDRA SOC “skin and subcutaneous tissue disorders” 
Hypertension 
MedDRA SMQ “hypertension” (narrow) 
Thyroid dysfunction 
MedDRA SMQ “thyroid dysfunction” (broad) 
Proteinuria 
MedDRA SMQ “proteinuria” (narrow) 
Hepatic function abnormal 
MedDRA SMQ “drug related hepatic disorders-comprehensive 
search” (narrow) 
Haemorrhages 
MedDRA SMQ “haemorrhages” (narrow) 
Infections 
MedDRA SOC “infections and infestations” 
Embolic and thrombotic events 
MedDRA SMQ “embolic and thrombotic events” (narrow) 
Gastrointestinal perforation 
MedDRA SMQ “gastrointestinal perforation” (narrow) 
Left ventricular ejection fraction decreased 
MedDRA SMQ “cardiac failure” (narrow) 
 
Time to first TEAESI will also be summarized by AESI category for each dose and/ or disease cohort in each 
study phase. Time to first TEAESI is defined as time interval from date of first administration of study treatment 
to the earliest onset date among TEAEs within the same AESI categories. That is, if a patient has multiple AEs 
occurrences under the same AESI category, the earliest AE onset date will be used as the first onset date to the 
AESI category.  
17.3. 
DEATHS 
Data on death will be listed, along with results of total number of patients died and cause of death summarized. 
Result of patients with on-study death, which is defined as the death after the first dose until 37 days after last 
dose, will also be tabulated. On-treatment death will be flagged. 
17.4. 
LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for Hematology, Serum chemistry, 
Coagulation, Urinalysis, 24-hours urine protein, and Thyroid function test.  


 
 
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Indexes collected for laboratory assessments are shown in table below: 
Laboratory Test 
Parameters 
Hematology 
red blood cell [RBC] count, hemoglobin, platelet count, white blood cell [WBC], 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, hematocrit, 
reticulocyte count 
Coagulation 
activated partial thromboplastin time [aPTT], international normalized ratio [INR] 
Serum chemistry 
total protein, albumin, glucose, blood urea nitrogen [BUN], creatinine, creatinine 
clearance, alkaline phosphatase [ALP], lactate dehydrogenase [LDH], total 
bilirubin, Aspartate Aminotransferase [AST], Alanine Aminotransferase [ALT], 
calcium, magnesium, potassium, sodium, chloride, total cholesterol, triglycerides, 
uric acid, bicarbonate, phosphorus  
Urinalysis 
pH, glucose, protein, and blood 
Thyroid function 
thyroid stimulating hormone [TSH], free T3, and free T4 
 
The non-protocol specified tests and urinalysis results will not be summarized; they will only be included in 
listings. Data recorded by the laboratory will be converted to the International System of Units (SI) and all 
presentations will use SI units. Quantitative laboratory measurements reported as “< X”, i.e., below the lower 
limit of quantification (LLQ), or “> X”, i.e., above the upper limit of quantification (ULQ), will be converted to X 
for the purpose of quantitative summaries, but will be presented as recorded, i.e., as “< X” or “> X” in the listings. 
Quantitative data collected between after date of ICF and up to 37 days following the last dose of study medication 
will be used for analysis. The following summaries will be provided for laboratory data: 
Both the scheduled and unscheduled assessments will be used to identify the worst post-baseline values. 
Listing of all laboratory data by patients, abnormal values identified according to normal range (low, normal and 
high) by programming and markedly abnormal criteria by investigators’ assessment will be flagged. 
17.4.1. LABORATORY SPECIFIC DERIVATIONS 
The SI unit conversion and CTCAE grade will be derived through programming. 
 
Observed value and change from baseline by visit (for quantitative measurements) 
 
Shift from baseline to worst post-baseline CTCAE toxicity for laboratory abnormalities  
 
Shift from baseline to the worst post-baseline investigators’ assessment (i.e., normal, abnormal but not 
clinically significant [NCS], abnormal and clinically significant [CS] for quantitative measurements and 
categorical measurements) 


 
 
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17.4.2. CTCAE GRADING FOR LABORATORY DATA 
To identify laboratory values of potential clinical importance, laboratory results will be graded according to NCI 
CTCAE Ver. 4.03, where applicable (APPENDIX 6). All grading will be based on laboratory values (being direct 
or some derived, corrected values) only, regardless of its interventional or symptomatic consequences. 
Some modifications to the grading system will be applied: 
Any graded abnormality that occurs following the initiation of study drug and represents at least a 1-grade change 
(i.e. increase or decrease) from the baseline assessment is defined as treatment emergent. The treatment-emergent 
laboratory abnormality defined by CTCAE will be summarized by CTCAE term, CTCAE toxicity grade, and visit. 
Any occurrence of grade 3 or grade 4 laboratory abnormality during the treatment period will also be summarized 
by visit.  
17.4.3. LABORATORY REFERENCE RANGES  
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
17.4.4. POTENTIAL DRUG-INDUCED LIVER INJURY (DILI) 
Below events will be identified via programming and summarized by categories and dose and/ or disease cohort 
for the SAS. Separate listings for patients with DILI, as defined below, will also be provided. 
 
Grade 5 refers to fatal outcomes, which cannot be determined solely by laboratory values, therefore will not 
appear in the grading system. 
 
A further category denoted Grade 0 would include all laboratory values within normal range except missing 
values. 
 
Missing results shall be graded as missing. 
 
For some specific parameters with CTCAE grading in both high and low direction (e.g., calcium, glucose, 
magnesium, potassium, sodium), CTCAE in hyper and hypo directions will be presented separately, i.e., 
hyper for higher values of concern and hypo for lower values of concern.  
 
Low: Below the lower limit of the laboratory reference range  
 
Normal: Within the laboratory reference range (upper and lower limit included) 
 
High: Above the upper limit of the laboratory reference range 


 
 
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Lab abnormalities meeting the biochemical criteria for Hy’s law is associated with a markedly increased 
possibility of severe DILI. These components will also be listed separately: 
17.5. 
ECG EVALUATIONS 
Results of the Electrocardiogram (ECG) will be included in the reporting of this study. Overall assessment of 
ECG up to 37 days following the date of last dose of study medication will be included for analysis. 
The following ECG parameters will be reported for this study: 
 
Hy’s Law: Serum AST or ALT >3 × ULN and ALP < 2x ULN and total bilirubin >2 × ULN 
 
POTENTIAL DRUG-INDUCED LIVER INJURY (DILI): Serum AST or ALT >3 × ULN and total 
bilirubin >2 × ULN 
 
AST: 
o 
 > 3x ULN and ≤ 5 x ULN, 
o 
> 5 x ULN and ≤ 8 x ULN, 
o 
> 8 x ULN and ≤ 10 x ULN, 
o 
> 10 x ULN and ≤ 20 x ULN,  
o 
> 20x ULN,  
o 
AST>5x ULN for more than 5 weeks 
 
ALT: 
o 
 > 3x ULN and ≤ 5 x ULN, 
o 
> 5 x ULN and ≤ 8 x ULN, 
o 
> 8 x ULN and ≤ 10 x ULN, 
o 
> 10 x ULN and ≤ 20 x ULN,  
o 
> 20x ULN,  
o 
> 5x ULN for more than 5 weeks 
 
ALP < 2 x ULN 
 
Total Bilirubin: 
o 
 >1.5 and ≤ 2 x ULN  
o 
> 2 x ULN 


 
 
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Overall assessment of ECG (Investigator’s judgment): Normal, NCS, CS. 
The following summaries will be provided for ECG data: 
Listing of ECG data (Assessment date, Timepoint, HR, PR interval, QT interval, QRS interval, RR interval, QTcF 
interval) by patients, with results which meet the markedly abnormal criteria being flagged. 
17.5.1. ECG SPECIFIC DERIVATIONS 
QTcF values will be derived from the QT and RR intervals based on the formula of  
𝑄𝑇𝑐𝐹ൌ
ொ்
√ோோ
య
, 
If QT and/or RR is missing, the QTcF will be left as missing. 
17.5.2. MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal criteria for ECG are listed in table below: 
Parameter (unit)  
 Criterion value   
 Heart Rate (bpm) 
 >120    
    
 <50   
 PR Interval (msec)  
 ≥ 210   
 RR Interval (msec) 
 > 1200   
 
 < 500   
 QRS Interval (msec)  
 ≥ 120   
    
 ≤ 50   
 QT Interval (msec)  
 ≥ 500  
    
 ≤ 300   
QTcF (msec) 
> 450  
 
Heart Rate (bpm) 
 
PR Interval (msec) 
 
QT Interval (msec) 
 
QRS Interval (msec) 
 
RR Interval (msec) 
 
QTcF Interval (msec) 
 
Observed and change from baseline by visit  
 
Markedly abnormal value and change of ECG by visit 
 
Shift table of change from baseline to worst post-baseline ECG assessment by investigator 


 
 
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> 480  
 
> 500 
 
≤ 300 
 
Increase from baseline > 30  
 
Increase from baseline > 60 
 
Decrease from baseline > 30  
 
Decrease from baseline > 60 
 
> 450 and increase from baseline > 30  
 
> 500 and increase from baseline > 60  
17.6. 
VITAL SIGNS 
The following Vital Signs measurements performed within 37 days after the date of last dose of study 
medication will be reported for this study: 
The following summaries will be provided for vital signs data: 
Listing of vital sign data will also be generated. 
 
17.6.1. VITAL SIGNS SPECIFIC DERIVATIONS  
There will be no specific derivations for vital signs. 
17.6.2. VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified and classified in accordance with 
the following predefined criteria:  
Vital Sign Parameter 
Criterion value   
SBP (mmHg),  
DBP (mmHg),  
Heart rate (bpm) 
Increase from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
 
Heart rate (bpm) 
 
Respiratory rate (bpm) 
 
Body Temperature (C) 
 
Weight (kg) 
 
Systolic blood pressure (mmHg) 
 
Diastolic blood pressure (mmHg) 
 
Observed and change from baseline by visit  
 
The frequency and percentage of patients with any potentially clinically significant findings defined in 
section 17.6.2 during the treatment period will be presented.    


 
 
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Vital Sign Parameter 
Criterion value   
Decrease from baseline of 
˃ 0 - ≤ 20  
˃ 20 - ≤ 40  
˃ 40  
Weight (kg) 
Percentage decrease from baseline of 
˂ 5%  
≥ 5 – < 10%  
≥ 10 - < 20%  
≥ 20% 
Percentage increase from baseline of 
˂ 5%  
≥ 5 – < 10%  
≥ 10 - < 20%  
≥ 20% 
 
 
17.7. 
PHYSICAL EXAMINATION  
The physical examination results collected will be listed. 
17.8. 
OTHER SAFETY ASSESSMENTS 
17.8.1. ECOG PERFORMANCE STATUS 
Summary of ECOG performance status by scheduled visit and change to worst post-baseline value will also be 
presented. All the ECOG performance status data will also be listed. 
17.8.2. ECHOCARDIOGRAM 
Baseline and change from baseline on left ventricular ejection fraction (LVEF) will be summarized by dose cohort 
(only in dose escalation phase) or tumor specific cohorts (only in dose expansion phase) and visit. Also, shift from 
baseline to worst post-baseline overall evaluation (i.e., normal, abnormal but NCS, abnormal and CS) will be 
summarized. Individual data will also be listed.  
17.8.3. PREGNANCY TEST 
Individual pregnancy information will be listed for the SAS. 
17.8.4. TUMOR MARKER 
CA125 level for patients with ovarian cancer, PSA for patients with prostate cancer, or other tumor markers (as 
appropriate) should be obtained as clinically indicated or with each tumor assessment. The individual tumor 
marker test results will be listed for SAS. 
 


 
 
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17.8.5. IMPACT OF COVID-19 
The study is conducted during the COVID-19 pandemic, additional data is collected for evaluating the impact of 
COVID-19. To eliminate potential hazards to patients and study staff due to the COVID-19 pandemic while 
ensuring patients safety and maintaining data integrity, patients are allowed remote visits during the pandemic. 
Data listing will be provided.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009; 45:228-247. 
Brookmeyer R., and Crowley J. (1982). A confidence interval for the median survival time. Biometrics, 29-41. 
 
 
 
 
18. REFERENCES  


 
 
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APPENDIX 1. SCHEDULE OF EVENTS 
Schedule of events is shown as below. 


 
 
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APPENDIX 2. PROGRAMMING CONVENTIONS FOR OUTPUTS 
Output Conventions 
For more details please refer to the general rules listed in the shell.   
 
Dates & Times 
Depending on data available, dates and times will take the form ddmmyyyyThh:mm:ss. 
 
Spelling Format 
English US. 
 
Presentation of Treatment Groups 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables 
Dose Escalation Phase: 3mg QD 
Dose Escalation Phase: Fruquintinib 3mg QD 
Dose Escalation Phase: 5mg QD 
Dose Escalation Phase: Fruquintinib 5mg QD 
Dose Expansion Phase (5mg QD): Cohort A  
Dose Expansion Phase: Cohort A 
Dose Escalation Phase: 5mg QD  
+ Dose Expansion Phase (5mg QD): Cohort A 
Dose Expansion Phase: Dose Escalation 
Fruquintinib 5mg QD + Cohort A 
Dose Escalation Phase + Dose Expansion Phase 
Dose Expansion Phase: Dose Escalation Phase + 
Dose Expansion Phase 
(Only for Patient Disposition, Demographic and 
Baseline Characteristics, Baseline Cancer 
Characteristics tables) 
 
Treatment Group 
For Listings 
Dose Escalation Phase: 3mg QD 
Dose Escalation Phase: Fruquintinib 3mg QD 
Dose Escalation Phase: 5mg QD 
Dose Escalation Phase: Fruquintinib 5mg QD 
Dose Expansion Phase (5mg QD): Cohort A  
Dose Expansion Phase: Cohort A 
 
Treatment Group 
For Figures 
Dose Escalation Phase: 3mg QD 
Dose Escalation Phase: Fruquintinib 3mg QD 
Dose Escalation Phase: 5mg QD 
Dose Escalation Phase: Fruquintinib 5mg QD 


 
 
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Treatment Group 
For Figures 
Dose Expansion Phase (5mg QD): Cohort A  
Dose Expansion Phase: Cohort A 
Dose Escalation Phase: 5mg QD  
and Dose Expansion Phase (5mg QD): Cohort A 
Pooling Dose Escalation 5 mg and Cohort A 
Dose Escalation Phase: 3mg QD  
+ Dose Escalation Phase: 5mg QD  
and Dose Expansion Phase (5mg QD): Cohort A 
Dose Escalation 3mg and Pooling Dose 
Escalation 5mg and Cohort A 
 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Baseline 
Baseline 
Cycle 1 Day 1 
C1D1 
Cycle 1 Day 8 
C1D8 
Cycle 1 Day 15 
C1D15 
Cycle 1 Day 22 
C1D22 
Cycle 2 Day 1 
C2D1 
Cycle 2 Day 15 
C2D15 
Cycle 3 Day 1 
C3D15 
Cycle 4 Day 1 
C4D1 
Cycle X Day 1 
CXD1 
…… 
……. 
End of Treatment 
EOT 
 
Listings 
All listings will be ordered by the following (unless otherwise indicated in the template): 
Assigned treatment group, unless otherwise specified 
Center-Patient Number 
Date (where applicable) 
 
 


 
 
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APPENDIX 3. BEST OVERALL RESPONSE WHEN CONFIRMATION 
OF CR AND PR ARE REQUIRED  
First TPR 
Second TPR[a] 
Best overall 
response*^ for ORR 
Best Overall Response for 
ORRUNCONFIRMED 
CR 
CR 
CR 
CR 
CR 
PR 
SD [b] or PD 
Unconfirmed CR 
CR 
SD 
SD [b] or PD  
Unconfirmed CR 
CR 
PD 
SD [b] or PD  
Unconfirmed CR 
CR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed CR 
PR 
CR 
PR 
Unconfirmed CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD [d] 
Unconfirmed PR 
PR 
PD 
SD [b] or PD 
Unconfirmed PR 
PR 
NE or NA 
SD [c] or NE or NA 
Unconfirmed PR 
NE 
NE 
NE 
NE 
NE 
CR 
SD 
Unconfirmed CR 
NE 
PR 
SD 
Unconfirmed PR 
NE 
SD 
SD 
SD 
NE or NA 
PD 
PD 
PD 
SD 
PD 
SD [b] or PD 
SD [b] or PD 
SD 
CR 
SD 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
SD 
SD 
NE or NA 
SD [c] or NE or NA 
SD [c] or NE 
PD 
No further 
evaluation 
PD 
PD 
CR = Complete Response; NE = Not Evaluable; NA = Not Available; ORR = Objective Response Rate; PD = Progressive 
Disease; PR= Partial Response; SD = Stable Disease.  
[a]The minimum interval for confirmation of CR and PR is 4 weeks.  
[b]Best response will be SD if the first time point overall response is after 49 days on study. Otherwise, the best response  
     will be PD. 
[c]Best response will be SD if the first time point overall response after 49 days on study.  Otherwise, the best response  
     will be NE. 


 
 
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[d]Best response will be SD provided the criteria for PD have not been met from the first to second assessment. 
* A best overall response of SD can only be made after the subject is on study for a minimum of 49 days (counted from  
   Cycle 1 Day 1).  If the subject is on study for less than 49 days, any tumor assessment indicating stable disease before this  
   time period will have a best response of NE unless PD is identified.  
^ Subsequent documentation of a CR may provide confirmation of a previously identified CR even with an intervening NE  
   (e.g., CR NE CR). Subsequent documentation of a PR may provide confirmation of a previously identified PR even with  
   an intervening NE or SD (e.g., PR NE PR or PR SD PR). However, only one (1) intervening NE or SD will be allowed  
   between PRs for confirmation. Note: in the following scenario, PR SD NE PR, the second PR is not a confirmation of the  
   first PR. 
 
 
 
 
 
 
 
 


 
 
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APPENDIX 4. VISIT-WINDOW MAPPING 


 
 
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APPENDIX 5. MEDDRA (VERSION 24.1) PREFERRED TERM LIST FOR AESI CATEGORIES  
AESI Category: Thyroid Dysfunction 
Anti-thyroid antibody 
Marine Lenhart syndrome 
Thyroid size decreased 
Anti-thyroid antibody decreased 
Multifocal fibrosclerosis 
Thyroid stimulating hormone deficiency 
Anti-thyroid antibody increased 
Myxoedema 
Thyroid stimulating immunoglobulin increased 
Anti-thyroid antibody positive 
Myxoedema coma 
Thyroid therapy 
Antithyroid arthritis syndrome 
Orbital decompression 
Thyroid tuberculosis 
Atrophic thyroiditis 
Photon radiation therapy to thyroid 
Thyroidectomy 
Autoimmune hypothyroidism 
Polyglandular autoimmune syndrome type II 
Thyroiditis 
Autoimmune thyroid disorder 
Polyglandular autoimmune syndrome type III 
Thyroiditis acute 
Autoimmune thyroiditis 
Post procedural hypothyroidism 
Thyroiditis chronic 
Basedow's disease 
Primary hyperthyroidism 
Thyroiditis fibrous chronic 
Biopsy thyroid gland abnormal 
Primary hypothyroidism 
Thyroiditis subacute 
Blood thyroid stimulating hormone abnormal 
Protein bound iodine decreased 
Thyrotoxic cardiomyopathy 
Blood thyroid stimulating hormone decreased 
Protein bound iodine increased 
Thyrotoxic crisis 
Blood thyroid stimulating hormone increased 
Radioactive iodine therapy 
Thyrotoxic myopathy 
Butanol-extractable iodine decreased 
Radiotherapy to thyroid 
Thyrotoxic periodic paralysis 
Butanol-extractable iodine increased 
Reverse tri-iodothyronine decreased 
Thyroxin binding globulin abnormal 
Congenital hypothyroidism 
Reverse tri-iodothyronine increased 
Thyroxin binding globulin decreased 
Congenital thyroid disorder 
Secondary hyperthyroidism 
Thyroxin binding globulin increased 
Endocrine ophthalmopathy 
Secondary hypothyroidism 
Thyroxine abnormal 
Euthyroid sick syndrome 
Silent thyroiditis 
Thyroxine decreased 
Exophthalmos 
Tertiary hypothyroidism 
Thyroxine free abnormal 
Free thyroxine index abnormal 
Thyreostatic therapy 
Thyroxine free decreased 
Free thyroxine index decreased 
Thyroglobulin absent 
Thyroxine free increased 
Free thyroxine index increased 
Thyroglobulin decreased 
Thyroxine increased 
Gamma radiation therapy to thyroid 
Thyroglobulin increased 
Thyroxine therapy 


 
 
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Generalised resistance to thyroid hormone 
Thyroglobulin present 
Toxic goitre 
Goitre 
Thyroid atrophy 
Toxic nodular goitre 
Hashimoto's encephalopathy 
Thyroid autotransplantation 
Transient hypothyroxinaemia of prematurity 
Hashitoxicosis 
Thyroid dermatopathy 
Tri-iodothyronine abnormal 
Hyperthyroidism 
Thyroid disorder 
Tri-iodothyronine decreased 
Hypothyroidic goitre 
Thyroid dysfunction in pregnancy 
Tri-iodothyronine free abnormal 
Hypothyroidism 
Thyroid electron radiation therapy 
Tri-iodothyronine free decreased 
Immune-mediated hyperthyroidism 
Thyroid function test abnormal 
Tri-iodothyronine free increased 
Immune-mediated hypothyroidism 
Thyroid gland scan abnormal 
Tri-iodothyronine free normal 
Immune-mediated thyroiditis 
Thyroid hemiagenesis 
Tri-iodothyronine increased 
Inappropriate thyroid stimulating hormone secretion 
Thyroid hormone replacement therapy 
Tri-iodothyronine uptake abnormal 
Infectious thyroiditis 
Thyroid hormones decreased 
Tri-iodothyronine uptake decreased 
Iodine uptake abnormal 
Thyroid hormones increased 
Tri-iodothyronine uptake increased 
Iodine uptake decreased 
Thyroid operation 
Ultrasound thyroid abnormal 
Iodine uptake increased 
Thyroid pain 
X-ray therapy to thyroid 
Malignant exophthalmos 
Thyroid releasing hormone challenge test abnormal 
 
 
 
 
AESI Category: Proteinuria 
Albumin globulin ratio increased 
Beta 2 microglobulin urine increased 
Protein urine 
Albumin urine present 
Globulinuria 
Protein urine present 
Albuminuria 
Microalbuminuria 
Proteinuria 
Bence Jones protein urine present 
Myoglobinuria 
Urine albumin/creatinine ratio increased 
Bence Jones proteinuria 
Orthostatic proteinuria 
Urine protein/creatinine ratio abnormal 
 
 
Urine protein/creatinine ratio increased 
 
 
 
AESI Category: Hypertension 
Accelerated hypertension 
Eclampsia 
Metabolic syndrome 
Aldosterone urine abnormal 
Ectopic aldosterone secretion 
Metanephrine urine abnormal 
Aldosterone urine increased 
Ectopic renin secretion 
Metanephrine urine increased 


 
 
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Angiotensin converting enzyme increased 
Endocrine hypertension 
Neurogenic hypertension 
Angiotensin I increased 
Epinephrine abnormal 
Non-dipping 
Angiotensin II increased 
Epinephrine increased 
Norepinephrine abnormal 
Angiotensin II receptor type 1 antibody positive 
Essential hypertension 
Norepinephrine increased 
Blood aldosterone abnormal 
Gestational hypertension 
Normetanephrine urine increased 
Blood aldosterone increased 
HELLP syndrome 
Orthostatic hypertension 
Blood catecholamines abnormal 
Hyperaldosteronism 
Page kidney 
Blood catecholamines increased 
Hypertension 
Postoperative hypertension 
Blood pressure abnormal 
Hypertension neonatal 
Pre-eclampsia 
Blood pressure ambulatory abnormal 
Hypertensive angiopathy 
Prehypertension 
Blood pressure ambulatory increased 
Hypertensive cardiomegaly 
Procedural hypertension 
Blood pressure diastolic abnormal 
Hypertensive cardiomyopathy 
Pseudoaldosteronism 
Blood pressure diastolic increased 
Hypertensive cerebrovascular disease 
Renal hypertension 
Blood pressure fluctuation 
Hypertensive crisis 
Renal sympathetic nerve ablation 
Blood pressure inadequately controlled 
Hypertensive emergency 
Renal vascular resistance increased 
Blood pressure increased 
Hypertensive encephalopathy 
Renin abnormal 
Blood pressure management 
Hypertensive end-organ damage 
Renin increased 
Blood pressure orthostatic abnormal 
Hypertensive heart disease 
Renin-angiotensin system inhibition 
Blood pressure orthostatic increased 
Hypertensive nephropathy 
Renovascular hypertension 
Blood pressure systolic abnormal 
Hypertensive urgency 
Retinopathy hypertensive 
Blood pressure systolic increased 
Labile blood pressure 
Secondary aldosteronism 
Catecholamine crisis 
Labile hypertension 
Secondary hypertension 
Catecholamines urine abnormal 
Malignant hypertension 
Superimposed pre-eclampsia 
Catecholamines urine increased 
Malignant hypertensive heart disease 
Supine hypertension 
Dialysis induced hypertension 
Malignant renal hypertension 
Systolic hypertension 
Diastolic hypertension 
Maternal hypertension affecting foetus 
Tyramine reaction 
Diuretic therapy 
Mean arterial pressure increased 
Withdrawal hypertension 
 
 
 
AESI Category: Haemorrhages 


 
 
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Abdominal wall haematoma 
Haemophilic pseudotumour 
Petechiae 
Abdominal wall haemorrhage 
Haemoptysis 
Pharyngeal contusion 
Abnormal uterine bleeding 
Haemorrhage 
Pharyngeal haematoma 
Abnormal withdrawal bleeding 
Haemorrhage coronary artery 
Pharyngeal haemorrhage 
Achenbach syndrome 
Haemorrhage foetal 
Pituitary apoplexy 
Acute haemorrhagic leukoencephalitis 
Haemorrhage in pregnancy 
Pituitary haemorrhage 
Acute haemorrhagic ulcerative colitis 
Haemorrhage intracranial 
Placenta praevia haemorrhage 
Administration site bruise 
Haemorrhage neonatal 
Polymenorrhagia 
Administration site haematoma 
Haemorrhage subcutaneous 
Post abortion haemorrhage 
Administration site haemorrhage 
Haemorrhage subepidermal 
Post procedural contusion 
Adrenal haematoma 
Haemorrhage urinary tract 
Post procedural haematoma 
Adrenal haemorrhage 
Haemorrhagic adrenal infarction 
Post procedural haematuria 
Anal fissure haemorrhage 
Haemorrhagic arteriovenous malformation 
Post procedural haemorrhage 
Anal haemorrhage 
Haemorrhagic ascites 
Post transfusion purpura 
Anal ulcer haemorrhage 
Haemorrhagic breast cyst 
Postmenopausal haemorrhage 
Anastomotic haemorrhage 
Haemorrhagic cerebellar infarction 
Postpartum haemorrhage 
Anastomotic ulcer haemorrhage 
Haemorrhagic cerebral infarction 
Post-traumatic punctate intraepidermal haemorrhage 
Aneurysm ruptured 
Haemorrhagic cyst 
Premature separation of placenta 
Angina bullosa haemorrhagica 
Haemorrhagic diathesis 
Procedural haemorrhage 
Anorectal varices haemorrhage 
Haemorrhagic disease of newborn 
Proctitis haemorrhagic 
Anticoagulant-related nephropathy 
Haemorrhagic disorder 
Prostatic haemorrhage 
Antiplatelet reversal therapy 
Haemorrhagic erosive gastritis 
Pulmonary alveolar haemorrhage 
Aortic aneurysm rupture 
Haemorrhagic gastroenteritis 
Pulmonary contusion 
Aortic dissection rupture 
Haemorrhagic hepatic cyst 
Pulmonary haematoma 
Aortic intramural haematoma 
Haemorrhagic infarction 
Pulmonary haemorrhage 
Aortic perforation 
Haemorrhagic necrotic pancreatitis 
Pulmonary haemorrhage neonatal 
Aortic rupture 
Haemorrhagic occlusive retinal vasculitis 
Puncture site bruise 
Aponeurosis contusion 
Haemorrhagic ovarian cyst 
Puncture site haematoma 
Application site bruise 
Haemorrhagic stroke 
Puncture site haemorrhage 


 
 
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Application site haematoma 
Haemorrhagic thyroid cyst 
Purpura 
Application site haemorrhage 
Haemorrhagic transformation stroke 
Purpura fulminans 
Application site purpura 
Haemorrhagic tumour necrosis 
Purpura neonatal 
Arterial haemorrhage 
Haemorrhagic urticaria 
Purpura non-thrombocytopenic 
Arterial intramural haematoma 
Haemorrhagic vasculitis 
Purpura senile 
Arterial perforation 
Haemorrhoidal haemorrhage 
Putamen haemorrhage 
Arterial rupture 
Haemostasis 
Radiation associated haemorrhage 
Arteriovenous fistula site haematoma 
Haemothorax 
Rectal haemorrhage 
Arteriovenous fistula site haemorrhage 
Heavy menstrual bleeding 
Rectal ulcer haemorrhage 
Arteriovenous graft site haematoma 
Henoch-Schonlein purpura 
Renal artery perforation 
Arteriovenous graft site haemorrhage 
Hepatic haemangioma rupture 
Renal cyst haemorrhage 
Astringent therapy 
Hepatic haematoma 
Renal haematoma 
Atrial rupture 
Hepatic haemorrhage 
Renal haemorrhage 
Auricular haematoma 
Hereditary haemorrhagic telangiectasia 
Respiratory tract haemorrhage 
Basal ganglia haematoma 
Hyperfibrinolysis 
Respiratory tract haemorrhage neonatal 
Basal ganglia haemorrhage 
Hypergammaglobulinaemic purpura of Waldenstrom 
Retinal aneurysm rupture 
Basilar artery perforation 
Hyphaema 
Retinal haemorrhage 
Bladder tamponade 
Iliac artery perforation 
Retinopathy haemorrhagic 
Bleeding varicose vein 
Iliac artery rupture 
Retroperitoneal haematoma 
Blood blister 
Iliac vein perforation 
Retroperitoneal haemorrhage 
Blood loss anaemia 
Immune thrombocytopenia 
Retroplacental haematoma 
Blood urine 
Implant site bruising 
Ruptured cerebral aneurysm 
Blood urine present 
Implant site haematoma 
Scleral haematoma 
Bloody discharge 
Implant site haemorrhage 
Scleral haemorrhage 
Bloody peritoneal effluent 
Incision site haematoma 
Scrotal haematocoele 
Bone contusion 
Incision site haemorrhage 
Scrotal haematoma 
Bone marrow haemorrhage 
Increased tendency to bruise 
Scrotal haemorrhage 
Brain contusion 
Induced abortion haemorrhage 
Shock haemorrhagic 
Brain stem haematoma 
Inferior vena cava perforation 
Skin haemorrhage 


 
 
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Brain stem haemorrhage 
Infusion site bruising 
Skin neoplasm bleeding 
Brain stem microhaemorrhage 
Infusion site haematoma 
Skin ulcer haemorrhage 
Breast haematoma 
Infusion site haemorrhage 
Small intestinal haemorrhage 
Breast haemorrhage 
Injection site bruising 
Small intestinal ulcer haemorrhage 
Broad ligament haematoma 
Injection site haematoma 
Soft tissue haemorrhage 
Bronchial haemorrhage 
Injection site haemorrhage 
Spermatic cord haemorrhage 
Bronchial varices haemorrhage 
Instillation site bruise 
Spinal cord haematoma 
Bullous haemorrhagic dermatosis 
Instillation site haematoma 
Spinal cord haemorrhage 
Bursal haematoma 
Instillation site haemorrhage 
Spinal epidural haematoma 
Cardiac contusion 
Intermenstrual bleeding 
Spinal epidural haemorrhage 
Carotid aneurysm rupture 
Internal haemorrhage 
Spinal subarachnoid haemorrhage 
Carotid artery perforation 
Intestinal haematoma 
Spinal subdural haematoma 
Catheter site bruise 
Intestinal haemorrhage 
Spinal subdural haemorrhage 
Catheter site haematoma 
Intestinal varices haemorrhage 
Spleen contusion 
Catheter site haemorrhage 
Intra-abdominal haematoma 
Splenic artery perforation 
Central nervous system haemorrhage 
Intra-abdominal haemorrhage 
Splenic haematoma 
Cephalhaematoma 
Intracerebral haematoma evacuation 
Splenic haemorrhage 
Cerebellar haematoma 
Intracranial haematoma 
Splenic varices haemorrhage 
Cerebellar haemorrhage 
Intracranial tumour haemorrhage 
Splinter haemorrhages 
Cerebellar microhaemorrhage 
Intraocular haematoma 
Spontaneous haematoma 
Cerebral aneurysm perforation 
Intrapartum haemorrhage 
Spontaneous haemorrhage 
Cerebral aneurysm ruptured syphilitic 
Intratumoural haematoma 
Stoma site haemorrhage 
Cerebral arteriovenous malformation haemorrhagic 
Intraventricular haemorrhage 
Stomatitis haemorrhagic 
Cerebral artery perforation 
Intraventricular haemorrhage neonatal 
Subarachnoid haematoma 
Cerebral cyst haemorrhage 
Iris haemorrhage 
Subarachnoid haemorrhage 
Cerebral haematoma 
Joint microhaemorrhage 
Subarachnoid haemorrhage neonatal 
Cerebral haemorrhage 
Jugular vein haemorrhage 
Subcapsular hepatic haematoma 
Cerebral haemorrhage foetal 
Kidney contusion 
Subcapsular renal haematoma 
Cerebral haemorrhage neonatal 
Lacrimal haemorrhage 
Subcapsular splenic haematoma 


 
 
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Cerebral microhaemorrhage 
Large intestinal haemorrhage 
Subchorionic haematoma 
Cervix haematoma uterine 
Large intestinal ulcer haemorrhage 
Subchorionic haemorrhage 
Cervix haemorrhage uterine 
Laryngeal haematoma 
Subclavian artery perforation 
Chest wall haematoma 
Laryngeal haemorrhage 
Subclavian vein perforation 
Choroidal haematoma 
Lip haematoma 
Subcutaneous haematoma 
Choroidal haemorrhage 
Lip haemorrhage 
Subdural haematoma 
Chronic gastrointestinal bleeding 
Liver contusion 
Subdural haematoma evacuation 
Chronic pigmented purpura 
Lower gastrointestinal haemorrhage 
Subdural haemorrhage 
Ciliary body haemorrhage 
Lower limb artery perforation 
Subdural haemorrhage neonatal 
Coital bleeding 
Lymph node haemorrhage 
Subendocardial haemorrhage 
Colonic haematoma 
Mallory-Weiss syndrome 
Subgaleal haematoma 
Conjunctival haemorrhage 
Mediastinal haematoma 
Subgaleal haemorrhage 
Contusion 
Mediastinal haemorrhage 
Subretinal haematoma 
Corneal bleeding 
Medical device site bruise 
Superior vena cava perforation 
Cullen's sign 
Medical device site haematoma 
Testicular haemorrhage 
Cystitis haemorrhagic 
Medical device site haemorrhage 
Thalamus haemorrhage 
Deep dissecting haematoma 
Melaena 
Third stage postpartum haemorrhage 
Diarrhoea haemorrhagic 
Melaena neonatal 
Thoracic haemorrhage 
Disseminated intravascular coagulation 
Meningorrhagia 
Thrombocytopenic purpura 
Diverticulitis intestinal haemorrhagic 
Menometrorrhagia 
Thrombotic thrombocytopenic purpura 
Diverticulum intestinal haemorrhagic 
Mesenteric haematoma 
Thyroid haemorrhage 
Duodenal ulcer haemorrhage 
Mesenteric haemorrhage 
Tongue haematoma 
Duodenitis haemorrhagic 
Mouth haemorrhage 
Tongue haemorrhage 
Ear haemorrhage 
Mucocutaneous haemorrhage 
Tonsillar haemorrhage 
Ecchymosis 
Mucosal haemorrhage 
Tooth pulp haemorrhage 
Encephalitis haemorrhagic 
Muscle contusion 
Tooth socket haemorrhage 
Enterocolitis haemorrhagic 
Muscle haemorrhage 
Tracheal haemorrhage 
Epidural haemorrhage 
Myocardial haemorrhage 
Traumatic haematoma 
Epistaxis 
Myocardial rupture 
Traumatic haemorrhage 


 
 
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Exsanguination 
Naevus haemorrhage 
Traumatic haemothorax 
Extra-axial haemorrhage 
Nail bed bleeding 
Traumatic intracranial haematoma 
Extradural haematoma 
Nasal septum haematoma 
Traumatic intracranial haemorrhage 
Extradural haematoma evacuation 
Neonatal gastrointestinal haemorrhage 
Tumour haemorrhage 
Extravasation blood 
Nephritis haemorrhagic 
Ulcer haemorrhage 
Eye contusion 
Nipple exudate bloody 
Umbilical cord haemorrhage 
Eye haematoma 
Occult blood positive 
Umbilical haematoma 
Eye haemorrhage 
Ocular retrobulbar haemorrhage 
Umbilical haemorrhage 
Eyelid bleeding 
Oesophageal haemorrhage 
Upper gastrointestinal haemorrhage 
Eyelid contusion 
Oesophageal intramural haematoma 
Ureteric haemorrhage 
Eyelid haematoma 
Oesophageal ulcer haemorrhage 
Urethral haemorrhage 
Femoral artery perforation 
Oesophageal varices haemorrhage 
Urinary bladder haematoma 
Femoral vein perforation 
Oesophagitis haemorrhagic 
Urinary bladder haemorrhage 
Foetal-maternal haemorrhage 
Omental haemorrhage 
Urinary occult blood 
Fothergill sign positive 
Optic disc haemorrhage 
Urinary occult blood positive 
Gallbladder haematoma 
Optic nerve sheath haemorrhage 
Urogenital haemorrhage 
Gastric haemorrhage 
Oral blood blister 
Uterine haematoma 
Gastric occult blood positive 
Oral contusion 
Uterine haemorrhage 
Gastric ulcer haemorrhage 
Oral mucosa haematoma 
Vaccination site bruising 
Gastric ulcer haemorrhage, obstructive 
Oral purpura 
Vaccination site haematoma 
Gastric varices haemorrhage 
Orbital haematoma 
Vaccination site haemorrhage 
Gastritis alcoholic haemorrhagic 
Orbital haemorrhage 
Vaginal haematoma 
Gastritis haemorrhagic 
Osteorrhagia 
Vaginal haemorrhage 
Gastroduodenal haemorrhage 
Ovarian haematoma 
Varicose vein ruptured 
Gastrointestinal anastomotic haemorrhage 
Ovarian haemorrhage 
Vascular access site bruising 
Gastrointestinal haemorrhage 
Palpable purpura 
Vascular access site haematoma 
Gastrointestinal polyp haemorrhage 
Pancreatic haemorrhage 
Vascular access site haemorrhage 
Gastrointestinal ulcer haemorrhage 
Pancreatic pseudocyst haemorrhage 
Vascular access site rupture 
Gastrointestinal vascular malformation haemorrhagic 
Pancreatitis haemorrhagic 
Vascular anastomotic haemorrhage 


 
 
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Genital contusion 
Papillary muscle haemorrhage 
Vascular graft haemorrhage 
Genital haemorrhage 
Paranasal sinus haematoma 
Vascular pseudoaneurysm ruptured 
Gingival bleeding 
Paranasal sinus haemorrhage 
Vascular purpura 
Graft haemorrhage 
Parathyroid haemorrhage 
Vascular rupture 
Grey Turner's sign 
Parotid gland haemorrhage 
Vein rupture 
Haemangioma rupture 
Pelvic haematoma 
Venous haemorrhage 
Haemarthrosis 
Pelvic haematoma obstetric 
Venous perforation 
Haematemesis 
Pelvic haemorrhage 
Ventricle rupture 
Haematochezia 
Penile contusion 
Vertebral artery perforation 
Haematocoele 
Penile haematoma 
Vessel puncture site bruise 
Haematoma 
Penile haemorrhage 
Vessel puncture site haematoma 
Haematoma evacuation 
Peptic ulcer haemorrhage 
Vessel puncture site haemorrhage 
Haematoma infection 
Pericardial haemorrhage 
Vitreous haematoma 
Haematoma muscle 
Perineal haematoma 
Vitreous haemorrhage 
Haematosalpinx 
Periorbital haematoma 
Vulval haematoma 
Haematospermia 
Periorbital haemorrhage 
Vulval haematoma evacuation 
Haematotympanum 
Periosteal haematoma 
Vulval haemorrhage 
Haematuria 
Peripartum haemorrhage 
Withdrawal bleed 
Haematuria traumatic 
Peripheral artery aneurysm rupture 
Wound haematoma 
Haemobilia 
Peripheral artery haematoma 
Wound haemorrhage 
Haemoperitoneum 
Peripheral exudative haemorrhagic chorioretinopathy 
 
Haemophilic arthropathy 
Peritoneal haematoma 
 
 
Periventricular haemorrhage neonatal 
 
 
 
 
AESI Category: Gastrointestinal perforation 
Abdominal abscess 
Focal peritonitis 
Oesophageal perforation 
Abdominal hernia perforation 
Gastric fistula 
Oesophageal rupture 
Abdominal wall abscess 
Gastric fistula repair 
Oesophageal ulcer perforation 
Abscess intestinal 
Gastric perforation 
Oesophageal-pulmonary fistula 


 
 
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Acquired tracheo-oesophageal fistula 
Gastric ulcer perforation 
Oesophagobronchial fistula 
Anal abscess 
Gastric ulcer perforation, obstructive 
Oesophagomediastinal fistula 
Anal fistula 
Gastrointestinal anastomotic leak 
Oesophagopleural fistula 
Anal fistula infection 
Gastrointestinal fistula 
Pancreatic fistula 
Anal fistula repair 
Gastrointestinal fistula repair 
Pancreatic fistula repair 
Anastomotic ulcer perforation 
Gastrointestinal perforation 
Peptic ulcer perforation 
Anovulvar fistula 
Gastrointestinal ulcer perforation 
Peptic ulcer perforation, obstructive 
Aortoenteric fistula 
Gastropleural fistula 
Peptic ulcer repair 
Aorto-oesophageal fistula 
Gastrosplenic fistula 
Perforated ulcer 
Appendiceal abscess 
Ileal perforation 
Perineal abscess 
Appendicitis perforated 
Ileal ulcer perforation 
Perirectal abscess 
Arterioenteric fistula 
Incisional hernia perforation 
Peritoneal abscess 
Atrio-oesophageal fistula 
Inguinal hernia perforation 
Peritoneocutaneous fistula 
Chemical peritonitis 
Intestinal fistula 
Peritonitis 
Colon fistula repair 
Intestinal fistula infection 
Peritonitis bacterial 
Colonic abscess 
Intestinal fistula repair 
Pneumoperitoneum 
Colonic fistula 
Intestinal perforation 
Pneumoretroperitoneum 
Colo-urethral fistula 
Intestinal ulcer perforation 
Procedural intestinal perforation 
Diverticular fistula 
Jejunal perforation 
Rectal abscess 
Diverticular perforation 
Jejunal ulcer perforation 
Rectal fistula repair 
Diverticulitis intestinal perforated 
Large intestinal ulcer perforation 
Rectal perforation 
Douglas' abscess 
Large intestine perforation 
Rectoprostatic fistula 
Duodenal perforation 
Lower gastrointestinal perforation 
Rectourethral fistula 
Duodenal rupture 
Mesenteric abscess 
Retroperitoneal abscess 
Duodenal ulcer perforation 
Neonatal intestinal perforation 
Small intestinal perforation 
Duodenal ulcer perforation, obstructive 
Oesophageal abscess 
Small intestinal ulcer perforation 
Duodenal ulcer repair 
Oesophageal fistula 
Spontaneous bacterial peritonitis 
Enterocolonic fistula 
Oesophageal fistula repair 
Umbilical hernia perforation 
Enterocutaneous fistula 
 
Upper gastrointestinal perforation 


 
 
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Fistula of small intestine 
 
 
 
 
 
AESI Category: Embolic and thrombotic events 
Acute aortic syndrome 
Embolism venous 
Pseudo-occlusion of internal carotid artery 
Acute myocardial infarction 
Endarterectomy 
Pulmonary artery occlusion 
Administration site thrombosis 
Eye infarction 
Pulmonary artery therapeutic procedure 
Adrenal thrombosis 
Femoral artery embolism 
Pulmonary artery thrombosis 
Amaurosis 
Fluorescence angiogram abnormal 
Pulmonary embolism 
Amaurosis fugax 
Foetal cerebrovascular disorder 
Pulmonary endarterectomy 
Angiogram abnormal 
Foetal vascular malperfusion 
Pulmonary infarction 
Angiogram cerebral abnormal 
Gastric infarction 
Pulmonary microemboli 
Angiogram peripheral abnormal 
Graft thrombosis 
Pulmonary thrombosis 
Angioplasty 
Haemorrhagic adrenal infarction 
Pulmonary tumour thrombotic microangiopathy 
Antiphospholipid syndrome 
Haemorrhagic cerebral infarction 
Pulmonary vein occlusion 
Aortic bypass 
Haemorrhagic infarction 
Pulmonary veno-occlusive disease 
Aortic embolus 
Haemorrhagic stroke 
Pulmonary venous thrombosis 
Aortic surgery 
Haemorrhagic transformation stroke 
Quadriparesis 
Aortic thrombosis 
Haemorrhoids thrombosed 
Quadriplegia 
Aortogram abnormal 
Hemiparesis 
Renal artery angioplasty 
Application site thrombosis 
Hemiplegia 
Renal artery occlusion 
Arterectomy 
Heparin-induced thrombocytopenia 
Renal artery thrombosis 
Arterectomy with graft replacement 
Hepatic artery embolism 
Renal embolism 
Arterial angioplasty 
Hepatic artery occlusion 
Renal infarct 
Arterial bypass operation 
Hepatic artery thrombosis 
Renal vascular thrombosis 
Arterial graft 
Hepatic infarction 
Renal vein embolism 
Arterial occlusive disease 
Hepatic vascular thrombosis 
Renal vein occlusion 
Arterial revascularisation 
Hepatic vein embolism 
Renal vein thrombosis 
Arterial stent insertion 
Hepatic vein occlusion 
Renal-limited thrombotic microangiopathy 
Arterial therapeutic procedure 
Hepatic vein thrombosis 
Retinal artery embolism 


 
 
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Arterial thrombosis 
Homans' sign positive 
Retinal artery occlusion 
Arteriogram abnormal 
Hypothenar hammer syndrome 
Retinal artery thrombosis 
Arteriogram carotid abnormal 
Iliac artery embolism 
Retinal infarction 
Arteriotomy 
Iliac artery occlusion 
Retinal vascular thrombosis 
Arteriovenous fistula occlusion 
Iliac vein occlusion 
Retinal vein occlusion 
Arteriovenous fistula thrombosis 
Implant site thrombosis 
Retinal vein thrombosis 
Arteriovenous graft thrombosis 
Incision site vessel occlusion 
Revascularisation procedure 
Artificial blood vessel occlusion 
Infarction 
Shunt occlusion 
Aseptic cavernous sinus thrombosis 
Inferior vena cava syndrome 
Shunt thrombosis 
Atherectomy 
Inferior vena caval occlusion 
SI QIII TIII pattern 
Atherosclerotic plaque rupture 
Infusion site thrombosis 
Silent myocardial infarction 
Atrial appendage closure 
Injection site thrombosis 
Spinal artery embolism 
Atrial appendage resection 
Inner ear infarction 
Spinal artery thrombosis 
Atrial thrombosis 
Instillation site thrombosis 
Spinal cord infarction 
Autoimmune heparin-induced thrombocytopenia 
Internal capsule infarction 
Spinal stroke 
Axillary vein thrombosis 
Intestinal infarction 
Splenic artery thrombosis 
Basal ganglia infarction 
Intra-aortic balloon placement 
Splenic embolism 
Basal ganglia stroke 
Intracardiac mass 
Splenic infarction 
Basilar artery occlusion 
Intracardiac thrombus 
Splenic thrombosis 
Basilar artery thrombosis 
Intraoperative cerebral artery occlusion 
Splenic vein occlusion 
Blindness transient 
Ischaemic cerebral infarction 
Splenic vein thrombosis 
Bone infarction 
Ischaemic stroke 
Stoma site thrombosis 
Brachiocephalic artery occlusion 
Jugular vein embolism 
Stress cardiomyopathy 
Brachiocephalic vein occlusion 
Jugular vein occlusion 
Stroke in evolution 
Brachiocephalic vein thrombosis 
Jugular vein thrombosis 
Strokectomy 
Brain stem embolism 
Lacunar infarction 
Subclavian artery embolism 
Brain stem infarction 
Lambl's excrescences 
Subclavian artery occlusion 
Brain stem stroke 
Left atrial appendage closure implant 
Subclavian artery thrombosis 
Brain stem thrombosis 
Leriche syndrome 
Subclavian vein occlusion 


 
 
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Budd-Chiari syndrome 
Mahler sign 
Subclavian vein thrombosis 
Capsular warning syndrome 
May-Thurner syndrome 
Superficial vein thrombosis 
Cardiac ventricular thrombosis 
Medical device site thrombosis 
Superior sagittal sinus thrombosis 
Carotid angioplasty 
Mesenteric arterial occlusion 
Superior vena cava occlusion 
Carotid arterial embolus 
Mesenteric arteriosclerosis 
Superior vena cava syndrome 
Carotid artery bypass 
Mesenteric artery embolism 
Surgical vascular shunt 
Carotid artery occlusion 
Mesenteric artery stenosis 
Testicular infarction 
Carotid artery stent insertion 
Mesenteric artery stent insertion 
Thalamic infarction 
Carotid artery thrombosis 
Mesenteric artery thrombosis 
Thrombectomy 
Carotid endarterectomy 
Mesenteric vascular insufficiency 
Thromboangiitis obliterans 
Catheter directed thrombolysis 
Mesenteric vascular occlusion 
Thromboembolectomy 
Catheter site thrombosis 
Mesenteric vein thrombosis 
Thrombolysis 
Catheterisation venous 
Mesenteric venous occlusion 
Thrombophlebitis 
Cavernous sinus thrombosis 
Microembolism 
Thrombophlebitis migrans 
Central venous catheterisation 
Monoparesis 
Thrombophlebitis neonatal 
Cerebellar artery occlusion 
Monoplegia 
Thrombosed varicose vein 
Cerebellar artery thrombosis 
Muscle infarction 
Thrombosis 
Cerebellar embolism 
Myocardial infarction 
Thrombosis corpora cavernosa 
Cerebellar infarction 
Myocardial necrosis 
Thrombosis in device 
Cerebral artery embolism 
Obstetrical pulmonary embolism 
Thrombosis mesenteric vessel 
Cerebral artery occlusion 
Obstructive shock 
Thrombosis prophylaxis 
Cerebral artery stent insertion 
Ophthalmic artery occlusion 
Thrombosis with thrombocytopenia syndrome 
Cerebral artery thrombosis 
Ophthalmic artery thrombosis 
Thrombotic cerebral infarction 
Cerebral congestion 
Ophthalmic vein thrombosis 
Thrombotic microangiopathy 
Cerebral hypoperfusion 
Optic nerve infarction 
Thrombotic stroke 
Cerebral infarction 
Ovarian vein thrombosis 
Thrombotic thrombocytopenic purpura 
Cerebral infarction foetal 
Paget-Schroetter syndrome 
Thyroid infarction 
Cerebral ischaemia 
Pancreatic infarction 
Transient ischaemic attack 
Cerebral microembolism 
Papillary muscle infarction 
Transverse sinus thrombosis 


 
 
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Cerebral microinfarction 
Paradoxical embolism 
Truncus coeliacus thrombosis 
Cerebral septic infarct 
Paraneoplastic thrombosis 
Tumour embolism 
Cerebral thrombosis 
Paraparesis 
Tumour thrombectomy 
Cerebral vascular occlusion 
Paraplegia 
Tumour thrombosis 
Cerebral venous sinus thrombosis 
Paresis 
Ultrasonic angiogram abnormal 
Cerebral venous thrombosis 
Pelvic venous thrombosis 
Ultrasound Doppler abnormal 
Cerebrospinal thrombotic tamponade 
Penile artery occlusion 
Umbilical cord occlusion 
Cerebrovascular accident 
Penile vein thrombosis 
Umbilical cord thrombosis 
Cerebrovascular accident prophylaxis 
Percutaneous coronary intervention 
Vaccination site thrombosis 
Cerebrovascular disorder 
Peripheral arterial occlusive disease 
Vascular access site thrombosis 
Cerebrovascular insufficiency 
Peripheral arterial reocclusion 
Vascular device occlusion 
Cerebrovascular operation 
Peripheral artery angioplasty 
Vascular graft 
Cerebrovascular stenosis 
Peripheral artery bypass 
Vascular graft occlusion 
Choroidal infarction 
Peripheral artery occlusion 
Vascular graft thrombosis 
Coeliac artery occlusion 
Peripheral artery stent insertion 
Vascular operation 
Collateral circulation 
Peripheral artery surgery 
Vascular pseudoaneurysm thrombosis 
Compression garment application 
Peripheral artery thrombosis 
Vascular stent insertion 
Coronary angioplasty 
Peripheral embolism 
Vascular stent occlusion 
Coronary arterial stent insertion 
Peripheral endarterectomy 
Vascular stent thrombosis 
Coronary artery bypass 
Peripheral revascularisation 
Vasodilation procedure 
Coronary artery embolism 
Peripheral vein occlusion 
Vena cava embolism 
Coronary artery occlusion 
Peripheral vein thrombus extension 
Vena cava filter insertion 
Coronary artery reocclusion 
Phlebectomy 
Vena cava filter removal 
Coronary artery surgery 
Pituitary infarction 
Vena cava thrombosis 
Coronary artery thrombosis 
Placental infarction 
Venogram abnormal 
Coronary bypass thrombosis 
Pneumatic compression therapy 
Venoocclusive disease 
Coronary endarterectomy 
Popliteal artery entrapment syndrome 
Venoocclusive liver disease 
Coronary revascularisation 
Portal shunt procedure 
Venous angioplasty 
Coronary vascular graft occlusion 
Portal vein cavernous transformation 
Venous occlusion 


 
 
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Deep vein thrombosis 
Portal vein embolism 
Venous operation 
Deep vein thrombosis postoperative 
Portal vein occlusion 
Venous recanalisation 
Device embolisation 
Portal vein thrombosis 
Venous repair 
Device occlusion 
Portosplenomesenteric venous thrombosis 
Venous stent insertion 
Device related thrombosis 
Post procedural myocardial infarction 
Venous thrombosis 
Diplegia 
Post procedural pulmonary embolism 
Venous thrombosis in pregnancy 
Directional Doppler flow tests abnormal 
Post procedural stroke 
Venous thrombosis limb 
Disseminated intravascular coagulation 
Post thrombotic syndrome 
Venous thrombosis neonatal 
Disseminated intravascular coagulation in newborn 
Postinfarction angina 
Vertebral artery occlusion 
Embolia cutis medicamentosa 
Postoperative thrombosis 
Vertebral artery thrombosis 
Embolic cerebellar infarction 
Postpartum thrombosis 
Vessel puncture site occlusion 
Embolic cerebral infarction 
Postpartum venous thrombosis 
Vessel puncture site thrombosis 
Embolic pneumonia 
Precerebral artery embolism 
Visceral venous thrombosis 
Embolic stroke 
Precerebral artery occlusion 
Visual acuity reduced transiently 
Embolism 
Precerebral artery thrombosis 
Visual midline shift syndrome 
Embolism arterial 
Profundaplasty 
 
 
Prosthetic cardiac valve thrombosis 
 
 
Prosthetic vessel implantation 
 
 
 
 
AESI Category: Hepatic function abnormal 
Acquired antithrombin III deficiency 
Gastric variceal ligation 
Hypothromboplastinaemia 
Acquired factor IX deficiency 
Gastric varices 
Icterus index increased 
Acquired factor V deficiency 
Gastric varices haemorrhage 
Immune-mediated cholangitis 
Acquired factor VIII deficiency 
Gastrooesophageal variceal haemorrhage prophylaxis 
Immune-mediated hepatic disorder 
Acquired factor XI deficiency 
Graft versus host disease in liver 
Immune-mediated hepatitis 
Acquired hepatocerebral degeneration 
Guanase increased 
International normalised ratio abnormal 
Acquired protein S deficiency 
Haemangioma of liver 
International normalised ratio increased 
Acute graft versus host disease in liver 
Haemorrhagic hepatic cyst 
Intestinal varices 
Acute hepatic failure 
Hepaplastin abnormal 
Intestinal varices haemorrhage 


 
 
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Acute on chronic liver failure 
Hepaplastin decreased 
Ischaemic hepatitis 
Acute yellow liver atrophy 
Hepatectomy 
Jaundice 
Alanine aminotransferase abnormal 
Hepatic adenoma 
Jaundice cholestatic 
Alanine aminotransferase increased 
Hepatic angiosarcoma 
Jaundice hepatocellular 
Allergic hepatitis 
Hepatic artery flow decreased 
Kayser-Fleischer ring 
Alloimmune hepatitis 
Hepatic atrophy 
Liver carcinoma ruptured 
Ammonia abnormal 
Hepatic calcification 
Liver dialysis 
Ammonia increased 
Hepatic cancer 
Liver disorder 
Anti factor X activity abnormal 
Hepatic cancer metastatic 
Liver function test abnormal 
Anti factor X activity decreased 
Hepatic cancer recurrent 
Liver function test decreased 
Anti factor X activity increased 
Hepatic cancer stage I 
Liver function test increased 
Antithrombin III decreased 
Hepatic cancer stage II 
Liver induration 
Ascites 
Hepatic cancer stage III 
Liver injury 
Aspartate aminotransferase abnormal 
Hepatic cancer stage IV 
Liver operation 
Aspartate aminotransferase increased 
Hepatic cirrhosis 
Liver palpable 
AST/ALT ratio abnormal 
Hepatic cyst 
Liver scan abnormal 
Asterixis 
Hepatic cyst ruptured 
Liver tenderness 
Autoimmune hepatitis 
Hepatic cytolysis 
Liver transplant 
Bacterascites 
Hepatic encephalopathy 
Lupoid hepatic cirrhosis 
Benign hepatic neoplasm 
Hepatic encephalopathy prophylaxis 
Lupus hepatitis 
Benign hepatobiliary neoplasm 
Hepatic enzyme abnormal 
Magnetic resonance imaging hepatobiliary abnormal 
Bile output abnormal 
Hepatic enzyme decreased 
Magnetic resonance proton density fat fraction 
measurement 
Bile output decreased 
Hepatic enzyme increased 
Mitochondrial aspartate aminotransferase increased 
Biliary ascites 
Hepatic failure 
Mixed hepatocellular cholangiocarcinoma 
Biliary cirrhosis 
Hepatic fibrosis 
Mixed liver injury 
Biliary fibrosis 
Hepatic function abnormal 
Molar ratio of total branched-chain amino acid to tyrosine 
Bilirubin conjugated abnormal 
Hepatic haemangioma rupture 
Nodular regenerative hyperplasia 
Bilirubin conjugated increased 
Hepatic hamartoma 
Nonalcoholic fatty liver disease 


 
 
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Bilirubin excretion disorder 
Hepatic hydrothorax 
Non-alcoholic steatohepatitis 
Bilirubin urine present 
Hepatic hypertrophy 
Non-cirrhotic portal hypertension 
Biopsy liver abnormal 
Hepatic hypoperfusion 
Ocular icterus 
Blood bilirubin abnormal 
Hepatic infiltration eosinophilic 
Oedema due to hepatic disease 
Blood bilirubin increased 
Hepatic lesion 
Oesophageal varices haemorrhage 
Blood bilirubin unconjugated increased 
Hepatic lipoma 
Parenteral nutrition associated liver disease 
Blood fibrinogen abnormal 
Hepatic mass 
Perihepatic discomfort 
Blood fibrinogen decreased 
Hepatic necrosis 
Peripancreatic varices 
Blood thrombin abnormal 
Hepatic neoplasm 
Portal fibrosis 
Blood thrombin decreased 
Hepatic neuroendocrine tumour 
Portal hypertension 
Blood thromboplastin abnormal 
Hepatic pain 
Portal hypertensive colopathy 
Blood thromboplastin decreased 
Hepatic sequestration 
Portal hypertensive enteropathy 
Bromosulphthalein test abnormal 
Hepatic steato-fibrosis 
Portal hypertensive gastropathy 
Cardiohepatic syndrome 
Hepatic steatosis 
Portal vein cavernous transformation 
Child-Pugh-Turcotte score abnormal 
Hepatic vascular resistance increased 
Portal vein dilatation 
Child-Pugh-Turcotte score increased 
Hepatic venous pressure gradient abnormal 
Portopulmonary hypertension 
Cholaemia 
Hepatic venous pressure gradient increased 
Primary biliary cholangitis 
Cholangiosarcoma 
Hepatitis 
Protein C decreased 
Cholestasis 
Hepatitis acute 
Protein S abnormal 
Cholestatic liver injury 
Hepatitis cholestatic 
Protein S decreased 
Cholestatic pruritus 
Hepatitis chronic active 
Prothrombin level abnormal 
Chronic graft versus host disease in liver 
Hepatitis chronic persistent 
Prothrombin level decreased 
Chronic hepatic failure 
Hepatitis fulminant 
Prothrombin time abnormal 
Chronic hepatitis 
Hepatitis toxic 
Prothrombin time prolonged 
Coagulation factor decreased 
Hepatobiliary cancer 
Prothrombin time ratio abnormal 
Coagulation factor IX level abnormal 
Hepatobiliary cancer in situ 
Prothrombin time ratio increased 
Coagulation factor IX level decreased 
Hepatobiliary cyst 
Radiation hepatitis 
Coagulation factor V level abnormal 
Hepatobiliary disease 
Regenerative siderotic hepatic nodule 
Coagulation factor V level decreased 
Hepatobiliary neoplasm 
Renal and liver transplant 


 
 
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Coagulation factor VII level abnormal 
Hepatobiliary scan abnormal 
Retrograde portal vein flow 
Coagulation factor VII level decreased 
Hepatoblastoma 
Reye's syndrome 
Coagulation factor X level abnormal 
Hepatoblastoma recurrent 
Reynold's syndrome 
Coagulation factor X level decreased 
Hepatocellular carcinoma 
Splenic varices 
Coma hepatic 
Hepatocellular foamy cell syndrome 
Splenic varices haemorrhage 
Computerised tomogram liver abnormal 
Hepatocellular injury 
Spontaneous bacterial peritonitis 
Congestive hepatopathy 
Hepatomegaly 
Steatohepatitis 
Cryptogenic cirrhosis 
Hepatopulmonary syndrome 
Steatohepatitis 
Diabetic hepatopathy 
Hepatorenal failure 
Subacute hepatic failure 
Drug-induced liver injury 
Hepatorenal syndrome 
Sugiura procedure 
Duodenal varices 
Hepatosplenomegaly 
Thrombin time abnormal 
Flood syndrome 
Hepatotoxicity 
Thrombin time prolonged 
Focal nodular hyperplasia 
Hyperammonaemia 
Total bile acids increased 
Foetor hepaticus 
Hyperbilirubinaemia 
Transaminases abnormal 
Galactose elimination capacity test abnormal 
Hypercholia 
Transaminases increased 
Galactose elimination capacity test decreased 
Hyperfibrinolysis 
Ultrasound liver abnormal 
Gallbladder varices 
Hypertransaminasaemia 
Urine bilirubin increased 
Gamma-glutamyltransferase abnormal 
Hypocoagulable state 
Varices oesophageal 
Gamma-glutamyltransferase increased 
Hypofibrinogenaemia 
Varicose veins of abdominal wall 
Gastric variceal injection 
Hypothrombinaemia 
White nipple sign 
 
 
X-ray hepatobiliary abnormal 
 
 
 
AESI Category: Left ventricular ejection fraction decreased 
Acute left ventricular failure 
Cardiohepatic syndrome 
Hepatojugular reflux 
Acute pulmonary oedema 
Cardiopulmonary failure 
Left ventricular failure 
Acute right ventricular failure 
Cardiorenal syndrome 
Low cardiac output syndrome 
Cardiac asthma 
Chronic left ventricular failure 
Neonatal cardiac failure 
Cardiac failure 
Chronic right ventricular failure 
Obstructive shock 
Cardiac failure acute 
Congestive hepatopathy 
Pulmonary oedema 


 
 
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Cardiac failure chronic 
Cor pulmonale 
Pulmonary oedema neonatal 
Cardiac failure congestive 
Cor pulmonale acute 
Radiation associated cardiac failure 
Cardiac failure high output 
Cor pulmonale chronic 
Right ventricular ejection fraction decreased 
Cardiogenic shock 
Ejection fraction decreased 
Right ventricular failure 
 
 
Ventricular failure 
APPENDIX 6. CLINICAL LABORATORY PARAMETERS CTCAE CRITERIA   
PARAM (SI Unit) 
Hypo 
Hyper 
ATOXGR 
  
  
  
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin (g/L) 
  
Hemoglobin 
increased 
Increase in >0 - 2 
gm/dL above ULN or 
above baseline if 
baseline is above ULN 
Increase in >2 - 4 
gm/dL above ULN or 
above baseline if 
baseline is above 
ULN  
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
~ 
Anemia 
  
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L 
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; 
<100 - 80g/L 
Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L 
~ 
Platelets (10^9/L) 
Platelet count 
decreased 
  
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L 
<75,000 - 
50,000/mm3; <75.0 - 
50.0 x 10e9 /L 
<50,000 - 
25,000/mm3; <50.0 - 
25.0 x 10e9 /L 
<25,000/mm3; 
<25.0 x 10e9 /L 
Leukocytes (10^9/L) 
White blood cell 
decreased 
  
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 /L 
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L 
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 


 
 
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Neutrophils (10^9/L) 
Neutrophil count 
decreased 
  
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L 
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L 
<500/mm3; <0.5 
x 10e9 /L 
Lymphocytes (10^9/L) 
Lymphocyte 
count decreased 
  
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L 
<200/mm3; <0.2 
x 10e9 /L 
  
Lymphocyte count 
increased 
~ 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
~ 
Activated Partial 
Thromboplastin Time (s) 
  
Activated partial 
thromboplastin time 
prolonged 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN; bleeding 
~ 
International Normalized 
Ratio 
  
INR increased 
>1.2 - 1.5 
>1.5 - 2.5 
>2.5 
~ 
Albumin (g/L) 
Hypoalbuminemia   
<LLN - 3 g/dL; <LLN - 
30 g/L 
<3 - 2 g/dL; <30 - 20 
g/L 
<2 g/dL; <20 g/L 
~ 
Glucose (mmol/L) 
Hypoglycemia 
  
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L 
<55 - 40 mg/dL; <3.0 
- 2.2 mmol/L 
<40 - 30 mg/dL; <2.2 
- 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L 
Creatinine (umol/L) 
  
Creatinine increased 
>1 - 1.5 x 
baseline; >ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline; >3.0 - 
6.0 x ULN 
>6.0 x ULN 
Alkaline Phosphatase 
(IU/L) 
  
Alkaline phosphatase 
increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 


 
 
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Aspartate Aminotransferase 
(IU/L) 
  
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alanine Aminotransferase 
(IU/L) 
  
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Serum Calcium (mmol/L) 
  
Hypercalcemia 
>ULN - 2.9 mmol/L 
>2.9 - 3.1 mmol/L 
>3.1 - 3.4 mmol/L 
>3.4 mmol/L 
Hypocalcemia 
  
<LLN - 2.0 mmol/L 
<2.0 - 1.75 mmol/L 
<1.75 - 1.5 mmol/L 
<1.5 mmol/L 
Magnesium (mmol/L) 
  
Hypermagnesemia 
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L 
~ 
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 mmol/L 
>8.0 mg/dL; 
>3.30 mmol/L 
Hypomagnesemia 
  
<LLN - 1.2 mg/dL; 
<LLN - 0.5 mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L 
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 mmol/L 
<0.7 mg/dL; <0.3 
mmol/L 
Potassium (mmol/L) 
  
Hyperkalemia 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Hypokalemia 
  
<LLN - 3.0 mmol/L  
~ 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
Sodium (mmol/L) 
  
Hypernatremia 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L 
>160 mmol/L 
Hyponatremia 
  
<LLN - 130 mmol/L 
- 
<130 - 120 mmol/L 
<120 mmol/L 
Total cholesterol (mmol/L) 
  
Cholesterol high 
>ULN - 300 mg/dL; 
>ULN - 7.75 mmol/L 
>300 - 400 mg/dL; 
>7.75 - 10.34 mmol/L 
>400 - 500 mg/dL; 
>10.34 - 12.92 
mmol/L 
>500 mg/dL; 
>12.92 mmol/L 


 
 
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Bilirubin (umol/L) 
  
Blood bilirubin 
increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Triglycerides (mmol/L) 
  
Hypertriglyceridemia 
150 mg/dL - 300 
mg/dL; 1.71 mmol/L - 
3.42 mmol/L 
>300 mg/dL - 500 
mg/dL; >3.42 mmol/L 
- 5.7 mmol/L 
>500 mg/dL - 1000 
mg/dL; >5.7 mmol/L 
- 11.4 mmol/L 
>1000 mg/dL; 
>11.4 mmol/L 
Urinary protein 
  
Proteinuria 
1+ proteinuria; urinary 
protein <1.0 g/24 hrs 
2+ proteinura; urinary 
protein 1.0 - 
3.4g/24hrs 
urinary protein >= 
3.5g/24hrs 
~